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+{
+  "question": [
+    "What are the potential benefits and risk associated with gene editing technologies like CRISPRR-Cas9?",
+    "How does epigenetics inluence gene expression without changing the underlying DNA sequence?",
+    "Describe the role of mitochondrial DNA in heredity and how it differs from nuclear DNA.",
+    "What are the ethical considerations surrounding prenatal genetic testing and the selective termination of pregnancies based on genetic factors?",
+    "Create a how-to guide for genetic sequencing.",
+    "Which genes give a predisposition to developing T1D?",
+    "What is ensembl",
+    "Which database can I use for genetic, genomics, phenotype, and disease-related data generated from rat research?",
+    "What is RGD?",
+    "What resources can I use to do pathway analyses?",
+    "Once a sperm combines with an egg, what determines how traits are passed onto the resulting lifeform?",
+    "Why is genetic tracing matrilineal rather than patrilineal?",
+    "Explain the process of DNA replication and how it ensures accurate copying of genetic information during cell division.",
+    "What are the potential benefits and risks associated with gene editing technologies like CRISPR-Cas9?",
+    "How does one tell the difference between X and Y DNA, with repsect to DNA tracing and determining QTLs?",
+    "For text and biological resources, do you mean add some books (on biology stuff) or/and web resources (as ensembl) on your system?",
+    "what is ensembl?",
+    "What is the difference between QTL mapping and GWAS?",
+    "How do I determine which gene in my QTL is causal for the trait?",
+    "Why do males have two Y chromosomes and females only one?",
+    "How does one tell the difference between X and Y DNA, with respect to DNA tracing and determining QTLs",
+    "Once a sperm combines with an egg, what determines how traits are  passed onto the resulting lifeform?",
+    "How can I add a new species to the GeneNetwork database?",
+    "which genes are typically associated with diabetes in QTL analyses?",
+    "In which diseases is the gene TCF7L2 involved?",
+    "Once a sperm combines with an egg, what determines how traits are   passed onto the resulting lifeform?",
+    "Can you explain what a ribosomal binding site at a high level and make it accessable to a non-expert?",
+    "Once a sperm combines with an egg, what determines how traits are   passed onto the resulting lifeform?",
+    "Can you explain the difference between sequencing with short reads vs long reads? Please make you answer accessible to a non-expert.",
+    "Can you explain why using a pangenome-based reference might be more   useful than simply using a single linear reference? Please make you   answer accessible to a non-expert.",
+    "Is all genetic regulation done through DNA (e.g., prompters,   repressors, activators) or are there other forms of genetic regulation?   Please make you answer accessible to a non-expert.",
+    "What are the different relationship between traits?",
+    "Can landscape of QTL and GWAS hits be used to find relationships between traits?"
+  ],
+  "answer": [
+    "### Potential Benefits of CRISPR-Cas9:  1. **Accelerated Genomic Research**: CRISPR-Cas9 tools have significantly accelerated the pace of genomic research by allowing highly efficient knockouts or edits of virtually any gene in cells or model organisms [1]. 2. **Clinical Trials and Stability**: Multiple CRISPR-Cas9-based clinical trials are in progress, and early trial results suggest that CRISPR-engineered cells are stable and do not cause acute adverse reactions in humans [1]. 3. **Functional Genomics**: CRISPR is set to make a significant impact on genomic screening and scientific discovery, with recent demonstrations showing great promise [2]. 4. **Targeted Gene Regulation and Epigenome Modifications**: CRISPR-Cas9 has been linked to various effector proteins to enable targeted gene regulation and epigenome modifications [3]. 5. **Precision Medicine**: CRISPR-Cas9 holds significant promise for the development of new disease models and precision-targeted therapies, particularly in molecular medicine [4]. 6. **Versatility in Applications**: CRISPR-Cas9 can induce genome edits by creating targeted DNA breaks that trigger site-specific DNA repair. It can also control the transcriptional output of genes or alter genome sequences using nucleotide base editing, which does not require DNA break repair [8].  ### Potential Risks of CRISPR-Cas9:  1. **Off-Target Effects**: CRISPR-Cas9 is known to generate off-target alterations, which can result in unwanted mutations and potentially cytotoxic effects [6]. 2. **Technical Challenges**: There are several technical challenges that need to be addressed to maximize the benefits of CRISPR technology [2]. 3. **Long-Term Safety**: While early trial results are promising, the long-term safety of CRISPR-engineered cells is yet to be determined [1]. 4. **Mismatch Tolerance**: The CRISPR-Cas9 system can tolerate certain mismatches to the DNA target, which could be a disadvantage as it may lead to unintended edits [7].  In summary, while CRISPR-Cas9 offers numerous benefits such as accelerating genomic research, enabling precision medicine, and providing versatile applications, it also poses risks like off-target effects, technical challenges, and concerns about long-term safety.",
+    "Epigenetics influences gene expression without changing the underlying DNA sequence through several mechanisms. These include:  1. **DNA Methylation**: This involves the addition of methyl groups to DNA, primarily at CpG sites, which can affect gene transcription by converting cytosine to 5-methylcytosine, thereby repressing gene activity [1], [4]. 2. **Histone Modifications**: Chemical modifications to histone proteins, such as methylation, acetylation, phosphorylation, and ubiquitination, can alter the chromatin structure, making genes more or less accessible for transcription [1], [6]. 3. **Non-coding RNAs (ncRNAs)**: These RNAs, including microRNAs (miRNAs), can regulate gene expression at the post-transcriptional level by binding to messenger RNAs (mRNAs) and preventing their translation into proteins [1], [6].  These epigenetic modifications are influenced by both genetic variants and environmental factors such as pollution, tobacco smoking, obesity, lack of physical activity, and alcohol consumption [2], [6]. These changes are heritable and can be passed from one generation to the next without altering the DNA sequence itself [4], [5].",
+    "Mitochondrial DNA (mtDNA) plays a unique role in heredity and differs significantly from nuclear DNA (nDNA) in several ways:  1. **Inheritance Pattern**: Mitochondrial DNA is inherited exclusively from the mother, a phenomenon known as maternal or extranuclear inheritance [4], [6], [7]. This contrasts with nuclear DNA, which is inherited from both parents.  2. **Replication and Segregation**: mtDNA replicates autonomously and independently of the cell cycle, unlike nuclear DNA which replicates during cell division [1], [5]. Mitochondria are semiautonomous organelles with their own replication, transcription, and translation systems [2].  3. **Genetic Variation and Mutation Rate**: Mitochondrial DNA has a higher mutation rate compared to nuclear DNA, approximately tenfold higher [2]. This can lead to a condition called heteroplasmy, where both mutated and normal mitochondria coexist within the same cell [1], [2].  4. **Structure and Size**: The mitochondrial genome is a short circular molecule, significantly smaller than the nuclear genome. The human mitochondrial genome is only 16,569 base pairs long and encodes 37 genes, whereas the nuclear genome consists of approximately 1500 genes related to mitochondrial function [8], [9].  5. **Functional Role**: mtDNA carries essential genetic information for cellular metabolism and energy generation, which is crucial for the functioning of the cell [10]. This is distinct from the broader range of functions encoded by nuclear DNA.  In summary, mitochondrial DNA is maternally inherited, replicates independently, has a higher mutation rate, and is structurally distinct from nuclear DNA. These differences underscore the unique role of mtDNA in heredity and cellular function.",
+    "The ethical considerations surrounding prenatal genetic testing and the selective termination of pregnancies based on genetic factors are multifaceted and complex. Key considerations include:  1. **Parental Beliefs and Attitudes**: Decisions about prenatal testing and subsequent actions, such as termination, are heavily influenced by parental beliefs about abortion, attitudes regarding disability, and their perceptions of the usefulness of the information revealed by genetic tests [2]. These personal beliefs and attitudes play a crucial role in shaping the ethical landscape of prenatal genetic testing.  2. **Informed Consent**: Ensuring that parents are fully informed about the implications of genetic testing is critical. This includes understanding the potential outcomes, the accuracy of the tests, and the possible decisions they may face based on the results [4]. Informed consent is a cornerstone of ethical medical practice, particularly in the context of genetic testing.  3. **Respect for Parental Decision-Making**: Ethical considerations must balance clinical benefits and risks with respect for parental decision-making. Parents should generally have the final authority in making decisions about their children's health care, including whether to undergo genetic testing and how to respond to the results [5].  4. **Social and Psychological Implications**: The ability to predict future diseases through genetic testing, coupled with limited options for prevention or treatment, has significant social and psychological implications. These must be addressed to ensure that parents are not unduly burdened by the information provided by genetic tests [7].  5. **Access and Equity**: Ethical issues also arise from the accessibility of genetic testing and the opportunities it creates. There are concerns about equitable access to these technologies and the potential for disparities in who can benefit from them [1].  6. **Family Communication Challenges**: Genetic testing results can create communication challenges within families, as they navigate the complex information and make decisions that affect their future [1].  In summary, the ethical considerations surrounding prenatal genetic testing and selective termination involve respecting parental beliefs and decision-making, ensuring informed consent, addressing social and psychological impacts, and promoting equitable access to genetic testing technologies. These considerations must be carefully balanced to navigate the ethical complexities of prenatal genetic testing.",
+    "### How-to Guide for Genetic Sequencing  Genetic sequencing is a powerful tool used to determine the order of nucleotides in DNA. This guide will walk you through the basic steps involved in genetic sequencing, referencing key resources for further information.  #### Step 1: Sample Preparation 1. **Collect DNA Sample**: Obtain a sample from the organism or tissue of interest. This could be blood, saliva, or tissue biopsy. 2. **Extract DNA**: Use a DNA extraction kit to isolate DNA from the sample. This involves cell lysis, removal of proteins and other contaminants, and purification of DNA.  #### Step 2: Library Preparation 1. **Fragment DNA**: Break the DNA into smaller fragments. This can be done using mechanical shearing or enzymatic digestion. 2. **Add Adapters**: Ligate specific adapter sequences to the ends of the DNA fragments. These adapters are necessary for the fragments to bind to the sequencing platform.  #### Step 3: Amplification 1. **PCR Amplification**: Amplify the DNA fragments using Polymerase Chain Reaction (PCR). This step increases the quantity of DNA to ensure there is enough material for sequencing.  #### Step 4: Sequencing 1. **Choose a Sequencing Platform**: Select an appropriate sequencing technology based on your needs. Common platforms include Illumina, Ion Torrent, and Pacific Biosciences [6], [9]. 2. **Load DNA onto the Sequencer**: Follow the manufacturer's instructions to load your prepared DNA library onto the sequencing machine. 3. **Run the Sequencer**: Initiate the sequencing run. The machine will read the nucleotide sequences of the DNA fragments and generate raw sequence data.  #### Step 5: Data Analysis 1. **Base Calling**: Use software like Phred to convert raw data into nucleotide sequences [10]. 2. **Sequence Assembly**: Assemble the short DNA sequences into longer contiguous sequences (contigs) using tools like Phrap or CAP3 [10]. 3. **Variant Calling**: Identify genetic variants by comparing the assembled sequences to a reference genome. This can be done using various bioinformatics tools.  #### Step 6: Interpretation 1. **Annotation**: Annotate the sequences to identify genes, regulatory elements, and other functional regions. 2. **Data Management**: Store and manage the high-throughput sequence data efficiently. This is crucial for handling large datasets generated by next-generation sequencing technologies [3], [4].  #### Additional Resources - **Next-Generation Sequencing (NGS)**: For a detailed understanding of NGS technologies and their applications, refer to Shendure and Ji's review on next-generation DNA sequencing [1], [5]. - **Sequencing Platforms**: For comparisons of different sequencing platforms, see the work by Quail et al. [6]. - **Bioinformatics Tools**: Explore various bioinformatics tools and software for sequence analysis and data management [10].  By following these steps and utilizing the referenced resources, you can successfully perform genetic sequencing and analyze the resulting data.",
+    "The genes that give a predisposition to developing Type 1 Diabetes (T1D) include:  1. **Major Histocompatibility Complex (MHC)** genes located in the HLA region of chromosome 6 [1], [2], [6]. 2. **Insulin gene (INS)** located in the IDDM2 locus on chromosome 11 [3]. 3. **CTLA-4 (Cytotoxic T-Lymphocyte Associated 4)** [2]. 4. **PTPN22 (Protein Tyrosine Phosphatase, Non-Receptor Type 22)** [2]. 5. **IL2RA/CD25 (Interleukin 2 Receptor Alpha)** [2]. 6. **IFIH1/MDA5 (Interferon-Induced Helicase 1)** [2].  These genes are strongly associated with T1D and contribute to the genetic susceptibility to the disease.",
+    "Ensembl is a comprehensive genomic database that identifies the positions of known human genes from public sequence database entries, often using tools like GENEWISE to predict their exon structures. It aims to provide a more accurate reflection of reality compared to ab initio predictions alone [1]. Additionally, Ensembl includes various genomic features such as different repeat classes, cytological bands, CpG island predictions, tRNA gene predictions, and expressed sequence clusters from the UniGene database [7]. It also reflects the progress of projects like the International Haplotype Map Project and allows users to view speculative data and develop personalized annotations [4].",
+    "You can use the Rat Genome Database (RGD) for genetic, genomics, phenotype, and disease-related data generated from rat research. The RGD is specifically mentioned as a platform for genetic and genomic research, including disease portals and phenotypic data [2], [5]. Additionally, it serves as a repository for various types of data such as QTLs, strains used as disease models, expression data, and more [5]. The database can be accessed at http://www.rgd.mcw.edu [1], [5].",
+    "RGD refers to a resource that provides information regarding physiological traits studied, strain combinations used, associated linkage statistics, and the genomic coordinates of the pQTL (protein Quantitative Trait Loci) region. For pQTL regions identified from RGD, the original data were examined, and the 99% confidence interval within the 2 logarithm of the odds (LOD) drop from the peak of linkage was estimated [1].",
+    "For pathway analyses, you can use the following resources:  1. **KEGG (Kyoto Encyclopedia of Genes and Genomes)**: This database allows you to cross-reference a list of genes with biological functions and genetic networks, including metabolic, signaling, or other regulation pathways [1], [4], [9], [10].  2. **Reactome**: A cross-referenced, manually curated, and peer-reviewed pathway database that provides enhanced pathway visualization [2], [3], [5], [7], [9], [10].  3. **WikiPathways**: A multifaceted pathway database that bridges metabolomics to other omics research [2], [3], [9], [10].  4. **HumanCyc**: Primarily a database of metabolic pathways [4].  5. **Pathway Commons**: A web resource for biological pathway data [6].  6. **BioCarta**: Provides pathway maps [8].  7. **BioGRID**: A genetic and protein interaction database [8].  8. **DAVID (Database for Annotation, Visualization, and Integrated Discovery)**: Offers gene ontology and pathway analysis [8].  9. **WebGestalt**: Provides gene ontology and pathway analysis [8].  These resources can help you determine whether a pathway is over-represented in your gene list and whether it is over-activated or under-activated [1].",
+    "Once a sperm combines with an egg, the traits passed onto the resulting lifeform are determined by several genetic and epigenetic factors:  1. **Chromosomal Segments**: Individuals inherit a patchwork of chromosomal segments from maternal and paternal chromosomes, which are combined during fertilization to form the zygote [2].     2. **Mendelian Laws**: The Mendel laws of segregation and independent assortment play a crucial role. Each parent passes a randomly selected allele for a given trait to the offspring, ensuring genetic diversity [5].  3. **Gene Activation and Regulation**: The process of gene activation and regulation is complex and involves several mechanisms:    - **Imprinting**: Genes can be marked with small chemical tags that determine whether they are activated or remain inactive after fertilization, depending on whether the modification was made by the father (in the sperm) or the mother (in the egg) [3], [4].    - **Maternal Effect**: The mother can alter gene activity in her offspring via the placenta [4].    - **Cis-regulation**: Instructions encoded within the embryo's DNA can directly control if and when a nearby gene becomes activated [4].  4. **Epigenetic Marks**: Epigenetic marks, which are less constrained and can be maintained, affect gene expression and phenotype later in development [6].  These factors collectively determine how traits are passed onto the resulting lifeform after the sperm combines with the egg.",
+    "Genetic tracing is often matrilineal rather than patrilineal primarily because mitochondrial DNA (mtDNA) is inherited solely from the maternal lineage. Unlike nuclear DNA, which is a combination of both paternal and maternal contributions, mtDNA is passed down from mothers to all their children without any admixture from the father [4], [5]. This uniparental inheritance of mtDNA simplifies the tracing of maternal lineage as it remains relatively unchanged through generations, making it a reliable marker for genetic studies [4], [5]. Additionally, humans have developed complex mechanisms to ensure this uniparental inheritance of mtDNA, which further supports its use in genetic tracing [4].",
+    "DNA replication is a critical process that ensures the accurate copying of genetic information during cell division. Here is an explanation of the process and how it maintains accuracy:  1. **Separation of DNA Strands**: During replication, the two strands of the mother cell DNA are separated [1], [2]. This separation is essential to expose the nucleotide sequences of each strand, which will serve as templates for the synthesis of new complementary strands.  2. **Formation of New Strands**: New nucleotides are assembled to form two double helices that are identical to the original DNA molecule [1], [2]. Each original strand pairs with a newly synthesized complementary strand, resulting in two DNA molecules, each consisting of one old and one new strand. This method is known as semi-conservative replication.  3. **Initiation at Replication Origins**: Replication begins at specific locations on the DNA molecule called replication origins. During the S phase of the cell cycle, replication starts from these origins [3].  4. **Replication Fork and Enzyme Activity**: The replication process involves the formation of a replication fork, where enzymes like DNA helicase unwind the DNA double helix. DNA polymerase then adds new nucleotides to the growing DNA strand by matching them with the complementary nucleotides on the template strand.  5. **Error Minimization and Repair Mechanisms**: Cells have mechanisms to monitor replication and minimize errors. For instance, cell-cycle checkpoints ensure coordination of DNA synthesis and repair with cell division [6]. Additionally, specific repair proteins can revert certain DNA injuries, ensuring the fidelity of the replication process [4].  6. **Postreplicative Repair**: If replication encounters obstacles such as DNA adducts, cells can induce DNA damage tolerance mechanisms. These mechanisms allow the completion of replication through error-free template switching using the sister chromatid or through translesion polymerases [9].  By following these steps and employing various error-checking and repair mechanisms, DNA replication ensures that genetic information is accurately copied and transmitted to daughter cells during cell division.",
+    "### Potential Benefits of CRISPR-Cas9:  1. **Accelerated Genomic Research**: CRISPR-Cas9 tools have significantly accelerated the pace of genomic research by enabling highly efficient knockouts or edits of virtually any gene in cells or model organisms [1].     2. **Clinical Trials and Stability**: Multiple CRISPR-Cas9-based clinical trials are in progress, and early trial results suggest that CRISPR-engineered cells are stable and do not cause acute adverse reactions in humans [1].  3. **Functional Genomics**: CRISPR-Cas9 is set to make a significant impact on genomic screening and scientific discovery, with recent demonstrations showing great promise [2].  4. **Targeted Gene Regulation and Epigenome Modifications**: CRISPR-Cas9 has been linked to various effector proteins to enable targeted gene regulation and epigenome modifications [3].  5. **Precision Medicine**: CRISPR-Cas9 holds significant promise for the development of new models and precision-targeted therapies for diseases such as Alzheimer's Disease (AD) [5].  6. **Versatility and Efficiency**: CRISPR-Cas9 provides a highly versatile platform that allows fast and efficient genome editing in an ever-growing list of organisms [10].  ### Potential Risks of CRISPR-Cas9:  1. **Off-Target Effects**: CRISPR-Cas9 is known to generate off-target alterations, which can result in unwanted mutations and potentially cytotoxic effects [4].  2. **Technical Challenges**: There are several technical challenges that need to be addressed to maximize the benefits of CRISPR-Cas9 technology [2].  3. **Long-Term Safety**: While early trial results are promising, the long-term safety of CRISPR-Cas9-engineered cells is yet to be determined [1].  4. **Mismatch Tolerance**: The CRISPR-Cas9 system can tolerate certain mismatches to the DNA target, which could potentially lead to unintended edits [8].  By considering these benefits and risks, researchers and clinicians can better navigate the development and application of CRISPR-Cas9 technologies.",
+    "To differentiate between X and Y DNA in the context of DNA tracing and determining quantitative trait loci (QTLs), one must consider the unique characteristics of each chromosome:  1. **Recombination Rates**: The Y chromosome largely does not undergo recombination, whereas the X chromosome has a slower recombination rate compared to autosomes. This difference in recombination rates has significant implications for the detection of QTLs [1].  2. **QTL Mapping**: QTLs are stretches of DNA closely linked to genes that influence specific phenotypes. The process of QTL mapping involves measuring phenotypes within a population and genotyping at numerous marker loci [2], [4]. Given the unique recombination characteristics of the X and Y chromosomes, the strategies for mapping QTLs on these chromosomes may differ.  3. **Genetic Markers and Phenotypic Traits**: When measuring correlations between genetic markers and phenotypic traits, the lack of recombination on the Y chromosome and the slower recombination on the X chromosome must be taken into account. This affects how QTLs linked to these chromosomes are identified and analyzed [10].  In summary, the primary differences between X and Y DNA in the context of DNA tracing and QTL determination lie in their recombination rates and the subsequent impact on QTL detection and mapping strategies.",
+    "For text and biological resources, it seems you are referring to adding web resources such as Ensembl to your system. This is evident from the context which mentions various web-based biological data management systems and genome browsers like BioMart, GBrowse, and Ensembl [1], [4]. These resources provide portals to current and archived public assemblies, as well as tools for searching and annotating genome assemblies [4], [6]. Therefore, it appears you are more focused on integrating web resources rather than books.",
+    "Ensembl is a genomic database that identifies the positions of known human genes from public sequence database entries, usually using tools like GENEWISE to predict their exon structures. It aims to provide a more accurate reflection of reality compared to ab initio predictions alone [1]. Ensembl also includes many genomic features other than predicted genes, such as different repeat classes, cytological bands, CpG island predictions, tRNA gene predictions, and expressed sequence clusters from the UniGene database [4].",
+    "The primary difference between QTL mapping and GWAS lies in their approaches and resolutions for identifying genetic associations with traits.  1. **QTL Mapping**:    - **Approach**: QTL mapping involves identifying segments of the genome (quantitative trait loci) that are associated with a particular phenotype. It typically uses linkage analysis to find statistically significant linkages between phenotypes and genotypes [7], [8].    - **Resolution**: Historically, QTL mapping has had low resolution, meaning it identifies larger genomic regions associated with traits rather than pinpointing specific genetic variants [6].  2. **GWAS (Genome-Wide Association Studies)**:    - **Approach**: GWAS is a holistic, whole-genome approach that analyzes the association between DNA polymorphisms and phenotypic traits across the entire genome. It establishes correlations between changes in DNA at specific loci and changes in disease traits within populations [2], [4].    - **Resolution**: GWAS allows for much finer mapping of QTLs compared to traditional linkage analysis, providing higher resolution in identifying specific genetic variants associated with traits [3].  In summary, while QTL mapping identifies broader genomic regions linked to traits with lower resolution, GWAS provides a finer, more detailed mapping of genetic associations across the entire genome [2], [3], [4], [6], [7], [8].",
+    "To determine which gene in your QTL is causal for the trait, you can follow these steps:  1. **Identify Candidate Genes**: Start by identifying candidate genes within the QTL interval. This can be done by looking at genes that are expressed in tissues likely to influence the traits of interest [6].  2. **Sequence Candidate Genes**: Sequence the cDNA of strong candidate genes to identify amino acid polymorphisms. This helps in detecting sequence differences in coding or regulatory regions between the two parental inbred strains [1], [6].  3. **Expression Studies**: Test for mRNA and protein expression differences in target tissues of the original strains used to detect the QTL. This will help refine the list of candidate genes [1].  4. **Fine Mapping**: Perform fine mapping of the QTL interval to shorten the list of plausible candidate polymorphisms [6].  5. **Correlation with Trait**: Use gene expression data to screen for genes within the QTL interval whose expression correlates with the trait of interest [7].  6. **Proof of Causality**: After refining the list of candidate genes, test them rigorously for proof of cause and effect. This involves proving definitively which nucleotide polymorphism underlies the QTL [1], [6].  By following these steps, you can systematically narrow down and identify the causal gene within your QTL.",
+    "The query appears to be based on a misunderstanding. Males do not have two Y chromosomes; they have one X and one Y chromosome, while females have two X chromosomes. This is clearly explained in the provided context:  - Males have an XY genotype, meaning they have one X chromosome and one Y chromosome [3]. - Females have an XX genotype, meaning they have two X chromosomes [3].  Additionally, it is noted that for each chromosome pair, one chromosome is inherited from the mother and one from the father [2]. Therefore, males inherit their Y chromosome from their father and their X chromosome from their mother, while females inherit one X chromosome from each parent.",
+    "To differentiate between X and Y DNA with respect to DNA tracing and determining quantitative trait loci (QTLs), consider the following points:  1. **Recombination Rates**:    - The Y chromosome largely does not undergo recombination, which means it is passed down relatively unchanged from father to son. This makes it useful for tracing paternal lineage [1].    - The X chromosome, on the other hand, does undergo recombination, but at a slower rate compared to autosomes. This slower recombination rate has significant implications for the detection of QTLs on the X chromosome [1].  2. **QTL Mapping**:    - QTLs are stretches of DNA closely linked to genes that underlie specific phenotypes. The process of QTL mapping involves identifying these regions to understand the genetic basis of heritable traits [2].    - The detection of QTLs on the X chromosome may be influenced by its slower recombination rate, which can affect the resolution and accuracy of QTL mapping compared to autosomes [1].  In summary, the primary differences between X and Y DNA in the context of DNA tracing and QTL determination lie in their recombination behaviors and how these behaviors impact the detection and mapping of QTLs. The Y chromosome's lack of recombination makes it a stable marker for paternal lineage tracing, while the X chromosome's slower recombination rate affects the detection of significant QTLs [1], [2].",
+    "Once a sperm combines with an egg, the traits passed onto the resulting lifeform are determined by several factors:  1. **Chromosomal Segments from Parents**: Individuals inherit a patchwork of chromosomal segments from both maternal and paternal chromosomes [1]. 2. **Mendelian Laws**: The Mendel laws of segregation and independent assortment play a crucial role. The law of segregation states that each parent passes a randomly selected allele for a given trait to their offspring [5]. 3. **Gene Activation and Regulation**: The process involves controlling which genes are active, when they activate, and for how long. This control can be achieved through mechanisms such as imprinting, maternal effect, cis-regulation, and other instructions encoded within the embryo's DNA [3], [4]. 4. **Epigenetic Marks**: Epigenetic marks, which are chemical modifications to DNA or histones, can affect gene expression and phenotype later in development [7].  These combined genetic and epigenetic factors determine how traits are passed onto and expressed in the resulting lifeform.",
+    "The provided context does not include specific instructions on how to add a new species to the GeneNetwork database. However, it does mention that data from multiple species have been integrated into GeneNetwork [1], [6]. This suggests that the process is possible, but the exact steps are not detailed in the given excerpts.  To add a new species to the GeneNetwork database, you may need to refer to the official GeneNetwork website (www.genenetwork.org) [5], [7], or contact their support team for detailed guidance. Additionally, reviewing the materials and methods information page linked to datasets in GeneNetwork [2] might provide further insights into the process.",
+    "In QTL (Quantitative Trait Loci) analyses, several genes have been identified as being associated with diabetes. Specifically:  1. **RASA1, Nnt, and PSK1** on chromosome 13 have been identified as candidate genes underlying diabetes-related traits [4]. 2. **PAX4** near the locus 7q32 has been identified in a genome-wide association study in a Chinese population as a susceptibility locus for type 2 diabetes [6]. 3. **Genes on chromosomes 8q24 and 7q11** have been associated with insulin sensitivity and insulin secretion, which are critical factors in the development of type 2 diabetes [2]. 4. **Genes on 5q11-q13 and 7q32** have been identified as significant susceptibility factors for type 1 diabetes [9].  These genes and loci are typically associated with diabetes in QTL analyses, highlighting the complex genetic architecture of the disease.",
+    "The gene TCF7L2 is primarily involved in Type 2 diabetes. This association is well-documented across multiple sources:  1. Single nucleotide polymorphisms in TCF7L2 are reproducibly associated with Type 2 diabetes and reduce the insulin response to glucose in nondiabetic individuals [2]. 2. The TCF7L2 locus represents the strongest known genetic determinant of Type 2 diabetes, with risk allele carriers showing impaired insulin production and beta-cell dysfunction [3]. 3. Variants of the TCF7L2 gene confer risk of Type 2 diabetes [4], [5]. 4. TCF7L2 is considered the strongest genetic determinant for the risk of developing Type 2 diabetes [7]. 5. Overexpression of TCF7L2 protein decreases the sensitivity of beta islet cells to secrete insulin, which is involved in the regulation of insulin secretion [9].  Thus, the gene TCF7L2 is significantly involved in Type 2 diabetes.",
+    "Once a sperm combines with an egg, the traits passed onto the resulting lifeform are determined by several factors:  1. **Chromosomal Segments from Parents**: Individuals inherit a patchwork of chromosomal segments from both maternal and paternal chromosomes [1].     2. **Mendelian Laws**: The Mendel laws of segregation and independent assortment play a crucial role. The law of segregation states that each parent passes a randomly selected allele for a given trait to their offspring [4].  3. **Gene Activation and Regulation**: The process involves controlling which genes are active, when they activate, and for how long. This control can be achieved through mechanisms such as imprinting, maternal effect, cis-regulation, and other instructions encoded within the embryo's DNA [3], [5].  4. **Epigenetic Marks**: Soon after fertilization, epigenetic marks can affect gene expression and phenotype later in development [8].  5. **Heritable Material**: The information passed from parents to offspring is coded in DNA molecules [7].  These factors collectively determine how traits are inherited and expressed in the resulting lifeform.",
+    "A ribosomal binding site (RBS) is a specific sequence of nucleotides in messenger RNA (mRNA) that is crucial for the initiation of protein synthesis. At a high level, you can think of it as a \"landing pad\" for the ribosome, which is the molecular machine that reads the mRNA and translates it into a protein.  Here's a simple analogy: Imagine the ribosome as a train and the mRNA as a track. The ribosomal binding site is like a train station where the train (ribosome) stops to pick up passengers (the instructions for making a protein). Without this station, the train wouldn't know where to start its journey.  In more technical terms, the RBS helps the ribosome to correctly position itself on the mRNA so that it can start translating the genetic code into a protein at the right spot. This process is essential for the proper expression of genes and the production of proteins that perform various functions in the cell [1], [2], [3].",
+    "Once a sperm combines with an egg, the traits passed onto the resulting lifeform are determined by several factors:  1. **Chromosomal Segments**: Individuals inherit a patchwork of chromosomal segments from maternal and paternal chromosomes due to phenomena such as mutations and gene conversion events during meiosis [1].  2. **Mendelian Laws**: The Mendel laws of segregation and independent assortment play a crucial role. The law of segregation states that each parent passes a randomly selected allele for a given trait to their offspring [4].  3. **Gene Activation and Regulation**: The process of trait determination also involves controlling which genes are active, when they activate, and for how long. This control can be achieved through mechanisms such as imprinting, maternal effect, and cis-regulation [3], [5].  4. **Epigenetic Marks**: Epigenetic marks, which are chemical modifications to DNA that do not change the DNA sequence but affect gene expression, also play a role. These marks can be inherited and influence gene expression and phenotype later in development [8].  5. **Heritable Material**: The information passed from parents to offspring is coded in DNA molecules, and any mutations in these genes can be inherited by the offspring [7].  In summary, the combination of chromosomal inheritance, Mendelian genetic laws, gene activation and regulation mechanisms, epigenetic marks, and the heritable DNA material all contribute to how traits are passed onto the resulting lifeform after fertilization.",
+    "Sure! Let's break down the difference between short-read and long-read sequencing in a way that's easy to understand.  ### Short-Read Sequencing: 1. **Read Length**: Short-read sequencing generates small fragments of DNA, typically around 50-300 base pairs long [4]. 2. **Technology**: This method is commonly used by platforms like Illumina [3]. 3. **Advantages**:     - **High Throughput**: It can produce a large amount of data quickly and is relatively cost-effective [4].    - **Accuracy**: Generally, short-read sequencing has a lower error rate per base compared to long-read sequencing [4]. 4. **Limitations**:    - **Complex Regions**: It struggles to accurately sequence complex regions of the genome, such as those with long repetitive elements or structural variations [6].    - **Assembly**: Because the reads are short, assembling them into a complete genome can be challenging and may leave gaps or errors [6].  ### Long-Read Sequencing: 1. **Read Length**: Long-read sequencing produces much longer fragments, often several kilobases (thousands of base pairs) in length [6]. 2. **Technology**: There are two main types:    - **Single-Molecule Real-Time Sequencing**: This method reads long DNA fragments directly without needing to amplify them [8].    - **Synthetic Long-Reads**: This method uses short-read technology to create long reads in a computational process [2]. 3. **Advantages**:    - **Complex Regions**: It can span complex or repetitive regions in a single read, making it easier to resolve these areas accurately [7].    - **Transcriptomics**: Long reads can cover entire mRNA transcripts, helping researchers understand gene structures and variations better [7]. 4. **Limitations**:    - **Cost and Throughput**: Long-read sequencing is generally more expensive and produces less data per run compared to short-read sequencing [4].    - **Error Rate**: The error rate per base can be higher than that of short-read sequencing, although this is improving with new technologies [4].  In summary, short-read sequencing is like reading a book by looking at many small snippets of text, which is fast and accurate but can be tricky if the text is very repetitive or complex. Long-read sequencing, on the other hand, is like reading longer passages at a time, which helps to understand the context better but might be slower and more expensive.",
+    "Using a pangenome-based reference can be more useful than using a single linear reference for several reasons:  1. **Capturing Genetic Diversity**: A single linear reference genome represents just one version of a species' DNA, which might not include all the genetic variations found in different individuals. A pangenome, on the other hand, includes multiple versions of genes and sequences from various individuals, capturing a broader spectrum of genetic diversity [3].  2. **Reducing Reference Bias**: When using a single linear reference, there's a risk of reference bias, which means that genetic variations not present in the reference genome might be missed or misinterpreted. A pangenome reduces this bias by including multiple genetic variants, making it more likely to accurately represent the genetic makeup of different individuals [1].  3. **Improving Disease Research**: By including a wider range of genetic variations, a pangenome can help researchers better understand the genetic basis of diseases. This comprehensive approach allows for more accurate identification of disease-associated genetic variants, which can lead to better diagnostics and treatments [6].  4. **Enhanced Analysis Tools**: The use of a pangenome can improve the performance of genetic analysis tools. For example, it can provide a more accurate benchmark for evaluating new sequencing technologies and analysis methods, leading to more reliable results [3].  5. **Overcoming Limitations of Single References**: A single reference genome assumes that the order and structure of genes are the same across all individuals, which is not always true. This assumption can lead to errors in genetic studies. A pangenome, by including multiple sequences, can account for these structural variations and provide a more accurate representation of the genome [2].  In summary, a pangenome-based reference is more useful because it captures the genetic diversity of a species, reduces reference bias, improves disease research, enhances analysis tools, and overcomes the limitations of using a single linear reference. This makes it a more comprehensive and accurate tool for genetic studies.",
+    "Not all genetic regulation is done solely through DNA elements like promoters, repressors, and activators. There are other forms of genetic regulation that play crucial roles in controlling gene expression. Here are some key points to consider:  1. **Non-Coding DNA**: Recent research has shown that much of the non-coding part of the genome, which does not code for proteins, is still active in regulating gene expression. This includes various regulatory activities that are not directly related to the traditional DNA elements like promoters and repressors [1].  2. **Chromatin Structure**: The structure of chromatin, which is the complex of DNA and proteins in the cell nucleus, plays a significant role in gene regulation. For example, histone acetylation, which involves adding acetyl groups to histone proteins, can decondense chromosomal structure and make DNA more accessible for transcription [9].  3. **Epigenetic Regulation**: Epigenetics involves changes in gene expression that do not alter the DNA sequence itself. This can include modifications like DNA methylation and histone modification, which affect how tightly DNA is wound around histones and thus its accessibility for transcription [6], [7].  4. **Post-Transcriptional Regulation**: After DNA is transcribed into RNA, there are additional layers of regulation. This includes processes like RNA splicing, editing, and degradation, which can influence how much of the RNA is available to be translated into protein [7].  5. **Translational and Post-Translational Regulation**: Even after RNA is translated into protein, there are mechanisms that regulate the activity, stability, and localization of proteins. These include modifications like phosphorylation and ubiquitination, which can alter protein function and lifespan [7].  In summary, while DNA elements like promoters, repressors, and activators are important for genetic regulation, there are multiple other layers of regulation involving chromatin structure, epigenetic modifications, and post-transcriptional and post-translational processes that also play critical roles in controlling gene expression.",
+    "The different relationships between traits can be categorized into several types based on the provided context:  1. **Correlation Among Traits in a Pair**: This refers to how traits within a pair are related to each other in terms of their correlation [1], [2], [3].  2. **Correlation Between a Trait Pair and Other Factors**: This involves examining how a pair of traits correlates with other external factors or conditions [1], [2], [3].  3. **High-Order Organization of Traits**:    - **Groups of Tightly Related Traits**: These are traits that share the same transcript mechanisms and are highly correlated with each other (modules 1, 2, 6, 7, 8) [6], [7], [8].    - **Groups of Distinct Traits with Shared Mechanisms**: These traits share the same transcript mechanisms but do not necessarily have high correlations among themselves (modules 3, 4, 5) [6], [7], [8].    - **Overlapping Traits in Different Groups**: Different groups of traits may have overlapping traits but typically differ in their underlying mechanisms [6], [7], [8].  These relationships highlight the complexity and interconnectedness of traits, showing that they can be related through direct correlations, shared mechanisms, or overlapping characteristics.",
+    "Yes, the landscape of QTL (Quantitative Trait Loci) and GWAS (Genome-Wide Association Studies) hits can be used to find relationships between traits. This can be achieved through several methods:  1. **Correlated Traits in Different Environments**: Multiple GWAS for the same trait in different environments can be treated as correlated traits, which helps in exploring the genetic and phenotypic basis of local adaptation [1].  2. **Mapping Pleiotropy**: Newer approaches map pleiotropy by simultaneously associating genomic loci with multiple traits, which can reveal relationships between traits [2].  3. **QTL-Trait-Trait Triads**: Causal inference in GWAS and QTL studies involves identifying pairs of traits with a common QTL and determining whether the QTL directly affects each of the two traits independently or if it affects only one trait, which then influences the other [4].  4. **Colocalization and Integration of Data**: Methods such as Bayesian tests for colocalization between pairs of genetic association studies using summary statistics, and Mendelian randomization integrating GWAS and eQTL data, can reveal genetic determinants of complex and clinical traits, thereby identifying relationships between traits [5].  These methods collectively demonstrate that the landscape of QTL and GWAS hits can indeed be used to find relationships between traits."
+  ],
+  "contexts": [
+    [
+      "neered nucleases, CRISPR-Cas9  tools have accelerated the pace of  genomic research by permitting  highly efficient knockouts or  edits of virtually any gene in cells  or model organisms. Multiple CRISPR-Cas9based clinical trials  are in progress or are expected  to begin soon. Although Cas9- engineered cells havent yet dem - onstrated efficacy at scale, early  trial results suggest that such  cells are stable and dont cause  acute adverse reactions in humans.  Long-term safety is yet to be de -",
+      "stageissetforCRISPRtomakeanenormousimpactongenomic screening and thus scientic discovery in the coming years, and recent demonstrations of this system have shown great promise (Shalem etal., 2015 ).However,a number of technical challenges must be addressed in order to maximize the benet of this technology. In this review, we will discuss current applications of CRISPR in functional genomics and provide a perspective on futuredevelopmentsinthisarea. CRISPR/Cas9 Genome Editing",
+      "heralding the age of genome editing. Furthermore, Cas9 or guide RNAs have been linked to various effector proteins to enable targeted gene regulation 12,13 and epigenome modifications14,15.  It is worth noting, however, that many of these feats had been demonstrated previously using other nucleases or DNA-binding proteins 1,16. In this Perspective, I shed light on early genome  editing platforms that laid the groundwork for the widespread use of CRISPRCas9 in research and medicine (Fig. 1 ).",
+      "CRISPR/CAS9 HOLDS SIGNIFICANT PROMISE FOR THE DEVELOPMENT OFNEW AD MODELS AND PRECISIONTARGETED AD THERAPY Clustered regularly interspaced short palindromic repeat (CRISPR)-Cas nucleases have revolutionizedthe eld of gene editing and have tremendous appli-cation in the eld of molecular medicine [98102].Despite a signicant surge in CRISPR/Cas9-mediated genome editing in various disease models,the progress in the eld of AD has lagged behindsubstantially. We believe that genome editing can sig-",
+      "81. Applications for CRISPRCas9 beyond genome editing",
+      "cline- or Tet-regulated Cas9 system. Current CRISPR/Cas systems arefrom Streptococcus pyogenes ,Streptococcus thermophilus ,Neisseria meningitides and Treponema denticola .2.5. Caveats of advanced genome editing tools Off-target effects . The DNA-binding domains of ZFNs and TALENs need to be very speci c for the target site to avoid off-target cleavage, which results in unwanted mutations and potentially cytotoxic effects [27]. CRISPR/Cas9 is also known to generate off-target alterations,",
+      "on transcriptional interfere nce (CRISPRi) and activation (CRISPRa) have also harnessed Cas9-based technologies for use in genome-wide studies ( 59,174). In addition, recent improvements in lentiviral library generation and propagation,as well as large-scale DNA and RNA synthesis, have allowedCRISPR-Cas9 technology to be exploited across multiple modelplatforms ( 59,175178). nCas9 The CRISPR-Cas9 system can tolerate certain mismatches to the DNA target since the required gRNAs are short. A disadvantage,",
+      "CRISPR-Cas9 can be used to in - duce genome edits by creating  targeted DNA breaks that trigger  site-specific DNA repair. In next- generation formats, it can also  control the transcriptional output  of genes or alter genome se - quences using a process of nu - cleotide base editing  that does not require  repair of DNA breaks.  As these technolo - gies continue to mature, it will  become increasingly possible to  alter cellular genomes efficiently  and accurately. Coming on the heels of engi -",
+      "S.P . Raikwar et al. / Alzheimers Disease: New Therapeutic Horizons 333 gene editing efciency of the CRISPR/Cas9 systems.",
+      "13. Kleinstiver BP, etal. High-fidelity CRISPRCas9 nucleases with no detectable genome-wide  off-target effects. Nature. 2016;529:4905.  14. Brane A, Tollefsbol T.Targeting telomeres and telomerase: studies in aging and disease uti- lizing CRISPR/Cas9 technology. Cells. 2019;8:186.  15. Wang H, etal. One-step generation of mice carrying mutations in multiple genes by CRISPR/ Cas-mediated genome engineering. Cell. 2013;153:9108."
+    ],
+    [
+      "to regulate lifetime and aging processes. In fact, epigenetics modulate gene expression without altering the DNA sequence. This is possible by means of different kinds of epigenetic modifications, including DNA methylation and histone modifications (which might affect gene transcription), and noncoding (nc)RNAs (which might change gene expression at the post-transcriptional level)[59]. Given the crucial role of epigenetics in the modulation of gene expression, its alteration can contribute to",
+      "can regulate gene expression while the underlying DNA sequence remains the same. The epigenome is influenced both by underlying genetic variants as well as by environ- mental factors including the social environment, health behaviors, and environmental pollutants [ 11]. Methylation of CpG dinucleotides, the best understood epigenetic mechanism, is also dynamic over the life course. It is well established that epigenomic patterns of DNA methylation change with age [ 12]. A recent study in lymphocytes",
+      "Epigenetics Changes arising from alterations in gene expression  levels that are caused by reversible chemical  modification of DNA, but not changes to the DNA  sequence passed on from parents to offspring.",
+      "Epigenetic changes refer to heritable changes in gene expression which do not involve changes in DNA sequences. Several epigenetic mechanisms have been found to regulate gene expression. Whilst the most studied mechanism relates to DNA methylation, other changes, including histone modi cations and non-coding RNAs, also play an important role, and can be transmitted from one generation to the next. DNA methylation involves the addition of methyl groups to DNA, mainly at CpG sites, which converts cytosine",
+      "EPIGENETIC STUDIES   An epigenetic mechanism is a biochemical alteration to the DNA molecule that  does not change the sequence of the DNA but does in  uence gene expression.   Epigenetics   is often de  ned as the study of mitotically and/or meiotically heri- table changes in gene function that cannot be explained by changes in DNA sequence (Russo, Martienssen, & Riggs, 1996, p. 1).   The epigenetic/epigenomic approach shares many advantages and disad-",
+      "ity and expression of genes without changing their DNA sequence [ 4]. These modications are: DNA methylation, histone modications, and ncRNAs including miRNA [4]. The en- vironment and lifestyle can induce epigenetic changes, such as pollution, tobacco smoking, obesity, lack of physical activity, and alcohol consumption [ 108]. Furthermore, exposure to such environmental factors can have a buttery effect: epigenetic modications may",
+      "epigenetics is the study of mitotically heritable alterations in gene expression potential that are not caused by changes in DNA sequence (Jaenisch and Bird,  2003 ). Hence, rather than encompassing all of developmental biology, modern epigenetics is focused on understanding the spe-ci c molecular mechanisms that convey cellular memory.   Within the nucleus, the mammalian genome is wrapped",
+      "gene expression can also occur by  trans-epigenetics ( Bonasio et al., 2010 ), in which proteins and RNAs inuence gene expres-sion and repression. Stable transcription factor networks are anexample of trans -epigenetics ( Young, 2011 ). Clearly, enzymes that modify DNA and histones (methyltransferases, demethy-lases, acetyltransferases, deacetylases) are central epigeneticregulatory mechanisms ( Rando and Chang, 2009 ). The essence of epigenetics is not only the establishment, but",
+      "pay attention to epigenetic effects on gene expressionmeaning changes that are heritable but that do not involve any change in DNA sequence (see Rutter 2006). Three key points are relevant. First, genes only have effects when they are expressed. Many genes are expressed in only some body tissues and only at certain phases in development. Second, there are multiple inherited DNA elements that do not code for proteins but yet which have important effects through their in  uence on gene expression. We need to",
+      "genetics of gene expression (i.e. regular genetical genomics) and the genetics of epigenetics could be studied simultaneously, thus revealing genes that directly or indirectly affect epigenetic gene states. An additional issue that could be addressed by such an approach is to estimate the percentage of variation in gene expression that can be explained by different epigenetic conformations."
+    ],
+    [
+      "drial DNA sequence variation seems impossible withoutan understanding of some important differences betweennuclear and mitochondrial genetics (Table I). Mitochon-drial DNA replicates autonomously and is inherited viathe cytoplasm of the parent cell with the individualmitochondrion being the segregating unit (Attardi et al.,1995). Thus, in the case of mitochondrial mutations bothmutated as well as normal mitochondria may be presentwithin the same cell. This situation has been termedheteroplasmy and can",
+      "cMitochondria are semiautonomous organelles; possess their own replication-, transcription- and translation system cExclusively maternal inheritance of mitochondrial DNA cMitotic segregation of mitochondrial DNAcan lead to hetero- plasmy, i.e., the proportion of genetically different populations ofmitochondria differs between generations of mitotically activecells cApproximately tenfold higher mutation rate compared with nuclear",
+      "DIFFERENCES BETWEEN MITOCHONDRIAL AND NUCLEAR GENETICS Arealisticassessmentoftherelevanceofmitochon-",
+      "In the fifth mode of inheritance, the disease mutation lies not on a chromosome in the nucleus but rather in mitochondrial DNA outside the nucleus. Mitochondria are inherited exclu- sively from an offsprings mother; because of this phenome- non, the mutation and thus the disease can be passed only from a mother to her offspring. This is maternal inheritance, also known as extranuclear inheritance (Figure 11). Representative disorders include various mitochondrial myopathies.",
+      "The regulation of the mitochondrial genome also reflects  its prokaryotic ancestry. While nuclear DNA undergoes replication during cell division, mtDNA replication occurs independently of cell cycle. The majority of the compo-nents for mtDNA replication are imported nuclear-encoded proteins, including the catalytic subunit of mtDNA poly -",
+      "Unlike the nuclear genome, which requires both paternal and maternal contributions, mtDNA is inherited solely from the maternal lineage. It is unclear what advantage a uniparental mtDNA transmission confers, but one possibil-ity is to minimize the number of distinct genomes to maxi-mize the efficiency of a multi-genomic system (Hill etal. 2019). In fact, humans have developed complex, redundant mechanisms to ensure uniparental inheritance of mtDNA (DeLuca and OFarrell 2012; Rojansky etal. 2016). Paternal",
+      "mitochondria and sperm are not, mitochondrial DNAis usually inherited from the mother. Therefore, mito-chondrial genes  and diseases due to DNA-sequencevariants in them  are transmitted in a matrilineal pat-tern that is distinctly different from the pattern of in-heritance of nuclear genes.  MONOGENIC CONDITIONS  Over the course of the 20th century, a combination",
+      "2. Mitochondrial DNA structure and properties Mitochondrial genomes (mt-genomes) are short circular molecules that, with the exception of viruses,represent the most economically packed forms ofDNA in the whole biosphere. The human mt-genomeis only 16,569bp long [9]; within this extension, wend the coding sequences for seven subunits of theNADH-ubiquitone reductase (respiratory complex I),the apocytochrome bof the ubiquitone cytochrome creductase (respiratory complex III), three subunits",
+      "Abstract The human mitochondrial genome consists of approximately 1500 genes, 37 encoded by the maternally inherited mitochondrial DNA (mtDNA) and the remainder encoded in the nuclear DNA (nDNA). The mtDNA is present in thousands of copies per cell and encodes",
+      "(mtDNA). MtDNA carries important genetic information concerning cellular metabolismand the generation of energy. It has been suggested that mitochondria and mtDNA could be of significance during early embryo development. Our work confirms this hypothesis. Specif- ically, our findings implicate mitochondria and their genome in female reproductive agingand the generation of embryonic chromosome abnormalities. Importantly, we describe a di-"
+    ],
+    [
+      "1999) raises practical and ethical issues of access to resulting opportunities and creates family communication challenges. Currently, prenatal testing for chromosomal diseases has become increasingly common (Moyer et al., 1999). Options such as pre-implantation genetic diagnosis (PGD) can identify over 1,250 disease-related mutations creating an opportunity for parents to select unaffected embryos for implantation in the womb (R. M. Green, 2008). Test results provide potential parents with information",
+      "undergo prenatal testing have determined that partners base their decision upon several factors, including, but not limited to: parental beliefs about abor-tion, attitudes regarding disability and their perceptions of the usefulness of having the information revealed by genetic tests (Moyer et al., 1999, p. 522). Abortion beliefs constitute a key issue in the decision-making process. Even though a majority of parents receiving abnormal prenatal test results terminate their pregnancies (Redlinger-Grosse,",
+      "Hum Genet 1995;57:12331241. 24. Committee on Bioethics. Ethical and policy issues in genetic testing and  screening of children. Pediatrics 2013;131:620622. 25. Ross LF, Saal HM, David KL, Anderson RR. Technical report: ethical and policy issues in genetic testing and screening of children. Genet Med 2013;15:   234245. 26. Wilfond B, Ross LF. From genetics to genomics: ethics, policy, and parental decision-making. J Pediatr Psychol 2009;34:639647.",
+      "Informed Consent and Genetic Testing    Genetic testing is increasingly used across the life continuum  for screening, diagnosis, and de termining the best treatment  of diseases. Obstetric and pediat ric nurses have traditionally  been involved in the genetic testing process with prenatal  screening for genetic conditions such as spina bifida and Down  syndrome, and newborn screening for genetic conditions such",
+      "Objective Ethical evaluation of genetic testing in children is traditionally based on balancing clinical benefits and risks. However, this focus can be inconsistent with the general practice of respecting parentaldecision-making about their childrens health care. We argue that respect for parental decision-making should play a larger role in shaping pediatric genetic testing practices, and play a similar role regarding decisions",
+      "prenatal decisions. Further research needs to investigate how different families engage in such discussions and decision-making pro-cesses, especially as prenatal testing becomes more common and better able to predict or prevent a wider range of genetic conditions.",
+      "all of the complex ethical and legal issues rel- evant to genetic testing would disappear if there were effective preventions or treatments available for genetic conditions. The ability to predict future disease in conjunction with a limited ability to do much about it has im- portant social and psychological implications that must be addressed in conducting genetic research. One final factor worth consideration in un- derstandingthesensitivitytogeneticmedicine",
+      "Newborn screening by tandem mass spec-trometry: ethical and social issues. Can J Public Health 2007;    98:   284286.   65 Belle-Isle L: Genetic testing for late onset dis- eases: a population and public health per-spective. Health Policy Res Bull 2001;    1:   11 12.   66 Williams-Jones B: Private genetic testing in  Canada: a summary. Health Law Rev 2001;   9:    1013.   67 Begleiter ML: Training for genetic counsel- lors. Nat Rev Genet 2002;   3:   557561.   68 Carroll JC, Reid AJ, Woodward CA, Per-",
+      "Although risk-based genetic testing for common diseases raise similar ethical issues to more  traditional genetic testing for rare diseases, new challenges are raised due to the type of information  revealed and access to tests. With thoughtful deliberation with health professionals, patients and  families, test developers and laboratories, insurers and other stakeholders, these issues can be  addressed to ensure the safe and appropriate use of these promising new clinical applications.     REFERENCES",
+      "against testing, parents should generally be given final decision-making authority. Ethical Considerations in Developing Policy for Comprehensive Genomic Testing In the near future, genomic testing is likely to become more accessible and will provide both information aboutthe risks of common conditions such as heart disease, diabetes, and hypertension as well as predictions aboutindividual responses to specific pharmaceuticals and other medical therapies (Aspinall & Hamermesh, 2007)."
+    ],
+    [
+      "36. Sequencing, H.G. Finishing the euchromatic sequence of the human genome. Nature 2004 ,431, 931945. 37. Heather, J.M.; Chain, B. The sequence of sequencers: The history of sequencing DNA. Genomics 2016 ,107, 18. [CrossRef] 38. Rothberg, J.M.; Leamon, J.H. The development and impact of 454 sequencing. Nat. Biotechnol. 2008 ,26, 11171124. [CrossRef] [PubMed] 39. Shendure, J.; Ji, H. Next-generation DNA sequencing. Nat. Biotechnol. 2008 ,26, 11351145. [CrossRef] [PubMed]",
+      "22. Karow, J. Qiagen launches GeneReader NGS System  atAMP; presents performance evaluation by broad.  GenomeWeb  [online], https:// www.genomeweb.com/ molecular-diagnostics/qiagen-launches-genereader- ngs-system-amp-presents-performance-evaluation   (4Nov 2015). 23. Smith,D.R. & McKernan,K. Methods of producing  and sequencing modified polynucleotides . US Patent  8058030 (2011). 24. Margulies,M. etal.  Genome sequencing in  microfabricated high-density picolitre reactors. Nature  437, 376380 (2005).",
+      "11 BIOINFORMATIC CHALLENGES FOR GENOMIC MEDICINE      Processing and managing of high-throughput sequence data     High throughput sequencing offers severa l advantages relative to array-based  genotyping or expression assays. First, unlike genotyping arrays, whole genome sequencing is not limited to interrogating onl y known sequence variants. Similarly, RNA- sequencing (RNA-seq) enables expression quanti fication of novel transcripts that are not",
+      "11 BIOINFORMATIC CHALLENGES FOR GENOMIC MEDICINE      Processing and managing of high-throughput sequence data     High throughput sequencing offers severa l advantages relative to array-based  genotyping or expression assays. First, unlike genotyping arrays, whole genome sequencing is not limited to interrogating onl y known sequence variants. Similarly, RNA- sequencing (RNA-seq) enables expression quanti fication of novel transcripts that are not",
+      "High-throughput bacterial genome sequencing: an embarrassment of choice, aworldof opportunity.NatRevMicrobiol2012;10:599-606. 11.CroucherNJ,DidelotX.Theapplicationof genomicstotracingbacterialpathogen transmission.CurrOpinMicrobiol2015;23:62-7. 12.ShendureJ,JiH.Next-generationDNAsequencing.NatBiotechnol2008;26:1135- 45. 13.MillerJR,KorenS,SuttonG.Assemblyalgorithmsfornext-generationsequencing data.Genomics2010;95:315-27. 14.OlsonND,LundSP,ColmanRE,FosterJT,SahlJW,SchuppJM,etal.Bestpractices",
+      "sequencing. Genome Res. 20, 11651173 (2010). 64. English,A.C. etal.  Assessing structural variation in a  personal genome-towards a human reference diploid  genome. BMC Genomics 16, 286 (2015). 65. Carneiro,M.O. etal.  Pacific Biosciences sequencing  technology for genotyping and variation discovery in  human data. BMC Genomics 13, 375 (2012). 66. Quail,M.A. etal.  A tale of three next generation  sequencing platforms: comparison of Ion T orrent,  Pacific Biosciences and Illumina MiSeq sequencers.",
+      "Nat. Biotechnol. 30, 10331036 (2012). 111. Chrystoja,C.C. & Diamandis,E.P . Whole genome  sequencing as a diagnostic test: challenges and  opportunities. Clin. Chem. 60, 724733 (2014). 112. McGuire,A.L. etal.  Point-counterpoint. Ethics and  genomic incidental findings. Science 340, 10471048  (2013). 113. Bowers,J. etal.  Virtual terminator nucleotides for  next-generation DNA sequencing. Nat. Methods 6,  593595 (2009). 114. Heger,M. Chinas Direct Genomics unveils new",
+      "sequencing. Bioinformatics 31, 20402042 (2015). 46. Qiagen.  Oncology insights enabled by knowledge base- guided panel design and the seamless workflow of the  GeneReader NGS system  Press Release. Qiagen   [online], http://www.genereaderngs.com/PROM-9192- 001_1100403_WP_GeneReader_NGS_0116_NA.pdf   (2016). 47. Forgetta,V. etal.  Sequencing of the Dutch elm disease  fungus genome using the Roche/454 GS-FLX Titanium  System in a comparison of multiple genomics core",
+      "FURTHER INFORMATION 10X Genomics: http://www.10xgenomics.com 454 Sequencing: http://www.454.com Advances in Genome Biology and Technology (AGBT):  http://www.agbt.org BGISEQ500: http://seq500.com/en/portal/Sequencer.shtml Illumina: http://www.illumina.com Ion Torrent: https://www.thermofisher.com/us/en/home/ brands/ion-torrent.html Oxford Nanopore Technologies: https://www.nanoporetech. com Pacific Biosciences: http://www.pacb.com Personal Genome Project: http://www.personalgenomes.org",
+      "DNA), and provide the means to link sequences containing applications. First,  base- callers like Phred (4,5) extract raw sequences from raw data. There are  also contig assemblers like Phrap (University of Washington, http://bozeman. mbt.washington.edu/phrap.docs/phrap.html ) or CAP3 (6) that assemble frag- ments to contigs and packages like consed (7) or GAP4 (8), which are used to  finish sequencing projects. These programs are not explained in detail here."
+    ],
+    [
+      "are involved in the development of the disease [127 ].  There is evidence that more  than twenty regions of the genome are involved in t he genetic susceptibility to T1D.   The genes most strongly associated with T1D are loc ated in the HLA region of  chromosome 6 [128].  Similar to T1D, T2D has a stro ng genetic component.  To date,  more than 50 candidate genes for T2D have been inve stigated in various populations  worldwide.  Candidate genes are selected due to the ir interference with pancreatic",
+      "pre-existing statistical support for a role in T1D-susceptibility: these are the major histocompatibility complex (MHC), the genes encod- ing insulin, CTLA-4 (cytotoxic T-lymphocyte associated 4) and PTPN22 (protein tyrosine phosphatase, non-receptor type 22), and the regions around the interleukin 2 receptor alpha ( IL2RA/CD25 ) and interferon-induced helicase 1 genes ( IFIH1 /MDA5)94. However, these signals can explain only part of the familial aggregation of T1D.",
+      "C. The Insulin Gene A lesser genetic predisposition to T1D is conferred by the IDDM2 locus on chromosome 11 containing the insu-lin gene region. A polymorphic region located 5 =of the insulin gene was rst reported in 1984 to be associatedwith T1D in caucasoids (39). Now established as a pri- TYPE 1 DIABETES: FROM CAUSE TO CURE 81 Physiol Rev VOL 91 JANUARY 2011 www.prv.org Downloaded from journals.physiology.org/journal/physrev (041.090.188.152) on July 14, 2023.",
+      "ception of the insulin gene (434). The genetic susceptibil-ity component of T1D allows some targeting of primarypreventive care to family members of diagnosed T1Dpatients, but there is no complete inheritance of the dis-ease. Nevertheless, the risk for developing T1D comparedwith people with no family history is /H110111015 times greater. Although /H1101170% of individuals with T1D carry",
+      "Genes signifying increased risk for both type 1 and type 2 dia-betes have been identified. Genomewide association studies have identified over 50 loci associated with an increased genetic risk of type 1 diabetes. Several T1D candidate genes for increased risk of developing type 1 diabetes have been sug-gested or identified within these regions, but the molecular basis by which they contribute to islet cell inflammation and beta cell destruction is not fully understood. 12 Also, several",
+      "14   carried out on large cohorts including collections of families with  affected sibling pairs (Pociot   et al., 2010). These studies have provided evidence for over forty T1D susceptibility regions ,  but the  exact mechanisms by which the variation found in these regions  confer susceptibility to  T1D is still not clear (Noble and Erlich, 2012). The most important genes contributing to T1D  susceptibility are located in the MHC class II region , also  referred to as t he Human Leukocyte",
+      "The ultimate proof of an inherited contribution to disease pathogenesis comes from the identication of susceptibility genes. As described below, an increasing number of T2D susceptibility genes have been discovered in the past decade, especially,but not exclusively, in monogenic subtypes. Collectively, these probably account for294 A. L. Gloyn and M. I. McCarthy",
+      "loci contribute to Type 1 Diabetes (T1D) susceptibility and age at T1D onset. Hum. Immunol. 66,301313 (2005). 9. Aly, T. A. et al. Extreme genetic risk for type 1A diabetes. Proc. Natl Acad. Sci. USA 103, 14074 14079 (2006). 10. Noble, J. A. et al. The HLA class I A locus affects susceptibility to type 1 diabetes. Hum. Immunol. 63,657664 (2002). 11. Honeyman, M. C., Harrison, L. C., Drummond, B., Colman, P. G. & Tait, B. D. Analysis of families at risk for insulin-dependent diabetes mellitus reveals that",
+      "failure linked to T2D genetic risk and pathophysiology. Single celltranscriptome analysis of human islet cells indicate that multiplemonogenic diabetes genes are highly expressed in beta cells (e.g., PDX1, PAX4, INS, HNF1A, andGCK)[27]. However, other non-beta cell types express genes mutated in monogenic diabetes (such as PAX6 and RFX6 ), congenital hyperinsulinemia ( HADH, UCP2 ) and those implicated as T2D GWAS target/effector genes [28].",
+      "chain promoter (Serreze and Leiter 2001). This observation, alongwith human genetic studies, suggests that increased T1D risk in humans may also result from the combination of rare and common variants within the human population (Concannon et al. 2009b). Despite the identification of several Iddgenes to date, this limited collection does not fully explain T1D pathogenesis or the underlying genetic architecture for T1D risk. One of the many Idd"
+    ],
+    [
+      "supported by a signicant BLAST match to one or more expressed sequences or proteins. Ensembl also identies the positions of known human genes from public sequence database entries, usually using GENEWISE to predict their exon structures. The total set of Ensembl genes should therefore be a much more accurate reection of reality than ab initio predictions alone, but it is clear that some novel genes are missed (Hogenesch et al. , 2001). Of the many novel genes that are detected, some are",
+      "supported by a signicant BLAST match to one or more expressed sequences or proteins. Ensembl also identies the positions of known human genes from public sequence database entries, usually using GENEWISE to predict their exon structures. The total set of Ensembl genes should therefore be a much more accurate reection of reality than ab initio predictions alone, but it is clear that some novel genes are missed (Hogenesch et al. , 2001). Of the many novel genes that are detected, some are",
+      "supported by a signicant BLAST match to one or more expressed sequences or proteins. Ensembl also identies the positions of known human genes from public sequence database entries, usually using GENEWISE to predict their exon structures. The total set of Ensembl genes should therefore be a much more accurate reection of reality than ab initio predictions alone, but it is clear that some novel genes are missed (Hogenesch et al. , 2001). Of the many novel genes that are detected, some are",
+      "populations as Ensembl reects the progress of the International Haplotype Map Project (Thorisson et al. , 2005). More speculative data, such as GENSCAN-predicted exons that have not been incorporated into Ensembl-conrmed genes, may also be viewed. This means that the display can be used as a workbench for the user to develop personalized an- notation. For example, one may discover novel exons by nding GENSCAN exon predictions which coincide with good matches to a fragment of the draft mouse",
+      "populations as Ensembl reects the progress of the International Haplotype Map Project (Thorisson et al. , 2005). More speculative data, such as GENSCAN-predicted exons that have not been incorporated into Ensembl-conrmed genes, may also be viewed. This means that the display can be used as a workbench for the user to develop personalized an- notation. For example, one may discover novel exons by nding GENSCAN exon predictions which coincide with good matches to a fragment of the draft mouse",
+      "populations as Ensembl reects the progress of the International Haplotype Map Project (Thorisson et al. , 2005). More speculative data, such as GENSCAN-predicted exons that have not been incorporated into Ensembl-conrmed genes, may also be viewed. This means that the display can be used as a workbench for the user to develop personalized an- notation. For example, one may discover novel exons by nding GENSCAN exon predictions which coincide with good matches to a fragment of the draft mouse",
+      "Ostell/Spidey/ SSAHA at Sanger Institute http://www.sanger.ac.uk/Software/analysis/SSAHA/ human and mouse genomes, where there are large full-length cDNA collections to guide the hunt for genes, Ensembl should be very reliable. From the beginning, many genomic features other than predicted genes were included in Ensembl: different repeat classes, cytological bands, CpG island predic- tions, tRNA gene predictions, expressed sequence clusters from the UniGene database",
+      "Ostell/Spidey/ SSAHA at Sanger Institute http://www.sanger.ac.uk/Software/analysis/SSAHA/ human and mouse genomes, where there are large full-length cDNA collections to guide the hunt for genes, Ensembl should be very reliable. From the beginning, many genomic features other than predicted genes were included in Ensembl: different repeat classes, cytological bands, CpG island predic- tions, tRNA gene predictions, expressed sequence clusters from the UniGene database",
+      "Ostell/Spidey/ SSAHA at Sanger Institute http://www.sanger.ac.uk/Software/analysis/SSAHA/ human and mouse genomes, where there are large full-length cDNA collections to guide the hunt for genes, Ensembl should be very reliable. From the beginning, many genomic features other than predicted genes were included in Ensembl: different repeat classes, cytological bands, CpG island predic- tions, tRNA gene predictions, expressed sequence clusters from the UniGene database",
+      "comprehensive, powerful, flexible and interactive gene set enrichment analysis toolkit. Nucleic Acids Research ,45(W1), W130W137. [44] Zhang, B., Kirov, S., & Snoddy, J. (2005). WebGestalt: an integrated system for exploring gene sets in various biological contexts. Nucleic Acids Research ,33(Web Server issue), W741-8. [45] McLaren, W., Gil, L., Hunt, S. E., Riat, H. S., Ritchie, G. R. S., Thormann, A., Flicek, P ., et al. (2016). The ensembl variant effect predictor. Genome Biology ,17(1), 122."
+    ],
+    [
+      "417 Use of Rat Genomics for Investigating the Metabolic Syndrome and phenotypic traits are available to the scientific community  in databases, such as Ensembl ( http://www.ensembl.or g), the  Rat Genome Database ( http://www.rgd.mcw.ed u), eQTL  Explorer ( http://www. web.bioinformatics.ic.ac.uk/eqtlexplore r)  or GeneNetwork ( http://www.genenetwork.or g). Additional  online rat genetic resources have been recently reviewed by  Twigger et  al. (11).",
+      "Howard Jacob (Medical College of Wisconsin) discussed the Rat Genome Database disease portals, a platform for genetic and genomic research. Thereare 845 strains of rats, 573 of which are inbred,including substrains. Historically, biologists usingthe rat as a model have been disease focused,studying diseases, related phenotypes, pathways, and biological processes. The Rat Genome Database",
+      "10. Consortium STAR, Saar K, Beck A, Bihoreau  MT, Birney E, Brocklebank D, Chen Y et  al  (2008) SNP and haplotype mapping for  genetic analysis in the rat. Nat Genet  40:560566  11. Twigger SN, Pruitt KD, Fernndez-Surez  XM, Karolchik D, Worley KC, Maglott DR  et al (2008) What everybody should know about the rat genome and its online resources.  Nat Genet 40:523527  12. Butcher LM, Beck S (2008) Future impact of  integrated high-throughput methylome anal- yses on human health and disease. J Genet",
+      "for linkage analyses using new methods of efficient genotyping  based on genechip microarrays (10). In addition, over 800,000  ESTs and 5,000 annotated rat gene sequences are available for  functional analyses of candidate genes. Development of new  methodologies for high throughput phenotyping, such as expres- sion profiling, are becoming routinely used. Most of these genetic 2. Recent  Advances in Rat  Genetics and  Genomics",
+      "serves as a repository of all rat QTLs related to thedisease area as well as associated mouse and humanQTLs, strains used as disease models, phenotypedata, related references, expression data, genome-wide views of disease genes, and QLS via GViewer,comparative maps of disease-related regions, cus-tomization of data sets and download options, and analysis and visualization of function and cellular localization makeup of gene sets (http://www.rgd.mcw.edu/). ENU mutagenesis is now being done with rats.",
+      "3. Can data sharing in rodent phenotyping help with replicability? Laboratory mice and rats are the main mammalian models currently used for high-throughput genomic and behavior genetic research, and are employed primarily to explore and test gene function. This is con- sidered by some to be the great challenge facing biologists today  (Collins et al., 2007 ). Rodent models are used extensively as part of preclinical development and testing of treatments for disease in hu-",
+      "Bioinformatics and Statistical Analysis R was used for basic analysis of phenotypic data. GeneNetwork (www.genenetwork.org) was used for correlation and genetic analyses. The original phenotypes published in this paper and all microarray data generated in these cohorts are available for public analysis or download using the GeneNetwork database (Species: Mouse, Group: BXD, Type: Adipose mRNA, Liver mRNA, or Muscle mRNA, then select the EPFL datasets). The three",
+      "[23]. Shimoyama M, De Pons J, Hayman GT, Laulederkind SJ, Liu W, Nigam R, Petri V , Smith JR,  Tutaj M, Wang S-J, The Rat Genome Database 2015: genomic, phenotypic and environmental  variations and disease, Nucleic acids research 43(D1) (2014) D743D750. [PubMed: 25355511]  [24]. Dickinson ME, Flenniken AM, Ji X, Teboul L, Wong MD, White JK, Meehan TF, Weninger WJ,  Westerberg H, Adissu H, High-throughput discovery of novel developmental phenotypes, Nature  537(7621) (2016) 508. [PubMed: 27626380]",
+      "database (dbSNP) build 130 to identify genes located inthe vicinity of selected SNPs. Homologues of the genes formouse and rat were identified using the NCBI's Homolo-Gene release 64. We included only those genes that wereevolutionarily conserved in three different species namelyhuman, mouse and rat. Analysis of microarray data",
+      "(data not shown). Therefore, it seems logical to position the rat field so themechanistic, disease-based research canbe integrated into the awesome power ofthe human and mouse genome projects. Progress of the Rat Genome Project Recognizing the usefulness of the rat as amodel system, NIH, led by the NationalHeart, Lung, and Blood Institute(NHLBI), has funded the Rat GenomeProject (RGP), the Rat Expressed Se-quence Tag (RGP EST) Project, and the Rat"
+    ],
+    [
+      "were identied using the RGD (68). This resource provides infor-mation regarding the physiological trait studied, strain combina-tion used, associated linkage statistics, and the genomic coordi-nates of the pQTL region. For pQTL regions identied from RGD,the original data (Supplementary Table S3) were examined, and the99% condence interval [within the 2 logarithm of the odds (LOD)drop from the peak of linkage] was estimated. Cis-eQTLs were",
+      "RGCs. The discovery of this relationship may help inguiding studies that explore the disease mechanismsassociated with altered protein transport and foldingin RGCs. In glaucoma, the identication and conr-mation of these two proteins in RGC health and dis-ease holds great promise for the development ofmolecular targets to slow or reverse RGC damage, which, in turn, will preserve vision. Experimental procedures Human donor eyes Human donor eyes were collected in accordance with the",
+      "RGCs. The discovery of this relationship may help inguiding studies that explore the disease mechanismsassociated with altered protein transport and foldingin RGCs. In glaucoma, the identication and conr-mation of these two proteins in RGC health and dis-ease holds great promise for the development ofmolecular targets to slow or reverse RGC damage, which, in turn, will preserve vision. Experimental procedures Human donor eyes Human donor eyes were collected in accordance with the",
+      "(http://www.cbil.upenn.edu/PaGE/). All microarray platforms and image-analysis software are supported. In addition, RAD is being used for CGH, ChIP , and SAGE data. RAD can produce MAGE-ML les for export of data to other databases or software packages. RAD is part of a more general Genomics Unied Schema, which provides a platform to integrate gene and transcript data from a variety of organisms. Advantages RAD is a scalable, Web-accessible database that can accommodate data from sev-",
+      "(http://www.cbil.upenn.edu/PaGE/). All microarray platforms and image-analysis software are supported. In addition, RAD is being used for CGH, ChIP , and SAGE data. RAD can produce MAGE-ML les for export of data to other databases or software packages. RAD is part of a more general Genomics Unied Schema, which provides a platform to integrate gene and transcript data from a variety of organisms. Advantages RAD is a scalable, Web-accessible database that can accommodate data from sev-",
+      "(http://www.cbil.upenn.edu/PaGE/). All microarray platforms and image-analysis software are supported. In addition, RAD is being used for CGH, ChIP , and SAGE data. RAD can produce MAGE-ML les for export of data to other databases or software packages. RAD is part of a more general Genomics Unied Schema, which provides a platform to integrate gene and transcript data from a variety of organisms. Advantages RAD is a scalable, Web-accessible database that can accommodate data from sev-",
+      "differentiallysusceptibletodeath,withalpha-RGCsandintrinsicallyphotosensitiveRGCs (ipRGCs) being less sensitive to cell death than other RGC subtypes in a mouse model of glaucoma. Keywo rds: retinal ganglion cells, gene regulatory networks, transcription factors, recombinant inbred strain, subtypes INTRODUCTION Theretinalganglioncell(RGC)isthenaloutputneuronoftheretina,projectingthroughtheoptic nerve to the brain, where it targets a number of functionally distinct areas: for visual perception,",
+      "AG18245 (DG), NIAAA U01AA014425 (LL), and P20 DA021131 (RW). We thank Derek Rains, Gurjit Rai, Meifen Lu, Richard Cushing, Erich Brauer, and Alan Weatherford for their invaluable technical assistance. Abbreviations BrdU bromodeoxyuridine CV cresyl violet GF growth fraction LOD likelihood of the odds LRS likelihood ratio statistic NSCs neural stem cells OB olfactory bulb DG dentate gyrus QTL quantitative trait locus RI recombinant inbred RMS rostral migratory stream SGZ subgranular zone",
+      "Rdh10, Lrat,) whose biology functions are directly associated w ith the metabolism of  retinoid.  RGR (retinal G protein-coupled receptor, protein of  Rgr ) is a protein that structurally resembles  visual pigments and other G protein-coupled recepto rs. Light isomerizes 11- cis - into all-trans - retinal, triggering a conformational transition of the opsin molecule that initiates phototransduction .  After bleaching all- trans -retinal leaves the opsin, and light sensitivity mu st be restored by",
+      "GeneNetwork system, we were able to define robust expression covariance signatures for RGCs and confirmed membership of Chrna6 within the RGC cell type of the retina using new array data sets and RT-PCR tracking through a progressive RGC loss mouse line. Chrna6  can be added as reliable biomarker for RGCs and RGC loss secondary to glaucoma. It is important to note that in addition to providing evidence for Chrna6 expression as a"
+    ],
+    [
+      "[3] and KEGG [4] all allow a list of genes to be crossed with biological functions and genetic networks, including metabolic, signalling or other regulation pathways. Basic statistical analysis (e.g., [5,6]) can then determine whether a pathway is over-represented in the list, and whether it is over-activated or under-activated. However, one can argue that introducing information on the path- way at this point in the analysis process sacrifices some statistical power to the simplicity of the approach. For",
+      "Sidiropoulos, K., Viteri, G., Sevilla, C., Jupe, S., Webber, M., Orlic -Milacic, M., et al. (2017).  Reactome enhanced pathway visualization. Bioinformatics  33, 3461 3467.  doi:10.1093/bioinformatics/btx441.   Slenter, D. N., Kutmon, M., Hanspers, K., Riutta, A., Windsor, J., Nunes, N., et al. (2018).  WikiPathways: a multifaceted pathway database bri dging metabolomics to other omics  research. Nucleic Acids Res.  46, D661 D667. doi:10.1093/nar/gkx1064.",
+      "Sidiropoulos, K., Viteri, G., Sevilla, C., Jupe, S., Webber, M., Orlic -Milacic, M., et al. (2017).  Reactome enhanced pathway visualization. Bioinformatics  33, 3461 3467.  doi:10.1093/bioinformatics/btx441.   Slenter, D. N., Kutmon, M., Hanspers, K., Riutta, A., Windsor, J., Nunes, N., et al. (2018).  WikiPathways: a multifaceted pathway database bri dging metabolomics to other omics  research. Nucleic Acids Res.  46, D661 D667. doi:10.1093/nar/gkx1064.",
+      "analysis, we restrict the analysis to curated, peer-reviewedpathways based on experimental evidence, and pathways inferred via gene homology. We draw candidate pathways from the collections listed in Figure 6 (see also Supplementary Materials). KEGG [146] and HumanCyc [147] are primarily databases of metabolic pathways, and are unlikely to be relevant to someJoint Analysis of Variants and Pathways in Disease PLOS Genetics | www.plosgenetics.org 11 October 2013 | Volume 9 | Issue 10 | e1003770",
+      "textual interface, also linking out to the original articles. Analysing participating pathways is an important aspect of any gene s functional analysis strategy. In this view, REACTOME (http://www.reactome.org) [13] is a cross referenced, manually curated and peer reviewed pathway database. LitInspector (http://www.litinspector.org) [14]and NetPath (http://www.netpath.org/index.html) [15] allow one to access curated signal transduction related lit-",
+      "I, Babur O, Anwar N, Schultz N, Bader GD, Sander C (2011) Pathway Commons, a web resource for biological pathway data. Nucleic Acids Res 39(Database issue):D685D690. doi:   10.1093/nar/gkq1039           6.    Baker EJ, Jay JJ, Bubier JA, Langston MA,  Chesler EJ (2012) GeneWeaver: a web-based system for integrative functional genomics. Nucleic Acids Res 40(Database issue):D1067D1076. doi:   10.1093/nar/gkr968            7.    Bubier JA, Phillips CA, Langston MA, Baker",
+      "67. Krmer, A., Green, J., Pollard, J. Jr. & Tugendreich, S. Causal analysis approaches in ingenuity pathway analysis. Bioinformatics   30, 523530 (2014). 68. Jassal, B. et al. The reactome pathway knowledgebase. Nucleic Acids Res. 48, D498D503 (2020). 69. Okonechnikov, K., Conesa, A. & Garca-Alcalde, F. Qualimap 2: advanced multi-sample quality control for high-throughput sequencing data. Bioinformatics 32, 292294 (2016).",
+      "Biocarta    pathway  maps  www.biocarta.com BioGRID    genetic  and  protein  interaction  database  thebiogrid.org AnalysisPLINK  processing  and  QC  of  genetic  data  sets  pngu.mgh.harvard.edu/ purcell/plink Bioconductor    processing  and  QC  of  expression  data  sets  www.bioconductor.org DAVID   gene  ontology,  pathway  analysis  david.abcc.ncifcrf.gov WebGestalt    gene  ontology,  pathway  analysis  bioinfo.vanderbilt.edu/webgestalt Sage",
+      "2004; Gene Ontology Consortium, 2015; The Gene Ontology Consortium, 2019) , KEGG  pathways  (Kanehisa and Goto, 2000; Kanehisa et al., 2012) , Panther pathways  (Mi et al., 2019a,  2019b) , Reactome pathways  (Sidiropoulos et al., 2017; Jassal et al., 2020) , and Wikipathway  pathways  (Pico et al., 2008; Slenter et al., 2018)  (Figure 31). As many different annotations as  wanted can be chosen by clicking on the + icon ( Figure 31). Also note, that the user can",
+      "2004; Gene Ontology Consortium, 2015; The Gene Ontology Consortium, 2019) , KEGG  pathways  (Kanehisa and Goto, 2000; Kanehisa et al., 2012) , Panther pathways  (Mi et al., 2019a,  2019b) , Reactome pathways  (Sidiropoulos et al., 2017; Jassal et al., 2020) , and Wikipathway  pathways  (Pico et al., 2008; Slenter et al., 2018)  (Figure 31). As many different annotations as  wanted can be chosen by clicking on the + icon ( Figure 31). Also note, that the user can"
+    ],
+    [
+      "the egg and the sperm. Such a process would result in genetic changes that will be copied into every cell of the future adult, including reproductive cells (Stock & Campbell, 2000), opening the door to irreversibly alter the human species. Inevitably, signifi  cant self-disclosure and discussion challenges await families",
+      "phenomena such as mutations and gene conversion events) occur in relevant meioses  leading up to the formation of the gametes (i.e., egg and sperm) which are combined  during fertilization and the formation of zygotes. Thus, individuals inherit a patch- work of chromosomal segments from maternal and paternal chromosomes.",
+      "a fertilized egg is a complicated process that relies on controlling: which genes are active; whenthese genes activate; and for how long they are active. In broad terms, there are four ways that thiscontrol can be achieved: First, inside the sperm or egg, genes can be marked with small chemical tags that flag these genes",
+      "to be activated (or remain inactive) after fertilization, depending on whether the modification wasmade by the father (in the sperm) or the mother (in the egg); this process is known as imprinting. Second, the mother can alter the gene activity in her offspring via the placenta; this process is known as maternal effect. Third, instructions encoded within the embryos DNA can directly control if, andwhen, a nearby gene becomes activated; this is known as  cis-regulation. Finally, similar instructions",
+      "(Figures 8 and 9). Two gametes (egg and sperm) ultimately  join into a single cell, the zygote, which has the full comple-ment of 23 chromosome pairs restored. If all goes well, the zygote gives rise to a live offspring. The Mendel Laws: Segregation and Independent  Assortment Both of the Mendel laws pertain directly to the process of  meiosis. The first Mendel law, the law of segregation, states  that each parent passes a randomly selected allele for a given",
+      "sex chromosome effects. (B)Soon after fertilization, male and female cells have sex-specic transcriptomes, epigenomes, and phenotypes (for example, male embryos grow faster than female embryos). At implantation, lineage determination begins and gene expression differences are reduced. Epigenetic marks, however, are less constrained and some are maintained, affecting gene expression, and phenotype later in development. Once specic lineages are established, differences in",
+      "the subset of that genetic information that is active.  But how does the differentiation process  begin?  The key insight in resolving this conundrum came from fly genetics and was the  realization that the egg is not a homogenous sack of protoplasm.  The maternally-derived genes  active in the fertilized egg are asymmetrically distributed such that at the first cell division each  daughter cell receives a different complement of factors.  Development continues as a",
+      "genes.  An altered gene may be passed on to every cell that develops from it.  The resulting features my help, harm, or have little or no effect on the offsprings success in its environment. (AAAS, pg. 109, 5B:9-12#4 ) 6. Heritable material: The information passed from parents to offspring is coded in DNA molecules (AAAS, pg 108, 5B:9-12#3) 7. Mutagens: Gene mutations can be caused by such things as radiation and chemicals.  When they occur in sex cells, the mutations can be passed onto offspring; if they",
+      "or father (sperm cell). Each gamete has a set of 23 unpaired chromosomes. Two human gametes (egg and sperm) combine  to create a cell (zygote) that contains the full human genome  of 23 paired chromosomes.Genetic Information Nondiscrimination Act (GINA) US federal legislation that makes it unlawful to discriminate  against individuals on the basis of their genetic profiles in regard to health insurance and employment. These protections  are intended to encourage Americans to take advantage of",
+      "spermatozoa: more than the sum of its parts? DNA, histones, pro - tamines and epigenetics. Reproduction 139:287301 Nilsson EE, Sadler-Riggleman I, Skinner MK (2018) Environmentally  induced epigenetic transgenerational inheritance of disease. Envi-ron Epigenet 4:dvy016Pembrey M, Saffery R, Bygren LO, Network in Epigenetic Epide-"
+    ],
+    [
+      "variation with cultural practices around lineage. In certain societies, individuals place greater importance on (and have greater knowledge about) one side of the family than another (unilineal descent). Thus, individuals in patrilineal groups trace relationships through males only so that your fathers brothers children are members of your family, but not your fathers sisters (Kottak, 2007 ). They are members of their husbands group or family. Efforts to create",
+      "maternal lineage membership with those who weredirectly genotyped. Based on these pedigree (matrilineal) relation-",
+      "in three-generation families, and read pair tracing DNMs with phased variants. In the former approach, we determined the parent of origin as in our previous  analysis4. For example, if an offspring of the proband was a carrier of the DNM  allele and had haplotype sharing to paternal chromosome of the proband, we  assigned the mutation to the father. Meanwhile, if the offspring was not a DNM  allele carrier, we would assign it to the maternal germline. We restricted the haplo -",
+      "Unlike the nuclear genome, which requires both paternal and maternal contributions, mtDNA is inherited solely from the maternal lineage. It is unclear what advantage a uniparental mtDNA transmission confers, but one possibil-ity is to minimize the number of distinct genomes to maxi-mize the efficiency of a multi-genomic system (Hill etal. 2019). In fact, humans have developed complex, redundant mechanisms to ensure uniparental inheritance of mtDNA (DeLuca and OFarrell 2012; Rojansky etal. 2016). Paternal",
+      "c) Mitochondrial DNA (maternal line testing) markers: mitochondrial DNA or mtDNA haploid is the maternally inherited mitochondrial genome (mtDNA) [ 44]. All children inherit mtDNA from their mother, with no admixture from the father. Like Y-line DNA, mtDNA is passed intact from one generation to the next but through maternal line. Mitochondrial DNA does not follow any surname. In fact, the surname changes in every generation when women marry. Polymorphisms of mtDNA",
+      "a family pedigree may be hampered if the participant is not familiar with her mothers relatives, but her mothers brothers children (her cousins) may be able to supplement her overall family history. Knowledge about the cultural system of unilineal descent avoids assuming the universality of bilateral descent. Cultural beliefs such as these also have implications in the conduct of genetic research in terms of confidentiality and autonomy (Benkendorf et al.,",
+      "225 three-generation families using haplotype sharing (Fig. 1c and  Methods), 80.4% were found to be of paternal origin (Extended Data  Fig. 1). Figure 1e shows a strong relationship between the number of  paternal DNMs and the fathers age at conception (1.47 per year, 95%  CI 1.341.59) and a weaker impact of the mothers age on the number  of maternal DNMs (0.37 per year, 95% CI 0.300.45). The parental origin of all DNMs was also assessed by read pair",
+      "sistent with a maternal imprinting effect in familiesfrom France [18], the USA[10, 18, 21] (Figure 2; Table3) and Canada [27]. However, in a large family dataset from the UK, and in smaller data sets fromDenmark and Sardinia, the transmission of VNTRsusceptibility alleles is more pronounced frommothersthanfromfathers,andnowsignicantlysoinUK families (Figure 2; Table 3). Comparison of theresults from the USAwith those from the UK suggestthat unexplained inter-population differences in thisparent-of-origin",
+      "started with the largest matrilineage and worked down the list. Theparticipants selected for mtDNA sequencing were selected inde-pendent of their cognitive or dementia status. 274 matrilineageswere represented by this dataset. As a result, the sequencedmitochondrial genomes also represent as many different majormitochondrial haplogroups and clusters as possible (Table 1).Selection was made blind to case-control status. 287 samples weresent to Family Tree DNA (www.familytreedna.com) for Sangersequencing of",
+      "genetics-based population divergence studies. Am J Phys Anthropol 128(2):415 423.22. Helgason A, Hrafnkelsson B, Gulcher JR, War d R, Stefnsson K (2003) A populationwide coalescent analysis of Icelandic matrilineal and patrilineal genealogies: Evidence for a faster evolutionary rate of mtDNA lineages than Y chromosomes. Am J Hum Genet 72(6): 1370 1388. 23. Amster G, Sella G (2015) Life history effects on the molecular clock of autosomes and sex chromosomes. Proc Natl Acad Sci USA 113(6):1588 1593."
+    ],
+    [
+      "the DNA, i.e. the whole genome. During replication the two strands of themother cell DNA are separated, and new nucleotides are put together to maketwo double helices identical to the original one, see Figure 2.1. TAAGACCG AT T CTGGCCCGTGGC. . . . . . .. . ATTCTGGCTAAGACCG. . . . . . . . Figure 2.1: A DNA chain consists of two strands of complementary nucleotides. When DNA is replicated, two double chains identical to the original one are created.",
+      "the DNA, i.e. the whole genome. During replication the two strands of themother cell DNA are separated, and new nucleotides are put together to maketwo double helices identical to the original one, see Figure 2.1. TAAGACCG AT T CTGGCCCGTGGC. . . . . . .. . ATTCTGGCTAAGACCG. . . . . . . . Figure 2.1: A DNA chain consists of two strands of complementary nucleotides. When DNA is replicated, two double chains identical to the original one are created.",
+      "The mechanism to maintain the rDNA copy number The gene amplication mechanism that counteracts recombination-mediated loss of rDNA copies is well studied in budding yeast [ 6,11]. During the S phase of the cell cycle, replication starts from replication origins, and isinhibited at the replication fork barrier site (RFB) by the function of the fork blocking protein, Fob1 (Fig. 3)[12]. This inhibition works as a recombinational hotspot toinduce amplication for copy number recovery as follow;",
+      "S and G2 when the DNA is replicated, providing a pristine secondcopy of the sequence (sister chromatid) for aligning the breaks. Incontrast, the less-accurate end joining is most relevant in the G1phase of the cell cycle, when a second copy is not available 14.  Finally, some single repair proteins directly revert certain injuries, such as O6-methylguanine methyltransferase, which removes  O6-methyl guanine. This highly mutagenic lesion permits base",
+      "Replication",
+      "genotoxic agents and to guarantee faithfulchromosome duplication and transmission to the offspring. In addition to DNA damage repair, cells monitor replication to minimize er-rors of DNA synthesis. In eukaryotes, cell-cycle checkpoints guarantee coordination of DNA synthesis and DNA repair with cell division.Genome instability is mainly due to sporadic replication or repair errors but can also take place in response to developmental or environ-mental signals, as occurs in meiosis, and antigen",
+      "This section will explain how cells normally divide. It will also desc ribe how an unexpected change in  the structure of DNA can sometimes cause harm to th e body. New tools to study genetic variations of  common diseases and to identify genetic variatio ns common to specific diseases will also be  presented.  Cell Division   Humans grow and develop as a result of a process called cell  division. There are two types of cell division  mitosis and meiosis.",
+      "and replicated (by a templating mechanism).  Each DNA molecule in a cell forms a single chromosome. (NRC, pg. 185, 9-12:C2#1) 4. Genes as information for building proteins: The genetic information in DNA molecules provide the instructions on assembling protein molecules. The code is virtually the same for all life forms. (AAAS, pg. 114, 5C:9-12#4 ) 5. Molecular nature of genes and mutations: Genes are segments of DNA molecules.  Inserting, deleting, or substituting DNA segments can alter genes.  An altered",
+      "When a replication fork encounters a DNA adduct, cells induce DNA damage toler-ance mechanisms that allow completion of replication. Adducts can be bypassed by postreplicative repair via translesion poly-merases (either faithful or error-prone) or via error-free template switching using the sister chromatid (64, 105). Postreplicativerepair guarantees genome stability by allowing completion of replication (albeit at the expense",
+      "genome instability in part because of the unique structureof replicating DNA molecules (Figure 2). When single-strand lesions occur in non-replicating molecules of DNA,the overall integrity of chromosomes is maintained byhydrogen bond base pairing on either side of these lesionsuntil they are repaired (Figure 2A). In contrast to non-replicating DNA, replicating DNA at replication forkscontains unwound, highly recombinogenic single-strandedtemplate DNA before this DNA is converted to double-strand DNA by"
+    ],
+    [
+      "neered nucleases, CRISPR-Cas9  tools have accelerated the pace of  genomic research by permitting  highly efficient knockouts or  edits of virtually any gene in cells  or model organisms. Multiple CRISPR-Cas9based clinical trials  are in progress or are expected  to begin soon. Although Cas9- engineered cells havent yet dem - onstrated efficacy at scale, early  trial results suggest that such  cells are stable and dont cause  acute adverse reactions in humans.  Long-term safety is yet to be de -",
+      "stageissetforCRISPRtomakeanenormousimpactongenomic screening and thus scientic discovery in the coming years, and recent demonstrations of this system have shown great promise (Shalem etal., 2015 ).However,a number of technical challenges must be addressed in order to maximize the benet of this technology. In this review, we will discuss current applications of CRISPR in functional genomics and provide a perspective on futuredevelopmentsinthisarea. CRISPR/Cas9 Genome Editing",
+      "heralding the age of genome editing. Furthermore, Cas9 or guide RNAs have been linked to various effector proteins to enable targeted gene regulation 12,13 and epigenome modifications14,15.  It is worth noting, however, that many of these feats had been demonstrated previously using other nucleases or DNA-binding proteins 1,16. In this Perspective, I shed light on early genome  editing platforms that laid the groundwork for the widespread use of CRISPRCas9 in research and medicine (Fig. 1 ).",
+      "cline- or Tet-regulated Cas9 system. Current CRISPR/Cas systems arefrom Streptococcus pyogenes ,Streptococcus thermophilus ,Neisseria meningitides and Treponema denticola .2.5. Caveats of advanced genome editing tools Off-target effects . The DNA-binding domains of ZFNs and TALENs need to be very speci c for the target site to avoid off-target cleavage, which results in unwanted mutations and potentially cytotoxic effects [27]. CRISPR/Cas9 is also known to generate off-target alterations,",
+      "CRISPR/CAS9 HOLDS SIGNIFICANT PROMISE FOR THE DEVELOPMENT OFNEW AD MODELS AND PRECISIONTARGETED AD THERAPY Clustered regularly interspaced short palindromic repeat (CRISPR)-Cas nucleases have revolutionizedthe eld of gene editing and have tremendous appli-cation in the eld of molecular medicine [98102].Despite a signicant surge in CRISPR/Cas9-mediated genome editing in various disease models,the progress in the eld of AD has lagged behindsubstantially. We believe that genome editing can sig-",
+      "81. Applications for CRISPRCas9 beyond genome editing",
+      "CRISPR-Cas9 can be used to in - duce genome edits by creating  targeted DNA breaks that trigger  site-specific DNA repair. In next- generation formats, it can also  control the transcriptional output  of genes or alter genome se - quences using a process of nu - cleotide base editing  that does not require  repair of DNA breaks.  As these technolo - gies continue to mature, it will  become increasingly possible to  alter cellular genomes efficiently  and accurately. Coming on the heels of engi -",
+      "on transcriptional interfere nce (CRISPRi) and activation (CRISPRa) have also harnessed Cas9-based technologies for use in genome-wide studies ( 59,174). In addition, recent improvements in lentiviral library generation and propagation,as well as large-scale DNA and RNA synthesis, have allowedCRISPR-Cas9 technology to be exploited across multiple modelplatforms ( 59,175178). nCas9 The CRISPR-Cas9 system can tolerate certain mismatches to the DNA target since the required gRNAs are short. A disadvantage,",
+      "13. Kleinstiver BP, etal. High-fidelity CRISPRCas9 nucleases with no detectable genome-wide  off-target effects. Nature. 2016;529:4905.  14. Brane A, Tollefsbol T.Targeting telomeres and telomerase: studies in aging and disease uti- lizing CRISPR/Cas9 technology. Cells. 2019;8:186.  15. Wang H, etal. One-step generation of mice carrying mutations in multiple genes by CRISPR/ Cas-mediated genome engineering. Cell. 2013;153:9108.",
+      "Since its discovery, CRISPR-Cas technology has ignited a biological revolu- tion by providing a highly versatile platform that allows fast and efficient genome  editing in an ever-growing list of organisms. In this chapter we will first describe  the most recent advances in the development and application of the CRISPR-Cas  platform in biomedical research. Then we will discuss the most recent and notable  basic research applications of this technology in the study of the molecular causes"
+    ],
+    [
+      "While most of the Y chromosome does not undergo recombination, the recombination rate of the X chromosomeis slower than that of the autosomes. This has important consequences on the detection of significant QTLs. For a comprehensive view of these issues, see(43). 9.Probe hybridization artifacts When several probes are available for the same gene, it is not uncommon to observe a difference in the mapping results",
+      "8 QTL Mapping     Allelic variation exists among natural populations and inbred strains, and this is  reflective of the segregation of quantitative tr ait loci (QTLs) [96]. QTLs are stretches of  DNA that are closely linked to genes that underlie a phenotype of interest. QTL analysis has been proven to be an invaluable tool to  help unravel heritable traits, by enabling  researchers to map different quantitative traits back to the genomic location involved in the regulation of these phenotypes.",
+      "8 QTL Mapping     Allelic variation exists among natural populations and inbred strains, and this is  reflective of the segregation of quantitative tr ait loci (QTLs) [96]. QTLs are stretches of  DNA that are closely linked to genes that underlie a phenotype of interest. QTL analysis has been proven to be an invaluable tool to  help unravel heritable traits, by enabling  researchers to map different quantitative traits back to the genomic location involved in the regulation of these phenotypes.",
+      "The basic  pr emise  of QTL  an alysis  is simple  (Ph illips  and Belknap, 2002 ) . First,  one must  meas  ure a speci  c phen  otype  within  a popul  ation. Next, the population must be genotyped at a hundred or more marker loci186 Boehm II et al.",
+      "genes underlying QTLs in animals and plants (see for example Shirley et al 2004,Korstanje & Paigen 2002, Fridman et al 2004). I should also point out, though, that even in a single QTL region isolated in a congenic strain, it is possible that there is more than one allele that aects the phenotype. So, you have a fair pointabout the challenges and complexities of QTL analysis. Koolhaas: There are dierent questions underlying both approaches. The QTL",
+      "genes underlying QTLs in animals and plants (see for example Shirley et al 2004,Korstanje & Paigen 2002, Fridman et al 2004). I should also point out, though, that even in a single QTL region isolated in a congenic strain, it is possible that there is more than one allele that aects the phenotype. So, you have a fair pointabout the challenges and complexities of QTL analysis. Koolhaas: There are dierent questions underlying both approaches. The QTL",
+      "through analysis of line crosses, quantitative trait loci (QTL) mapping, and verification of candidate genes with quantitative complementation tests or genetic engineering (e.g.,McGuire and Tully 1987; Chandra et al. 2001; Dierick and Greenspan 2006; Edwardset al. 2006). They can also be used to study the underlying physiological, neural, andmolecular mechanisms of the differences in behavior between selected and controllines, or between divergently selected lines.",
+      "through analysis of line crosses, quantitative trait loci (QTL) mapping, and verification of candidate genes with quantitative complementation tests or genetic engineering (e.g.,McGuire and Tully 1987; Chandra et al. 2001; Dierick and Greenspan 2006; Edwardset al. 2006). They can also be used to study the underlying physiological, neural, andmolecular mechanisms of the differences in behavior between selected and controllines, or between divergently selected lines.",
+      "genetic background. Gene identification of QTL should be distinguished from identification of the quanti- tative trait nucleotide (QTN). The latter is a daunting task, since SNPs are so frequent. Final proof for a QTN in mice would require placing a genomic segment containing theputative QTN from a donor mouse strain on the background of another strain using homologous recombination and reproducing the phenotype of the donor strain.",
+      "measuring correlations between genetic markers and phenotypic  traits in a population. Individuals are scored for their  phenotype      for  a particular trait, and their genotype at a marker. If there is a differ- ence in mean phenotype between those individuals with one geno- type at a particular locus compared with the other, than we can infer  that there is a QTL linked to that marker [ 40 ,  153 ]. 2.3  Analysis and QTL  MappingDavid G. Ashbrook and Reinmar Hager"
+    ],
+    [
+      "for people to exchange data easily over the Web. Two other notable developments are BioMart and GBrowse. The BioMart project (http://www.biomart.org/), originally a spin-off from Ensembl, offers a generic data management system that allows complex searches of biological data such as sequence annotation. The GBrowse project (Stein et al. , 2002; http://www.gmod.org/) has produced a generic genome browser that can be customized to organize, display and query a new genome scale data set. These",
+      "for people to exchange data easily over the Web. Two other notable developments are BioMart and GBrowse. The BioMart project (http://www.biomart.org/), originally a spin-off from Ensembl, offers a generic data management system that allows complex searches of biological data such as sequence annotation. The GBrowse project (Stein et al. , 2002; http://www.gmod.org/) has produced a generic genome browser that can be customized to organize, display and query a new genome scale data set. These",
+      "for people to exchange data easily over the Web. Two other notable developments are BioMart and GBrowse. The BioMart project (http://www.biomart.org/), originally a spin-off from Ensembl, offers a generic data management system that allows complex searches of biological data such as sequence annotation. The GBrowse project (Stein et al. , 2002; http://www.gmod.org/) has produced a generic genome browser that can be customized to organize, display and query a new genome scale data set. These",
+      "(http://ensembl.org/ ) and the National Center for Biotechnology Information (NCBI) (http://www.ncbi.nlm.nih.gov/ ) all provide portals to the most current, and archived public assemblies. These sites also provide means of searching the assem- blies, such as BLAST (Altschul et al. , 1997), BLAT (Kent, 2002) and SSAHA (Ning et al. , 2001) as well as precomputed annotation for the genome assemblies that can be readily incorporated into comparative genomic analyses.",
+      "(http://ensembl.org/ ) and the National Center for Biotechnology Information (NCBI) (http://www.ncbi.nlm.nih.gov/ ) all provide portals to the most current, and archived public assemblies. These sites also provide means of searching the assem- blies, such as BLAST (Altschul et al. , 1997), BLAT (Kent, 2002) and SSAHA (Ning et al. , 2001) as well as precomputed annotation for the genome assemblies that can be readily incorporated into comparative genomic analyses.",
+      "(http://ensembl.org/ ) and the National Center for Biotechnology Information (NCBI) (http://www.ncbi.nlm.nih.gov/ ) all provide portals to the most current, and archived public assemblies. These sites also provide means of searching the assem- blies, such as BLAST (Altschul et al. , 1997), BLAT (Kent, 2002) and SSAHA (Ning et al. , 2001) as well as precomputed annotation for the genome assemblies that can be readily incorporated into comparative genomic analyses.",
+      "resources. We present an easy-to-adopt module that weaves together several important bioin-formatic tools so students can grasp how these tools are used in answering research questions.Students integrate information gathered from websites dealing with anatomy (Mouse BrainLibrary), quantitative trait locus analysis (WebQTL from GeneNetwork), bioinformatics and geneexpression analyses (University of California, Santa Cruz Genome Browser, National Center forBiotechnology Informations Entrez Gene, and the",
+      "References Altman RB. Building successful biological databases. Briefings in Bioinformatics. 2004; 5:45.  [PubMed: 15153301]  Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, et al. Gene ontology: Tool for the  unification of biology. The Gene Ontology Consortium. Nature Genetics. 2000; 25:2529.  [PubMed: 10802651]  Ashish N, Ambite JL, Muslea M, Turner JA. Neuroscience data integration through mediation: an",
+      "Sequences, Protein Structures, Complete Genomes, Tax- onomy, Medical Genetics resources (see later), and others (see   http://www.ncbi.nlm.nih.gov/Database/index.html     for a complete listing of databases).  Entrez   PubMed provides  access to full-text articles at journal websites and other related web resources, some of which are free to the  public. This site also provides links to other molecular biology resources.      The National Center for Biotechnology Information (  http://",
+      "Sequences, Protein Structures, Complete Genomes, Tax- onomy, Medical Genetics resources (see later), and others (see   http://www.ncbi.nlm.nih.gov/Database/index.html     for a complete listing of databases).  Entrez   PubMed provides  access to full-text articles at journal websites and other related web resources, some of which are free to the  public. This site also provides links to other molecular biology resources.      The National Center for Biotechnology Information (  http://"
+    ],
+    [
+      "supported by a signicant BLAST match to one or more expressed sequences or proteins. Ensembl also identies the positions of known human genes from public sequence database entries, usually using GENEWISE to predict their exon structures. The total set of Ensembl genes should therefore be a much more accurate reection of reality than ab initio predictions alone, but it is clear that some novel genes are missed (Hogenesch et al. , 2001). Of the many novel genes that are detected, some are",
+      "supported by a signicant BLAST match to one or more expressed sequences or proteins. Ensembl also identies the positions of known human genes from public sequence database entries, usually using GENEWISE to predict their exon structures. The total set of Ensembl genes should therefore be a much more accurate reection of reality than ab initio predictions alone, but it is clear that some novel genes are missed (Hogenesch et al. , 2001). Of the many novel genes that are detected, some are",
+      "supported by a signicant BLAST match to one or more expressed sequences or proteins. Ensembl also identies the positions of known human genes from public sequence database entries, usually using GENEWISE to predict their exon structures. The total set of Ensembl genes should therefore be a much more accurate reection of reality than ab initio predictions alone, but it is clear that some novel genes are missed (Hogenesch et al. , 2001). Of the many novel genes that are detected, some are",
+      "Ostell/Spidey/ SSAHA at Sanger Institute http://www.sanger.ac.uk/Software/analysis/SSAHA/ human and mouse genomes, where there are large full-length cDNA collections to guide the hunt for genes, Ensembl should be very reliable. From the beginning, many genomic features other than predicted genes were included in Ensembl: different repeat classes, cytological bands, CpG island predic- tions, tRNA gene predictions, expressed sequence clusters from the UniGene database",
+      "Ostell/Spidey/ SSAHA at Sanger Institute http://www.sanger.ac.uk/Software/analysis/SSAHA/ human and mouse genomes, where there are large full-length cDNA collections to guide the hunt for genes, Ensembl should be very reliable. From the beginning, many genomic features other than predicted genes were included in Ensembl: different repeat classes, cytological bands, CpG island predic- tions, tRNA gene predictions, expressed sequence clusters from the UniGene database",
+      "Ostell/Spidey/ SSAHA at Sanger Institute http://www.sanger.ac.uk/Software/analysis/SSAHA/ human and mouse genomes, where there are large full-length cDNA collections to guide the hunt for genes, Ensembl should be very reliable. From the beginning, many genomic features other than predicted genes were included in Ensembl: different repeat classes, cytological bands, CpG island predic- tions, tRNA gene predictions, expressed sequence clusters from the UniGene database",
+      "database, which aims to compile a non-redundant, curated data set representing current knowledge of known genes (Wheeler et al. , 2002; http://www.ncbi.nlm.nih. gov/entrez/query.fcgi?db=gene). Like the Ensembl protocol, many Acembly- predicted structures (the NCBI estimate 42 per cent) are incomplete. These struc- tures can be displayed alongside ab initio gene models, Ensembl-predicted genes, and matching UniGene clusters to allow users to make their own conclusions about the likeliest gene structure.",
+      "database, which aims to compile a non-redundant, curated data set representing current knowledge of known genes (Wheeler et al. , 2002; http://www.ncbi.nlm.nih. gov/entrez/query.fcgi?db=gene). Like the Ensembl protocol, many Acembly- predicted structures (the NCBI estimate 42 per cent) are incomplete. These struc- tures can be displayed alongside ab initio gene models, Ensembl-predicted genes, and matching UniGene clusters to allow users to make their own conclusions about the likeliest gene structure.",
+      "database, which aims to compile a non-redundant, curated data set representing current knowledge of known genes (Wheeler et al. , 2002; http://www.ncbi.nlm.nih. gov/entrez/query.fcgi?db=gene). Like the Ensembl protocol, many Acembly- predicted structures (the NCBI estimate 42 per cent) are incomplete. These struc- tures can be displayed alongside ab initio gene models, Ensembl-predicted genes, and matching UniGene clusters to allow users to make their own conclusions about the likeliest gene structure.",
+      "populations as Ensembl reects the progress of the International Haplotype Map Project (Thorisson et al. , 2005). More speculative data, such as GENSCAN-predicted exons that have not been incorporated into Ensembl-conrmed genes, may also be viewed. This means that the display can be used as a workbench for the user to develop personalized an- notation. For example, one may discover novel exons by nding GENSCAN exon predictions which coincide with good matches to a fragment of the draft mouse"
+    ],
+    [
+      "traditional QTL mapping and GWASsapproaches can benefit from systems-biological approaches by filling in criticalinformation about the molecular phenotypes that stand between DNAvariation and complex disease (figure5). The incorporation of data fromhigh-throughput molecular profilingtechnologies, such as gene expressionmicroarrays, can better define a diseaseby identifying groups of genes thatrespond to or covary with disease-associated traits. Network analysis ofdisease-associated genes allows",
+      "knowledge of the true QTL location (Doss et al. 2005 ), which can be used to empirically estimate the power of aGWAS performed at a similar scale (Hao et al. 2008 ; Schadt et al. 2008 ). A GWAS on its own does little more than establish correlations between changes in DNA at agiven locus and changes in a disease trait of interest, with respect to populations of interest. Further, these studies on",
+      "genotypes. Since association studies allow for a mu ch finer mapping of the QTL  than that obtained with linkage analysis, there is a trade-off to consider between  power and resolution when choosing the mapping stra tegy. Genome-wide associa-  tion studies (GWAS) have naturally been used to per form genetical genomics  studies in humans [18, 24-27] and are emerging in m odel organisms studies using  outbred populations [28].   8.2.2  Combining studies",
+      "genetically also mapped to the same genomic location. In order to locate the positions of genes that are responsible for a certain trait, GWAS can be conducted. GWAS is a quan- titative approach to analyze the association of whole genome DNA polymorphisms and a phe- notypic trait, thereby localizing the genes un- derlining the trait. Genome-Wide Association Studies (GWAS) GWAS is a holistic whole-genome approach to robustly determine the association of DNA polymorphisms with correlated phenotypic",
+      "(PHMs) use principles of MR embedded within a Bayesian hierarchical model to detect interac-tions between regulatory elements [ 98]. Furthermore, GWAS is often integrated with the QTL analysis despite the fact that many GWAS loci are not strong eQTL loci [ 56]. GWAS-eQTL colocalization methods, including RTC [ 145], QTLMacth [ 158], Sherlock [ 159], and coloc [ 160], are based on the concept that disease-",
+      "association studies (GWAS) or linkage studies (Enoch 2013). QTL mapping studies historically had very low resolution,and many have been performed using populations for whichlimited genetic data exist. Publications of gene expressionstudies typically highlight a few interesting gene centered results, but the bulk of information is rejected due to concern",
+      "pairs that include many genes within the seg- ment. On the other hand, GWAS may point to several or even many genomic locations for the trait of interest, complicating further functional analysis. Analysis of Quantitative Trait Loci (QTL) QTL analysis reveals statistically signicant linkage between phenotypes and genotypes, thereby providing explanation for the genetic basis of variation in complex traits (Falconer and Mackay, 1996; Lynch and Walsh, 1998). In a sense, QTL analysis can be viewed as incom-",
+      "QTL mapping QTL mapping using GeneNetwork has been described in detail elsewhere ( Mulligan et al., 2017 ). However, in brief, quantitative trait loci (QTLs) are segments of the genome affecting a particular phenotype ( Falconer and Mackay, 1996 ). QTL mapping, identifying",
+      "3. Genetic Mapping Methods Several statistical approaches have been developed for genome-wide linkage analysis of  traditional phenotypes. The same approaches can be used to map eQTLs. These approaches  range from single marker tests ( t-test, ANOVA, and simple regression analysis) to multiple  locus mapping methods. The only major difference is that eQTL studies involve tens of  thousands of expression traits and require fast algorithms. Since an eQTL study tests for",
+      "plete GWAS analysis with limited number of markers that does not cover the entire genome. As such, if one or few QTLs are found, there may be more QTLs in the genome to be dis- covered. More importantly, in the absence of closely linked markers in the genomic regions containing signicant QTLs for the trait, the most signicant genes responsible for the trait can be missed. However, because of historical reasons such as the lack of genome-wide mark- ers, or the lack of funding, QTL analysis is still"
+    ],
+    [
+      "candidate genes. These candidate genes must then betested for a causal link to the phenotype. A good starting point would be sequencing the cDNA of strong candidate genes to identify amino acid polymorphisms and testingfor mRNA and protein expression differences in target tissues of the original strains used to detect the QTL. Sequencing and expression studies will rene the list ofcandidate genes that can then be tested rigorously for proof of cause and effect. The nal proof of a causal gene",
+      "candidate genes. These candidate genes must then betested for a causal link to the phenotype. A good starting point would be sequencing the cDNA of strong candidate genes to identify amino acid polymorphisms and testingfor mRNA and protein expression differences in target tissues of the original strains used to detect the QTL. Sequencing and expression studies will rene the list ofcandidate genes that can then be tested rigorously for proof of cause and effect. The nal proof of a causal gene",
+      "do you identify the responsible gene within a QTL that you have identified?  Generally, one starts by performing a strain survey to find two parental inbred  strains that have a markedly different trait. One can now look up many different  traits of inbred mice online at the Mouse Phenome Database ( http://phenome. jax.org/pub-cgi/phenome/mpdcgi?rtn=docs/home ). However, the trait you may  want to study may not be present in wild type mice, so you may want to cross",
+      "used to test the hypothesis at locus-specific sig-nificance (LRS 12). In doing so, an additional 7 cQTLs are observed as consistent in both diets(Fig. 2I, red number). Solving QTLs: Finding the quantitative trait gene For cis-QTLs, the causal factors can be quickly identified: With few exceptions, they will be driv-en by variants within the gene itself or imme-diately adjacent. For trans-QTLs, mQTLs, and cQTLs, the identification of the causal quanti-",
+      "data is to find a quantitative trait locus, or QTL. A QTL  (http://gn1.genenetwork.org/glossary.html#Q ) is an area on a chromosome that can contain  one or many genes, that is linked to a change in phenotype. After a  QTL that is responsible for  the apparent variation  in phenotype  has been identified , one can  start stu dying the  genes  within that locus  to identify  the likely causal gene .     Once the data  is normalized appropriately  (in our case, no normalization was required) , the QTL",
+      "candidate genes that are expressed in tissues likely to inuence the traits of interest(Su et al 2004). These candidate genes are then sequenced in the two parental inbred strains looking for sequence dierences in coding or regulatory regions. After ne mapping the QTL interval and shortening the list of plausible candidate polymorphisms, the major challenge remains /C246 proving denitively which nucleotide polymorphism underlies the QTL. The most direct proof",
+      "because these strains have been genotyped at more than 14,000 markers, including single nucleotide polymorphisms (SNP). Hundreds of genes may lie within a QTL interval, so identifying the underlying genes requires complementary methods. One method is to use BXD gene expression data (a public resource at www.genenetwork.org) to screen for genes within the QTL interval whose expression correlates with the trait of interest [23].",
+      "candidate genes that are expressed in tissues likely to inuence the traits of interest(Su et al 2004). These candidate genes are then sequenced in the two parental inbred strains looking for sequence dierences in coding or regulatory regions. After ne mapping the QTL interval and shortening the list of plausible candidate polymorphisms, the major challenge remains /C246 proving denitively which nucleotide polymorphism underlies the QTL. The most direct proof",
+      "curate approaches to identify various types of QTL according to their molecular features, in par- ticular to control various confounding factors, such as dietary habit and population structure. Fine Mapping of Causal Variants and Causal Genes Despite the identi cation of large numbers of QTLs, it remains challenging to establish causal",
+      "to date, only a small handful of genes have been definitively identified for complex traits.  Our own efforts to identify a causal gene were stymied by the compound nature of QTLs  and the high gene density  in Qrr1 , and in Vol8a . Furthermore, it is now becoming clear  that in addition to the canonical candidate genes, there are multiple spliced variants,  microRNAs, and epigenetic factors to be considered.     With what appears to be an increasingly complex genom ic landscape, it is now all"
+    ],
+    [
+      "that accounts for the significant difference. One explanationis a contribution of the Y chromosome from the B strain. Sincethe cross was non-reciprocal all F2 mice carried the B strain Ychromosome. Thus, males carrying Chr X B QTL alleles andthe B Y chromosome differ in two ways from females carry-ing Chr X A alleles (or AB but B alleles are recessive) and noY chromosome, but in only one way from males carrying ChrX A/J QTL alleles because they share the B Y chromosome.However, pursuit of the identity of",
+      "women comprises 2 X chromosomes and in men 1 X and 1 Y chromosome (Figure 2). For each chromosome pair, 1 chro- mosome was inherited from the mother and 1 from the father. The full set of chromosomes is collectively called the genome.  The human genome is largely contained within the nucleus  of each cell, where it is separated from the rest of the cell functions. However, a small amount of DNA exists outside  the nucleus in the mitochondria and is considered to be part of  the human genome.",
+      "betweenmalesandfemalesisthesexchromosomes.MaleshaveanXYgenotypeand femaleshaveanXXgenotype.TheXisamuchlargerchromosome,165.5x106bpsvs. 16.0x106bps,withapproximately30timesmoregenesthantheYchromosome.To compensateforthelargernumberofgenes,andtoensurefemalesdonothaveover expressionofgenesresidingontheXchromosome,oneoftheXchromosomesis inactivated(7).TheXinactivationoccursearlyindevelopmentandisarandomprocess. Onlyasmallportionoftheinactivatedchromosomeretainstranscriptionalability.This",
+      "mammals. Instead of a dominant gene for maleness on the Y chromosome, it is the ratioof X chromosomes to autosomes that determines gender. The 2:2 ratio of XX femalesand the 1:2 ratio in XY males produce different ratios of regulatory proteins encoded byX-linked and autosomal genes. Those regulatory genes in turn cause transcripts of theregulatory Sex-lethal (Sxl) gene to be spliced differently in males and females, which be-",
+      "mammals. Instead of a dominant gene for maleness on the Y chromosome, it is the ratioof X chromosomes to autosomes that determines gender. The 2:2 ratio of XX femalesand the 1:2 ratio in XY males produce different ratios of regulatory proteins encoded byX-linked and autosomal genes. Those regulatory genes in turn cause transcripts of theregulatory Sex-lethal (Sxl) gene to be spliced differently in males and females, which be-",
+      "gins the process of sexual differentiation. A fly with two X chromosomes can thereforecarry a Y and still be a fertile female, leading to a paradoxical sex chromosome system inwhich males inherit X chromosomes from their fathers (figure 16.13).  Rice and Chippindale (2001) used a combination of these genetic techniques to test",
+      "gins the process of sexual differentiation. A fly with two X chromosomes can thereforecarry a Y and still be a fertile female, leading to a paradoxical sex chromosome system inwhich males inherit X chromosomes from their fathers (figure 16.13).  Rice and Chippindale (2001) used a combination of these genetic techniques to test",
+      "ity on the X chromosome compared to the other five strains(Figure 2B ). Compared to females, males had a deficiency of heterozygous X-linked SNP loci ( Supplementary Figure S2 ), which was expected because males are hemizygous. The resid-ual X-linked heterozygous SNPs in males could be due to mis-assembled autosomal contigs on the X chromosome, multiplecopies on the X, or homology between X and autosomalsequences. Chromosome XAutosomesProportion of SNP lociHomozygous SNPs Heterozygous SNPs",
+      "sex chromosome   Y chromosome:  One of the two sex chromosomes, X and Y. See also; X chromosome,  sex chromosome",
+      "one Y chromosome. Human chromosomes are typically displayed pictorially in a karyotype, as shown in Figure 9, arranged according to length and position of the centromere (i.e., the most con-stricted area of a chromosome). The ends of the chromosomesare called telomeres. Most human karyotypes look identicalbecause they are constructed from cells arrested in the phaseof the cell cycle when chromosomes are most condensed. During this phase of the cell cyc le, allelic differences cannot be detected."
+    ],
+    [
+      "While most of the Y chromosome does not undergo recombination, the recombination rate of the X chromosomeis slower than that of the autosomes. This has important consequences on the detection of significant QTLs. For a comprehensive view of these issues, see(43). 9.Probe hybridization artifacts When several probes are available for the same gene, it is not uncommon to observe a difference in the mapping results",
+      "8 QTL Mapping     Allelic variation exists among natural populations and inbred strains, and this is  reflective of the segregation of quantitative tr ait loci (QTLs) [96]. QTLs are stretches of  DNA that are closely linked to genes that underlie a phenotype of interest. QTL analysis has been proven to be an invaluable tool to  help unravel heritable traits, by enabling  researchers to map different quantitative traits back to the genomic location involved in the regulation of these phenotypes.",
+      "8 QTL Mapping     Allelic variation exists among natural populations and inbred strains, and this is  reflective of the segregation of quantitative tr ait loci (QTLs) [96]. QTLs are stretches of  DNA that are closely linked to genes that underlie a phenotype of interest. QTL analysis has been proven to be an invaluable tool to  help unravel heritable traits, by enabling  researchers to map different quantitative traits back to the genomic location involved in the regulation of these phenotypes.",
+      "genetic background. Gene identification of QTL should be distinguished from identification of the quanti- tative trait nucleotide (QTN). The latter is a daunting task, since SNPs are so frequent. Final proof for a QTN in mice would require placing a genomic segment containing theputative QTN from a donor mouse strain on the background of another strain using homologous recombination and reproducing the phenotype of the donor strain.",
+      "The basic  pr emise  of QTL  an alysis  is simple  (Ph illips  and Belknap, 2002 ) . First,  one must  meas  ure a speci  c phen  otype  within  a popul  ation. Next, the population must be genotyped at a hundred or more marker loci186 Boehm II et al.",
+      "verify the difference, and the data were then ana-lyzed by the QTL detection method of Belknap et al.(1997) based on allele frequency differences betweenthe two lines. When a difference was confirmed,individual genotypes and individual behavioral re-sponses to MA were used to estimate the position ofthe bQTL using the interval mapping methods as implemented in R/qtl (Broman et al. 2003). The lat-",
+      "X axis depicts 19 autosomes and X chromoso me. The Y axis is the likelihood ratio statistic from a single QTL model. Two  QTLs, on chromosomes 1 and 11, are significant at a mu ltiple test corrected permut ation threshold as shown. Chromosome 1 and 11 likeli hood ratio statistic plots Figure 2 Chromosome 1 and 11 likelih ood ratio statistic plots . Interval mapping plots of chromosomes 1 and 11, showing more  detail of Figure 1. 2 LOD support inte rvals are shown in Mb on the X axis.",
+      "genes underlying QTLs in animals and plants (see for example Shirley et al 2004,Korstanje & Paigen 2002, Fridman et al 2004). I should also point out, though, that even in a single QTL region isolated in a congenic strain, it is possible that there is more than one allele that aects the phenotype. So, you have a fair pointabout the challenges and complexities of QTL analysis. Koolhaas: There are dierent questions underlying both approaches. The QTL",
+      "genes underlying QTLs in animals and plants (see for example Shirley et al 2004,Korstanje & Paigen 2002, Fridman et al 2004). I should also point out, though, that even in a single QTL region isolated in a congenic strain, it is possible that there is more than one allele that aects the phenotype. So, you have a fair pointabout the challenges and complexities of QTL analysis. Koolhaas: There are dierent questions underlying both approaches. The QTL",
+      "model at the QTL assumes that the original lines arexed for different alleles although genes can besegregating elsewhere. Hence, it is possible to combineinformation about the QTL across families. The assumption of xation at the QTL can be tested by"
+    ],
+    [
+      "phenomena such as mutations and gene conversion events) occur in relevant meioses  leading up to the formation of the gametes (i.e., egg and sperm) which are combined  during fertilization and the formation of zygotes. Thus, individuals inherit a patch- work of chromosomal segments from maternal and paternal chromosomes.",
+      "the egg and the sperm. Such a process would result in genetic changes that will be copied into every cell of the future adult, including reproductive cells (Stock & Campbell, 2000), opening the door to irreversibly alter the human species. Inevitably, signifi  cant self-disclosure and discussion challenges await families",
+      "a fertilized egg is a complicated process that relies on controlling: which genes are active; whenthese genes activate; and for how long they are active. In broad terms, there are four ways that thiscontrol can be achieved: First, inside the sperm or egg, genes can be marked with small chemical tags that flag these genes",
+      "to be activated (or remain inactive) after fertilization, depending on whether the modification wasmade by the father (in the sperm) or the mother (in the egg); this process is known as imprinting. Second, the mother can alter the gene activity in her offspring via the placenta; this process is known as maternal effect. Third, instructions encoded within the embryos DNA can directly control if, andwhen, a nearby gene becomes activated; this is known as  cis-regulation. Finally, similar instructions",
+      "(Figures 8 and 9). Two gametes (egg and sperm) ultimately  join into a single cell, the zygote, which has the full comple-ment of 23 chromosome pairs restored. If all goes well, the zygote gives rise to a live offspring. The Mendel Laws: Segregation and Independent  Assortment Both of the Mendel laws pertain directly to the process of  meiosis. The first Mendel law, the law of segregation, states  that each parent passes a randomly selected allele for a given",
+      "the subset of that genetic information that is active.  But how does the differentiation process  begin?  The key insight in resolving this conundrum came from fly genetics and was the  realization that the egg is not a homogenous sack of protoplasm.  The maternally-derived genes  active in the fertilized egg are asymmetrically distributed such that at the first cell division each  daughter cell receives a different complement of factors.  Development continues as a",
+      "sex chromosome effects. (B)Soon after fertilization, male and female cells have sex-specic transcriptomes, epigenomes, and phenotypes (for example, male embryos grow faster than female embryos). At implantation, lineage determination begins and gene expression differences are reduced. Epigenetic marks, however, are less constrained and some are maintained, affecting gene expression, and phenotype later in development. Once specic lineages are established, differences in",
+      "genes.  An altered gene may be passed on to every cell that develops from it.  The resulting features my help, harm, or have little or no effect on the offsprings success in its environment. (AAAS, pg. 109, 5B:9-12#4 ) 6. Heritable material: The information passed from parents to offspring is coded in DNA molecules (AAAS, pg 108, 5B:9-12#3) 7. Mutagens: Gene mutations can be caused by such things as radiation and chemicals.  When they occur in sex cells, the mutations can be passed onto offspring; if they",
+      "or father (sperm cell). Each gamete has a set of 23 unpaired chromosomes. Two human gametes (egg and sperm) combine  to create a cell (zygote) that contains the full human genome  of 23 paired chromosomes.Genetic Information Nondiscrimination Act (GINA) US federal legislation that makes it unlawful to discriminate  against individuals on the basis of their genetic profiles in regard to health insurance and employment. These protections  are intended to encourage Americans to take advantage of",
+      "spermatozoa: more than the sum of its parts? DNA, histones, pro - tamines and epigenetics. Reproduction 139:287301 Nilsson EE, Sadler-Riggleman I, Skinner MK (2018) Environmentally  induced epigenetic transgenerational inheritance of disease. Envi-ron Epigenet 4:dvy016Pembrey M, Saffery R, Bygren LO, Network in Epigenetic Epide-"
+    ],
+    [
+      "GeneNetwork have reinvigorated it, including the addition  of data from  10 species, multi -omics  analysis, updated code, and new tools. The new GeneNetwork is now an exciting resource for  predictive medicine and systems genetics, which is constantly being maintained and improved.    Here, we give a brief overview of the process  for carrying out some of the most common  functions on GeneNetwork, as a gateway to deeper analyses , demonstrating how a small",
+      "addition to this, GeneNetwork can be used to study correlations between traits and to perform data mining in genomic regions containing candidates for quantitative trait genes (Hoffman et al., 2011). All datasets in GeneNetwork are linked to a materials and methods information page that summarizes experimental details relating to the dataset. Databases within GeneNetwork include the transcriptome database, the BXD published",
+      "publication, and links to the dataset database and to the published paper (4C). There is also an option  to add this trait to your collection by pressing the Add button (4D), or to view this trait in an ear lier  version of GeneNetwork, GN1 (4E).",
+      "Bayesian inference of species networks from multilocus sequence data. Mol. Biol. Evol. 35, 504517 (2018). 167. Flouri, T ., Jiao, X., Rannala, B. & Yang, Z. A Bayesian  implementation of the multispecies coalescent   model with introgression for phylogenomic analysis. Mol. Biol. Evol. 37, 12111223 (2020). 168. Kubatko, L. in Handbook of Statistical Genomics    (eds Balding, D., Moltke, I. & Marioni, J.) 219245  (Wiley, 2019). 169. Rannala, B., Edwards, S., Leach, A. D. & Yang, Z.",
+      "subnetworks   GeneNetwork (www.genenetwork.org) is a depository of data- sets and tools for use in complex systems biology approaches in  order to generate or predict higher order gene function ( 23, 24 ).",
+      "on different cross types, such as F 2crosses (B6BTBRF2, B6D2F2, BH/HB F2, CastB6/B6Cast F2, B6JxB6N F2), butalso on more complex outbred crosses such as the HS, the CC, and the Hybrid Mouse Diversity Panel. Recently, data from other species has also been integrated into GeneNet- work (human, rat, monkey, fruit ies, and others) to facilitate the translational research of results into other species. To this end, GeneNetwork provides many tools for the analysis of",
+      "GeneNetwork (www.genenetwork.org). The web -based software further allows extraction of sets of",
+      "Phenotypes Database attheGeneNetwork (www.",
+      "Phenotypes Database attheGeneNetwork (www.",
+      "Phenotypes Database attheGeneNetwork (www."
+    ],
+    [
+      "genes that are responsible for obesity-associated diabetes. By the generation of subcongenic lines of a QTL, if pos- sible starting with chromosome substitution strains, thensmall critical regions that harbor the gene(s) in question can be identied with certainty. Sequence analysis and mRNA proling together with gene targeting in-vitro andin-vivo may lead to a solid chain of evidence linking sequence differences with altered molecular, cellular, and",
+      "tensive nondiabetic families, the QTLs on chromosomes 8q24 and 7q11, which are located in regions previouslyidentied as harboring type 2 diabetesassociated genes,may govern insulin sensitivity and insulin secretion in thepresence of insulin resistance before development of overttype 2 diabetes. Follow-up ne-scale mapping aroundthese loci and well-designed candidate gene studies, inparticular, are strongly encouraged. ACKNOWLEDGMENTS",
+      "studies used the QTL approach for statistical analysis of genotypes and phenotypes measured in the crosses. The concept of genetic dissection of diabetes into quantitative endophenotypes was introduced and resulted in the detection of genetic loci responsible for the control of fasting glycemia [39,42] , fasting insulinemia [39,43] , glucose tolerance [39,41,42] , insulin secretion induced by glucose or arginine [39], body weight [39,41,44] , adiposity [39], b-",
+      "indicating that risk factors exist on both genetic back- grounds [ 29]. QTL mapping studies indicate that these murine metabolic traits have a complex genetic architec- ture that is not dominated by any single allele [ 2931], much like humans [ 32,33]. Prior work identied candidate genes on Chr 13 that might underlie diabetes-related traits, including RASA1, Nnt, andPSK1. RASA1 show strong sequence differences between B6 and D2 strains [ 34]. Rasche et al. [ 35] reported that",
+      "genetic background [4]. Linkage analyses have shown that several quantitative trait loci interact with each other and with the environment to elicit obesity syndromes that are potentially diabetic. Several recent genome-wide associa- tion studies have identified novel candidate genes for T2DM but the effect of these variants on disease suscepti- bility is generally low, with odds ratios mostly around 1.5 [5-11]. Multiple studies on the transcriptome level have been per-",
+      "(2011). 7. Steinthorsdottir, V. et al. Identification of low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes. Nat. Genet.   46, 294298 (2014).8. Ma, R. C. et al. Genome-wide association study in a Chinese population  identifies a susceptibility locus for type 2 diabetes at 7q32 near PAX4.  Diabetologia 56, 12911305 (2013). 9. Huyghe, J. R. et al. Exome array analysis identifies new loci and low-frequency",
+      "nificant QTL, strongly associated with body weight (Galli et al.1996; Gauguier et al. 1996). Moreover, Gauguier and colleagues(1996) mapped a QTL linked to postprandial insulin secretion intheregionofChr4wherewedetectedasuggestiveQTL.DifferentNIDDM models (obese OLETF rats and lean GK rats) may carryalleles conferring NIDDM susceptibility in the same genes. Thecombined results imply the possibility of common genetic factorsunderlyingNIDDMinhumans,notwithstandingthehighdegreeofgenetic heterogeneity in human",
+      "data indicates that variants regulating islet gene transcription influence type 2 diabetes(T2D) predisposition and glucose homeostasis. However, the specific genes through whichthese regulatory variants act remain poorly characterized. We generated expression quanti-tative trait locus (eQTL) data in 118 human islet samples using RNA-sequencing and high-density genotyping. We identified fourteen loci at which cis-exon-eQTL signals overlapped",
+      "linkage analysis assists in the identication of possiblegene-gene interactions and that 5q11-q13 and 7q32together constitute a signicant susceptibility factorfor type 1 diabetes. Diabetes 53:15841591, 2004Type 1 diabetes is a common multifactorial dis- ease characterized by autoimmune destructionof the insulin-producing /H9252-cells in the endocrine pancreas, resulting in deranged metabolic ho-",
+      "model for common forms of NIDDM in humans associ-ated with obesity. This study identies the location of amajor QTL and additional independent QTLs contrib-uting to development of hyperglycemia in TH malemice. We have also elucidated genegene interactionsbetween QTLs in the development of NIDDM, detect-ing new QTLs that reveal their signicant effects onlywhen they interact with other QTLs. This complexinheritance pattern associated with genegene inter-actions may be of prime importance in"
+    ],
+    [
+      "T. I., de Bakker, P . I. et al (2006). TCF7L2",
+      "single nucleotide polymorphisms in TCF7L2 are reproduc-ibly associated with type 2 diabetes and reduce the insulinresponse to glucose in nondiabetic individuals. Diabetes55:28902895 135. Cauchi S, Meyre D, Dina C, Choquet H, Samson C, Gallina S, Balkau B, Charpentier G, Pattou F, StetsyukV, Scharfmann R, Staels B, Fru  hbeck G, Froguel P 2006 Transcription factor TCF7L2 genetic study in the Frenchpopulation: expression in human /H9252-cells and adipose tissue",
+      "rs7903146 and rs12255372 in intron 3 of the TCF7L2 gene [20], associated with a ~45% increase in Type 2 diabetes risk per allele. As such, the TCF7L2 locus presently repre- sents the strongest known genetic determinant of Type 2diabetes. Risk allele carriers show impaired insulin produc-tion [21] and b-cell dysfunction in vitro [22]. TCF7L2 (previously referred to as TCF-4) is a high-mobility group box-containing transcription factor involved in Wingless-type MMTV integration site (Wnt)",
+      "et al. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2  diabetes. Nat Genet . 2006;38:320-23.   Sladek R, Rocheleau G, Rung J, Dina C, Shen L, Serre D, et al. A genome- [9] wide association study identifies novel risk loci for type 2 diabetes. Nature .  2007;445:881-85.  Kirchhoff K, Machicao F, Haupt A, Schafer SA, Tschritter O, Staiger H, et al. [10] Polymorphisms in the TCF7L2, CDKAL1 and SLC30A8 genes are associated",
+      "transcription factor 7-like 2 ( TCF7L2 ) gene confers risk of type 2 diabetes. Nat Genet. 2006; 38:320323. [PubMed: 16415884] 172. Gloyn AL, Noordam K, Willemsen MA, Ellard S, Lam WW, et al. Insights into the biochemical and genetic basis of glucokinase activation from naturally occurring hypoglycemia mutations. Diabetes. 2003; 52:24332440. [PubMed: 12941786] 173. Pearson ER, Donnelly LA, Kimber C, Whitley A, Doney AS, et al. Variation in TCF7L2",
+      "L. Mechanisms by which common variants in the TCF7L2 gene  increase risk of type 2 diabetes. J Clin Invest  2007; 117: 2155-2163  [PMID: 17671651 DOI: 10.1172/JCI30706] 164 Gloyn AL , Braun M, Rorsman P. Type 2 diabetes susceptibility  gene TCF7L2 and its role in beta-cell function. Diabetes  2009; 58:  800-802 [PMID: 19336690 DOI: 10.2337/db09-0099] 165 da Silva Xavier G , Loder MK, McDonald A, Tarasov AI, Carzaniga  R, Kronenberger K, Barg S, Rutter GA. TCF7L2 regulates late",
+      "tion. Although the disease progression results from aninterplay of environmental factors and genetic predisposi- tion, in recent years TCF7L2 gene has been considered the strongest genetic determinant for the risk of developingT2DM [ 24,19,20]. The gene encodes a transcription factor of the canonical Wnt signaling pathway, expressed in several tissues, known to have developmental roles indetermining cell fate, survival, proliferation and movement [9]. Wnt signaling plays an important role also in B-cell",
+      "transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2diabetes. Nat Genet 38:320 3231422 Diabetologia (2007) 50:1418 1422",
+      "genes which also play a significant role in the risk and  pathogenesis of the disease[158,159]. The association  of TCF7L2  gene variants with type 2 diabetes and  its mechanism of action received special attention  by several investigators[161,162]. Over expression of the protein was shown to decrease the sensitivity of  beta islet cells to secrete insulin[163,164] and was more  precisely involved in the regulation of secretary granule  fusion that constitute a late event in insulin secretion",
+      "Muggeo M, Stoico V, Negri C, Pignatti PF, Bonora E, Bonadonna RC (2011) Variants and haplotypes of TCF7L2 are associatedwithb-cell function in patients with newly diagnosed type 2 diabetes: the Verona Newly Diagnosed Type 2 Diabetes Study (VNDS) 1. J Clin Endocrinol Metab 96(2):E389E393 13. Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, Pasternak RC, Smith SC Jr, Stone NJ, National Heart, Lung, and Blood Institute, American College of Cardiol-"
+    ],
+    [
+      "phenomena such as mutations and gene conversion events) occur in relevant meioses  leading up to the formation of the gametes (i.e., egg and sperm) which are combined  during fertilization and the formation of zygotes. Thus, individuals inherit a patch- work of chromosomal segments from maternal and paternal chromosomes.",
+      "the egg and the sperm. Such a process would result in genetic changes that will be copied into every cell of the future adult, including reproductive cells (Stock & Campbell, 2000), opening the door to irreversibly alter the human species. Inevitably, signifi  cant self-disclosure and discussion challenges await families",
+      "a fertilized egg is a complicated process that relies on controlling: which genes are active; whenthese genes activate; and for how long they are active. In broad terms, there are four ways that thiscontrol can be achieved: First, inside the sperm or egg, genes can be marked with small chemical tags that flag these genes",
+      "(Figures 8 and 9). Two gametes (egg and sperm) ultimately  join into a single cell, the zygote, which has the full comple-ment of 23 chromosome pairs restored. If all goes well, the zygote gives rise to a live offspring. The Mendel Laws: Segregation and Independent  Assortment Both of the Mendel laws pertain directly to the process of  meiosis. The first Mendel law, the law of segregation, states  that each parent passes a randomly selected allele for a given",
+      "to be activated (or remain inactive) after fertilization, depending on whether the modification wasmade by the father (in the sperm) or the mother (in the egg); this process is known as imprinting. Second, the mother can alter the gene activity in her offspring via the placenta; this process is known as maternal effect. Third, instructions encoded within the embryos DNA can directly control if, andwhen, a nearby gene becomes activated; this is known as  cis-regulation. Finally, similar instructions",
+      "the subset of that genetic information that is active.  But how does the differentiation process  begin?  The key insight in resolving this conundrum came from fly genetics and was the  realization that the egg is not a homogenous sack of protoplasm.  The maternally-derived genes  active in the fertilized egg are asymmetrically distributed such that at the first cell division each  daughter cell receives a different complement of factors.  Development continues as a",
+      "genes.  An altered gene may be passed on to every cell that develops from it.  The resulting features my help, harm, or have little or no effect on the offsprings success in its environment. (AAAS, pg. 109, 5B:9-12#4 ) 6. Heritable material: The information passed from parents to offspring is coded in DNA molecules (AAAS, pg 108, 5B:9-12#3) 7. Mutagens: Gene mutations can be caused by such things as radiation and chemicals.  When they occur in sex cells, the mutations can be passed onto offspring; if they",
+      "sex chromosome effects. (B)Soon after fertilization, male and female cells have sex-specic transcriptomes, epigenomes, and phenotypes (for example, male embryos grow faster than female embryos). At implantation, lineage determination begins and gene expression differences are reduced. Epigenetic marks, however, are less constrained and some are maintained, affecting gene expression, and phenotype later in development. Once specic lineages are established, differences in",
+      "or father (sperm cell). Each gamete has a set of 23 unpaired chromosomes. Two human gametes (egg and sperm) combine  to create a cell (zygote) that contains the full human genome  of 23 paired chromosomes.Genetic Information Nondiscrimination Act (GINA) US federal legislation that makes it unlawful to discriminate  against individuals on the basis of their genetic profiles in regard to health insurance and employment. These protections  are intended to encourage Americans to take advantage of",
+      "Proponents of the evo-devo view rightly point out that evolution occurs through changes in the  development of traits, which may or may not have changes in DNA as their root cause.  The  processes that produce traits occur during development and involve more than just genes.    All animals begin life as a fertilized egg, a single cell containing mitochondria and other  organelles, and enough maternally derived RNA and proteins to kick start development and"
+    ],
+    [
+      "promoters ,regulatory proteins and their binding sites,  ribosomal binding sites terminators ,et. RegulonDB contains  both documentation and prediction objects. In  addition it is linked with Swiss -prot, with microarray  databases for analysis and visualization of microarray  experiments.[5]     WIT   The WIT (What Is There) (http://wit.mcs.anl.gov/WIT2/)  is a comparable computational system for analysis of  sequenced genomes and generation of metabolic",
+      "promoters ,regulatory proteins and their binding sites,  ribosomal binding sites terminators ,et. RegulonDB contains  both documentation and prediction objects. In  addition it is linked with Swiss -prot, with microarray  databases for analysis and visualization of microarray  experiments.[5]     WIT   The WIT (What Is There) (http://wit.mcs.anl.gov/WIT2/)  is a comparable computational system for analysis of  sequenced genomes and generation of metabolic",
+      "promoters ,regulatory proteins and their binding sites,  ribosomal binding sites terminators ,et. RegulonDB contains  both documentation and prediction objects. In  addition it is linked with Swiss -prot, with microarray  databases for analysis and visualization of microarray  experiments.[5]     WIT   The WIT (What Is There) (http://wit.mcs.anl.gov/WIT2/)  is a comparable computational system for analysis of  sequenced genomes and generation of metabolic",
+      "173. Griffey, R. H.; Greig, M. J.; Haoyun, A.; Sasmor, H.; Manalili, S. Targeted Site-Specific Gas-Phase Cleavage of Oligoribonucleotides. Application in Mass Spectrometry-Based Identification of Ligand Binding Sites. J. Am. Chem. Soc. 1999, 121, 474475. 174. Hanson, C. L.; Fucini, P.; Ilag, L. L.; Nierhaus, K. H.; Robinson, C. V. Dissociation of Intact Escherichia coli Ribosomes in a Mass Spectrome- terEvidence for Conformational Change in a Ribosome Elongation",
+      "or chloramphenicol Immobilized targetDissociation of ribosome and release of mRNA5Poly(AAA)3 mRNA Isolation of mRNART-PCRdsDNA Mutagenesis by error-prone PCR Fig. 35.5.  Schematic presentation of a ribosome display round. The gene of interest is  transcribed from dsDNA into mRNA and translated into proteins by in vitro techniques.  The ribosomes remain tethered to the mRNA by either cold shock or chloramphenicol.  This step ensures that the genotype remains coupled to the phenotype. The proteins are",
+      "270 G.L. Sutphin e t a l. gene (Hinneb usch 2005 ). The m echanism of re gulation i s t hought to in v o lv e r el- ati v e a v a ilability of the l ar ge and small r ibosome s ub units. Specically , w hen 60Sribosomal sub unit l e v els a re lo w , ternary comple x e s containing initiation f actors and 40S ribosomal sub units are p roposed to more frequently scan through the",
+      "then used to develop synthetic gene networks with defined outputs, without significant post-hoc adjustments 22,4751. Alternatively, syn- thetic ribosome binding site (RBS) sequences can be used to optimize protein expression levels. Recently, Salis et al. 52 have developed a  thermodynamic model for predicting the relative translational ini -",
+      "Philips, R.M., 2017 How Many Ribosomes Are in a Cell? [WWW Document]. URL http:// book.bionumbers.org/how-many-ribosomes-are-in-a-cell/ ((accessed 7.24.16) n.d.). R Core Team, 2014. R: a Language and Environment for Statistical Computing. R Founda- tion for Statistical Computing, Vienna, Austria. Sigurdson, A.J., Ha, M., Hauptmann, M., Bhatti, P., Sram, R.J., Beskid, O., Tawn, E.J.,",
+      "structure, and to find sites that are likely to be cleaved or modified; interac- tion or catalytic mechanisms can be simulated. Bioinformatic resources on  the WWW range from the determination of the molecular weight to complex  threading and three-dimensional (3D) prediction algorithms. A huge list of  tools can be found on the ExPASy proteomic tools homepage (65). Because  of the great variety of programs available, several of these single tools have",
+      "tiation rates for a protein with different upstream RBS sequences, a model that can also be used to rationally forward-engineer RBS sequences to give desired protein expression. In addition, protein degradation can be controlled by tagging proteins with degradation-targeting peptides that impart different degradation dynamics 53. By automating the construction and characterization of biomo-"
+    ],
+    [
+      "phenomena such as mutations and gene conversion events) occur in relevant meioses  leading up to the formation of the gametes (i.e., egg and sperm) which are combined  during fertilization and the formation of zygotes. Thus, individuals inherit a patch- work of chromosomal segments from maternal and paternal chromosomes.",
+      "the egg and the sperm. Such a process would result in genetic changes that will be copied into every cell of the future adult, including reproductive cells (Stock & Campbell, 2000), opening the door to irreversibly alter the human species. Inevitably, signifi  cant self-disclosure and discussion challenges await families",
+      "a fertilized egg is a complicated process that relies on controlling: which genes are active; whenthese genes activate; and for how long they are active. In broad terms, there are four ways that thiscontrol can be achieved: First, inside the sperm or egg, genes can be marked with small chemical tags that flag these genes",
+      "(Figures 8 and 9). Two gametes (egg and sperm) ultimately  join into a single cell, the zygote, which has the full comple-ment of 23 chromosome pairs restored. If all goes well, the zygote gives rise to a live offspring. The Mendel Laws: Segregation and Independent  Assortment Both of the Mendel laws pertain directly to the process of  meiosis. The first Mendel law, the law of segregation, states  that each parent passes a randomly selected allele for a given",
+      "to be activated (or remain inactive) after fertilization, depending on whether the modification wasmade by the father (in the sperm) or the mother (in the egg); this process is known as imprinting. Second, the mother can alter the gene activity in her offspring via the placenta; this process is known as maternal effect. Third, instructions encoded within the embryos DNA can directly control if, andwhen, a nearby gene becomes activated; this is known as  cis-regulation. Finally, similar instructions",
+      "the subset of that genetic information that is active.  But how does the differentiation process  begin?  The key insight in resolving this conundrum came from fly genetics and was the  realization that the egg is not a homogenous sack of protoplasm.  The maternally-derived genes  active in the fertilized egg are asymmetrically distributed such that at the first cell division each  daughter cell receives a different complement of factors.  Development continues as a",
+      "genes.  An altered gene may be passed on to every cell that develops from it.  The resulting features my help, harm, or have little or no effect on the offsprings success in its environment. (AAAS, pg. 109, 5B:9-12#4 ) 6. Heritable material: The information passed from parents to offspring is coded in DNA molecules (AAAS, pg 108, 5B:9-12#3) 7. Mutagens: Gene mutations can be caused by such things as radiation and chemicals.  When they occur in sex cells, the mutations can be passed onto offspring; if they",
+      "sex chromosome effects. (B)Soon after fertilization, male and female cells have sex-specic transcriptomes, epigenomes, and phenotypes (for example, male embryos grow faster than female embryos). At implantation, lineage determination begins and gene expression differences are reduced. Epigenetic marks, however, are less constrained and some are maintained, affecting gene expression, and phenotype later in development. Once specic lineages are established, differences in",
+      "or father (sperm cell). Each gamete has a set of 23 unpaired chromosomes. Two human gametes (egg and sperm) combine  to create a cell (zygote) that contains the full human genome  of 23 paired chromosomes.Genetic Information Nondiscrimination Act (GINA) US federal legislation that makes it unlawful to discriminate  against individuals on the basis of their genetic profiles in regard to health insurance and employment. These protections  are intended to encourage Americans to take advantage of",
+      "Proponents of the evo-devo view rightly point out that evolution occurs through changes in the  development of traits, which may or may not have changes in DNA as their root cause.  The  processes that produce traits occur during development and involve more than just genes.    All animals begin life as a fertilized egg, a single cell containing mitochondria and other  organelles, and enough maternally derived RNA and proteins to kick start development and"
+    ],
+    [
+      "for sequencing on existing short-read instrumentation,  after which data are split by barcode and reassembled  with the knowledge that fragments sharing barcodes Barcodes A series of known bases  addedto a template molecule  either through ligation or  amplification. After  sequencing, these barcodes  can be used to identify which  sample a particular read is  derived from. Figure 5 | Real-time and synthetic long-read sequencing approaches.",
+      "sequence 2D read. Synthetic long-reads.  Unlike true sequencing platforms,  synthetic long-read technology relies on a system of  barcoding to associate fragments that are sequenced on  existing short-read sequencers61. These approaches par - tition large DNA fragments into either microtitre wells  or an emulsion such that very few molecules exist in  each partition. Within each partition the template frag - ments are sheared and barcoded. This approach allows",
+      "sequencing. This platform is used by the Illumina  suite of platforms. 36. Dohm,J.C., Lottaz,C., Borodina,T . &  Himmelbauer,H. Substantial biases in ultra-short read  data sets from high-throughput DNA sequencing.  Nucleic Acids Res. 36, e105 (2008). 37. Nakamura,K. etal.  Sequence-specific error profile  ofIllumina sequencers. Nucleic Acids Res. 39, e90  (2011). 38. Minoche,A.E., Dohm,J.C. & Himmelbauer,H.  Evaluation of genomic high-throughput sequencing  data generated on Illumina HiSeq and genome",
+      "Comparison of short-read platforms.  Individual short- read sequencing platforms vary with respect to through - put, cost, error profile and read structure (TABLE1 ).  Despite the existence of several NGS technology pro - viders, NGS research is increasingly being conducted  within the Illumina suite of instruments21. Although  this implies high confidence in their data, it also raises  concerns about systemic biases derived from using a  single sequencing approach2628. As a consequence, new",
+      "short-read sequencing. arXiv, arXiv:1203.3907v2, https://arxiv.org/abs/ 12073907 . Garrison, E., Sire n, J., Novak, A.M., Hickey, G., Eizenga, J.M., Dawson, E.T., Jones, W., Garg, S., Markello, C., Lin, M.F., et al. (2018). Variation graph toolkit improves read mapping by representing genetic variation in the reference. Nat. Biotechnol. 36, 875879 . Giambartolomei, C., Vukcevic, D., Schadt, E.E., Franke, L., Hingorani, A.D.,",
+      "or  transcriptomic structure53. Long-read sequencing Overview.  It has become apparent that genomes are  highly complex with many long repetitive elements,  copy number alterations and structural variations that  are relevant to evolution, adaptation and disease5456.  However, many of these complex elements are so long  that short-read paired-end technologies are insufficient  to resolve them. Long-read sequencing delivers reads in  excess of several kilobases, allowing for the resolution of",
+      "these large structural features. Such long reads can span  complex or repetitive regions with a single continuous  read, thus eliminating ambiguity in the positions or size  of genomic elements. Long reads can also be useful for  transcriptomic research, as they are capable of span - ning entire mRNA transcripts, allowing researchers to  identify the precise connectivity of exons and discern  geneisoforms. Currently, there are two main types of long-read tech -",
+      "nologies: single-molecule real-time sequencing  approaches  and synthetic approaches that rely on existing short- read technologies to construct long reads  insilico . The  single-molecule approaches differ from short-read  approaches in that they do not rely on a clonal popula - tion of amplified DNA fragments to generate detectable Figure 2 | Sequencing by ligation methods. a | SOLiD sequencing. Following cluster  generation or bead deposition onto a slide, fragments are sequenced by ligation, in",
+      "Tools for alignment-free analyses of sequencing data The vast majority of next-generation sequencing experiments in mouse have read alignment  to a reference genome as their first step. However, the primary data from any sequencing  experiment are the reads themselves. Recognition that the raw reads are information-rich has  led to the development of alignment-free algorithms for error correction (among many  others, Chaisson and Pevzner 2008 ), abundance estimation ( Patro et al. 2014 ), and de novo",
+      "(right). Sequencing adaptors (depicted by short red bars and short purple bars) are subsequently ligated to each cDNA fragment (green lines) and short sequence reads (single end or paired ends) from each cDNA are generated using high-throughput sequencing technology. The resulting sequence reads [short lines beneath the genome sequence with three genes shown (fat blue bars)] are aligned with the reference genome to"
+    ],
+    [
+      "When reliable prior knowledge exists about the variant composition in a pan-genome (typi- cally obtained via read-to-reference mapping), there are computational tools that can transform a linear reference sequence and a set of variant calls into graphs (18).This approach bypasses the computationallyexpensiveall-versus-allalignmentstepalongwiththeuncertaintiesofsubsequent graph construction, but the trade-off is increased reference bias and a potentially incomplete",
+      "(Karolchik et al. 2014 )] and Ensembl ( Flicek et al. 2013 ). Use of a single haploid reference  sequence as an anchor for all studies of genetic variation in mouse offers many practical  advantages. But the dependency on a reference genome requires several assumptions about  the nature of genetic variation which may be violated in practicethe strongest of which is  that of genomic collinearity (i.e., conserved marker order) between strains. We consider the",
+      "for at least 500 ancestrally diverse humans. This resource willalso provide a set of highly accurate genomes that can be used as a benchmarking dataset to improve short-read analysis tools. Even more importantly, these genomes allow completelynew designs for more effective short-read analysis strategiesthat overcome many of the limitations described above. Transitioning to a pan-genome reference will require develop-",
+      "2018;562(7726):203-209. http://doi.org/10.1038/s41586-018-0579-z 110. Li R, Li Y, Zheng H, et al. Building the sequence map of the human pan-genome. Nat Biotechnol . 2010;28(1):57-63. http://doi.org/10. 1038/nbt.1596 111. Vernikos G, Medini D, Riley DR, Tettelin H. Ten years of pan- genome analyses. Curr Opin Microbiol . 2015;23:148-154. http:// doi.org/10.1016/j.mib.2014.11.016 112. Miga KH, Wang T. The need for a human pangenome reference sequence. Annu Rev Genomics Hum Genet . 2021;22:81-102. http://",
+      "Whilemostpan-genomesconstructedtodateareprimarilygene-basedbecauseoftherelative easeofcomparingandcategorizingdiscreteunitsdefinedbytranscriptionandtranslation,theim- portanceofnoncodingandrepetitivesequencesisunquestionable.Itwouldthereforebeextremely powerfultodefineacomprehensivesequence-basedpan-genomethatincludesinformationabout therelativepositionofallsequences.Unfortunately,interpretingnoncodingsequencevariationischallenging.Indeed,evenforclassesofnoncodingsequencesofknownimportance,e.g.,promot-",
+      "assessment  will improve our understanding of the reference to  better assemble and interpret future  genome sequences.     We have previously developed a method to assess the risk of a patient for 55 diseases using a  quantitative human disease -SNP association database, and showed that we could suggest useful  and clinical relevant information using his personal genome sequence  (16). Here, we queried  the  reference genome sequence against our databa se and  identified  3,556 disease -susceptib ility",
+      "The shortcomings of a single, linear reference genome per species are well appreciated, and richer reference datastructures are an active area of research (Church et al. 2015 ). An alternative is de novo assembly of the genomes of commonly used strains. The Sanger Mouse GenomesProject is using a combination of long-insert jumping libraries and optical mapping to build de novo assemblies",
+      "undertake comprehensive and  powerful explorations rather than  being confined to testing hypoth - eses focused on candidate path - ways. With the completion of the  first reference sequence of the  human genome,3 attention shifted  from searching for genes to dis - covering their functions. System - atic genetic mapping in families  and populations helped scientists  pinpoint the genetic variants that  contribute to human disease.",
+      "points, nding statistical associations, modeling and run ning predic- tors, or constructing and pruning networks of detected rela tions. In the following paragraphs I will explore these opportunities in detail. 1.4.1 Population reference genomes Genomes are relatively similar between individuals, there fore, instead of assembling the complete sequence for each person, we only de termine points of DNA variation compared to a reference genome. Subs equently,",
+      "having a reference genome for a related specie s certainly makes the process easier. The  availability of long-read sequences vastly improves our ability to assemble new genomes, and new  technologies, such as PacBio  and Nanopore, are now able to give reads between 100-1000  kilobases, an order of m agnitude longer than current Illumina sequencing (Shendure et al.  2017).  Combining these new technologies with traditional short read NGS will greatly improve our ability"
+    ],
+    [
+      "al., 2012 ; Hindhorff, 2009; Barrett et al ., 2007 ). Recent efforts by the Encyclopedia of DNA  elements (ENCODE) consortium, to characterise the human genome, have revealed that most  of the non -coding part of the genome is not inactive but is associated with  different forms of  regulatory activity (ENCODE, 2012 ; Thurman, 2012 ). One important regulatory process that  takes place within the genome is the (in-) activation  of gene expression through the interaction",
+      "network of transcriptional regulators. Nature 403,  335338 (2000). 18. Gardner,T ., Cantor,C. & Collins,J. Construction of a  genetic toggle switch in Escherichia coli. Nature 403,  339342 (2000). 19. Kauffman,S.A. Metabolic stability and epigenesis in  randomly constructed genetic nets. J.Theor. Biol. 22,  437467 (1969). 20. Thomas,R. Boolean formalization of genetic control  circuits. J.Theor. Biol. 42, 563585 (1973). REVIEWS NATURE REVIEWS | GENETICS   ADV ANCE ONLINE PUBLICATION | 11",
+      "25   2.8 REGULATION OF GENE EXPRESSION     Apart  from the protein coding sequences, there are other biologically relevant nucleic acid  sequences that play other important roles in the genome such as regulation of gene expression  and maintenance of the chromatin structure (Pique -Regis  et al., 2011). Regu lation of gene  expression involves  a process that leads to increase or decrease in the production of specific",
+      "expression is regulated at many levels, but gene transcription  represents an essential and, in many cases, dominant point of control. Protein-coding genes are transcribed from promoters,  which represent genomic regions that recruit basal transcrip- tion factors and RNA polymerase II. Physiological levels of gene expression and responses to internal and external signals require the actions of additional sequence-specific transcrip- tion factors that recruit nucleosome-remodeling complexes,",
+      "regulatory elements  and variants thereof that may affect gene expression particularly through  the binding of transcription factors (TFs) to DNA.   The suggestion that the  genetic determinants of complex diseases are perh aps better sought in  problems associated with gene regulation is due to findings that many of the disease associated  variants occur in non -coding DNA sequences within the genome  (ENCODE, 2012; Schuab et",
+      "through multiple cell divisions at the transcriptio nal and epigenetic level need to be more 204  carefully examined and have evolved as an exciting area of research. 205   206  Epigenetics and transcriptional regulation  207  Regulation of gene expression relies on the ac cessibility of DNA to various transcription 208  factors, co-activators/co-repressors, and the transcriptional machinery. DNA is first wrapped 209",
+      "post-translationally, translationally, transcriptionally, or epigenetically  (Lempradl   et al, 2015; Zong  et al, 2017) . It seems likely that these different layers of  regulation can operate cooperatively on different time- scales . More permanent   adaptations might be expected following persistent regulation on a more transient  levelfor example,  lowered transcriptional activity of a gene might follow  a  period of low functional  activity of its protein. Elucidating the means of such",
+      "important  component in the regulation of gene expression with between  10  and  20%  of  the  transcriptome  being  regulated  by  DNA variation. 2. Technologies The  study  of  DNA  and  its  downstream  effects  is  very  much a  technology  driven  process.  Most  of  the  rst  screens  looking  at DNA  changes in disease involved looking at segregation in fam- ilies  because  there  were  no  reasonable  technologies  at  the  time",
+      "the cytosine and adenine nucleotides[31]. In addition, the c hromosomal structure of DNA can be decondensated by histone acetylatio n (trans- fer of acetyl groups to DNA organizational elements), makin g it more accessible for transcription[87]. The transcriptional ex pression of genes is further regulated by genetic variants themselves[7]. Fi nally, proteins form a complex network of interactions[265] that, in turn, a lso regulate gene expression[331].",
+      "eterogeneity and common, small effect genetic variants will be assessed.  h  D (c) Regulatory Signals:  Co-regulation of genes via shared transcriptional networks provides the basis for context-dependent gene  expression, an understanding of which is vital to the understanding of disease etiology and disease progression. In  particular, transcription factors (TF) and their transcription factor binding sites (TFBS) provide a key component in the understanding of how co-regulation is achieved."
+    ],
+    [
+      "3, 4 and 5 suggest previously unknown connections between traits. We next characterized pairs of traits within each group of traits (trait pairs) to show that the quality of these pairs is not lower than in existing methods. We focused on three main properties of trait pairs: the correlation among traits in a pair; the correlation between a trait pair and the",
+      "3, 4 and 5 suggest previously unknown connections between traits. We next characterized pairs of traits within each group of traits (trait pairs) to show that the quality of these pairs is not lower than in existing methods. We focused on three main properties of trait pairs: the correlation among traits in a pair; the correlation between a trait pair and the",
+      "3, 4 and 5 suggest previously unknown connections between traits. We next characterized pairs of traits within each group of traits (trait pairs) to show that the quality of these pairs is not lower than in existing methods. We focused on three main properties of trait pairs: the correlation among traits in a pair; the correlation between a trait pair and the",
+      "taxonomy of traits is that it allows researchers to turn theirattention to the ways temperament and personality traitsexpress themselves in daily life and to the fundamental pro-cesses underlying variations in these traits. In this section, we rst describe the traits and then review some of the mostinteresting current work on the psychological and evolutionaryunderpinnings of each trait. A more detailed description of thecomponents of these traits is found in Caspi and Shiner (2006).Because relatively less",
+      "ditions and related totraits ofinter est,often bycomparing two groups differing forthetrait. Darvasi (2003) states that thereisanundeclar eddispute among resear chers who study complex traits :::Onone side areclassical geneticists :::ontheother areproponents ofgene expr ession analysis :::.Darvasi goes ontooutline thepossible advantages ofcombining these techniques over and above either technique alone. Inaddition tobetter correlating ge-",
+      "three types of high-order organization of traits. (i) Groups of tightly related traits that share thesame transcripts mechanisms (modules 1, 2, 6, 7, 8, e.g., Figure 3 ). (ii) Groups of distinct traits that share the same transcripts mechanism, but not necessarily high correlations among them (modules 3, 4, 5, e.g., Figure 4 ). (iii) Different groups commonly have overlapping traits, but typically differ in their underlying mechanisms ( Figure 2B ).",
+      "three types of high-order organization of traits. (i) Groups of tightly related traits that share thesame transcripts mechanisms (modules 1, 2, 6, 7, 8, e.g., Figure 3 ). (ii) Groups of distinct traits that share the same transcripts mechanism, but not necessarily high correlations among them (modules 3, 4, 5, e.g., Figure 4 ). (iii) Different groups commonly have overlapping traits, but typically differ in their underlying mechanisms ( Figure 2B ).",
+      "three types of high-order organization of traits. (i) Groups of tightly related traits that share thesame transcripts mechanisms (modules 1, 2, 6, 7, 8, e.g., Figure 3 ). (ii) Groups of distinct traits that share the same transcripts mechanism, but not necessarily high correlations among them (modules 3, 4, 5, e.g., Figure 4 ). (iii) Different groups commonly have overlapping traits, but typically differ in their underlying mechanisms ( Figure 2B ).",
+      "of varying effect sizes (small to moderate), interact with each other across time to manifest as individual genotypic and phenotypic traits. These traits contribute to normal variation in human behavior. Yet, these trait variants also increase the susceptibility of a disorder or a condition for many others.",
+      "action will open a Correlation Plot page in which you can examine the relationship between the two traits. Look for linearity and outliers. 3.3.1. Selection and Saving Multiple Traits The list of traits on the Correlation Results page represents traits that may be related in some way. You may want to select a group of them for further analysis. For example, use the checkboxes to the left of each entry to check entries 1, 9, 10, 14, 16, 18, traits related to brain size. Click the Add to collection"
+    ],
+    [
+      "ST, see [40,120122]). Such tools may also offer a way of incorporating GxE interactions, as multiple GWAS for the same trait in different environments can be treated as correlatedtraits [123]. As association data for a greater variety of populations, species, and traits becomes available, we view the methods described outhere as a productive way forward in developing a quantitativeframework to explore the genetic and phenotypic basis of local adaptation. Materials and Methods",
+      "has been achieved by quantitative trait loci mapping, admixture  mapping and GW AS131, which have limited power to detect  small-effect-size genes. Newer approaches map pleiotropy by simultaneously associating genomic loci with multiple traits 54  and can also detect epistatic interactions using machine learning algorithms 132.Detecting the genomic signatures of correlational selectionCorrelational selection could potentially be inferred from  signatures of selective sweeps at loci under strong selection",
+      "pairs that include many genes within the seg- ment. On the other hand, GWAS may point to several or even many genomic locations for the trait of interest, complicating further functional analysis. Analysis of Quantitative Trait Loci (QTL) QTL analysis reveals statistically signicant linkage between phenotypes and genotypes, thereby providing explanation for the genetic basis of variation in complex traits (Falconer and Mackay, 1996; Lynch and Walsh, 1998). In a sense, QTL analysis can be viewed as incom-",
+      "studies.    There are  many possible causal networks even in a simple syst em consisting of  a genomic locus (QTL) and two traits, T1 and T2 ( Figure 1 ). Causal inference in  GWLS and GWAS involves, in its simplest form, the i dentification of pairs of traits  with a common QTL (QTL-trait-trait triads) and dete rmining whether the QTL  directly affects each of two traits (independent), or if the QTL affects only one trait",
+      "tions by matching patterns of expression QTL and GWAS. Am. J. Hum. Genet. 92, 92 160. Giambartolomei, C. et al. (2014) Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. PLoS Genet. 10, e1004383 161. Porcu, E. et al. (2019) Mendelian randomization integrating GWAS and eQTL data reveals genetic determinants of com-plex and clinical traits. Nat. Commun. 10, 3300 162. Zhu, Z. et al. (2016) Integration of summary data from GWAS",
+      "knowledge of the true QTL location (Doss et al. 2005 ), which can be used to empirically estimate the power of aGWAS performed at a similar scale (Hao et al. 2008 ; Schadt et al. 2008 ). A GWAS on its own does little more than establish correlations between changes in DNA at agiven locus and changes in a disease trait of interest, with respect to populations of interest. Further, these studies on",
+      "Another method to identify candidate genes is to leverage data generated in another population or species. Phenome-wide association studies (PheWAS) take a gene or variant of interest and nd all reported associations in GWAS datasets. A number of these GWAS tools exist, using either different methods, or different human cohorts (https://atlas.ctglab. nl/PheWAS, http://pheweb.sph.umich.edu/, accessed on 2 February 2022). Mouse QTL mapping has high power but low precision (i.e., we can detect a QTL, but",
+      "Another method to identify candidate genes is to leverage data generated in another population or species. Phenome-wide association studies (PheWAS) take a gene or variant of interest and nd all reported associations in GWAS datasets. A number of these GWAS tools exist, using either different methods, or different human cohorts (https://atlas.ctglab. nl/PheWAS, http://pheweb.sph.umich.edu/, accessed on 2 February 2022). Mouse QTL mapping has high power but low precision (i.e., we can detect a QTL, but",
+      "Another method to identify candidate genes is to leverage data generated in another population or species. Phenome-wide association studies (PheWAS) take a gene or variant of interest and nd all reported associations in GWAS datasets. A number of these GWAS tools exist, using either different methods, or different human cohorts (https://atlas.ctglab. nl/PheWAS, http://pheweb.sph.umich.edu/, accessed on 2 February 2022). Mouse QTL mapping has high power but low precision (i.e., we can detect a QTL, but",
+      "narrow regions ofthegenome harboring trait associated genetic variants. Itisstill, however, a challenge toidentify causal genes and several approaches have been developed that canassist inbridging thisgap. Specifically, systems genetics approaches involving theintegration of other types of-omics data have proven useful [25]. Two systems genetics approaches for informing GWAS areexpression quantitative trait loci(eQTL) discovery and co-expression"
+    ]
+  ]
+}
\ No newline at end of file