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{
"question": [
"Create a how-to guide for genetic sequencing.",
"What is the significance of the length of telomeres?",
"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?",
"How does one tell the difference between X and Y DNA, with respect to DNA tracing and determining QTLs?"
],
"answer": [
"1. Start with an initial linkage or association: This is the first step in a genetic study where a trait or disease is linked to a specific region of the genome. 2. Perform Laboratory Genotyping: This involves determining the genetic variation of an individual by examining their DNA sequence using biological assays and comparing it to a standard sequence. 3. Use Genomic Sequence: The role of genomic sequence is crucial at every stage. It serves as a common thread that ties all the stages together. 4. Establish True Orthology: Determine the true orthology between genes in different species. If two genes are truly orthologous, their evolution closely follows patterns of speciation. 5. Apply Bioinformatics: Use bioinformatics tools and techniques to analyze the data. This can be applied to sequence data from any collection of organisms. 6. Understand Genome Structure and Content: Provide an overview of genome structure and content to provide a context for subsequent discussions. 7. Improve DNA Sequencing Methods: Constantly work on improving DNA sequencing methods with the ultimate goal of sequencing a human genome in a single day for a cost of about US $1,000. 8. Interpret the Information: The major challenge ahead is the interpretation of this information. Understand how our genes interact with each other, and how the environment contributes to the development of health and disease. 9. Consider the Implications: Understand the individual and societal implications of knowing our genome sequence. 10. Keep Up with Technological Advances: With further technological advances, other previously unimaginable research approaches will become real.",
"The length of telomeres is significant as it is associated with aging, disease, and mortality. Longer telomeres are generally associated with better health outcomes, including protection from age-related diseases, better cognitive function, and healthier lipid profiles. Shorter telomeres, on the other hand, have been linked to higher risks of heart disease, infection-related death, and other diseases. Telomere length can also be influenced by factors such as stress, with high-stress situations potentially leading to faster telomere shortening and premature aging.",
"The traits are determined by the combination of genes from both the sperm and the egg. This process involves meiosis, where each gamete (sperm and egg) contributes one chromosome to each pair, resulting in a zygote with a full complement of 23 chromosome pairs. The process of recombination or crossing over, where similar DNA sequences from the paired chromosomes swap genetic material, also plays a crucial role in determining the traits of the offspring. This results in a shuffling of genetic material and contributes to the genetic variation seen among offspring.",
"Genetic tracing is matrilineal due to the inheritance of mitochondrial DNA (mtDNA), which is passed from mother to all her children without any admixture from the father. This allows for a clear lineage tracing through the maternal line. In contrast, Y-DNA is passed from father to son, allowing for patrilineal tracing, but it does not provide information about the genetic contributions of other ancestors in a family tree.",
"The difference between X and Y DNA is not explicitly discussed in the context of determining QTLs in the provided text. However, in general, X and Y chromosomes are different in size and gene content, which can be identified through genetic sequencing. In the context of QTL studies, these differences could potentially influence the traits being studied. However, the specific process of how this is done in QTL mapping is not detailed in the provided text."
],
"contexts": [
[
"To overcome the lack of phenotypic information in the 1000 Genomes Project, The ClinSeq Project was developed to pilot large-scale genome sequencing for research in genomic medicine at the National Institutes of Health Clinical Research Center in Bethesda, MD. 40 The study seeks to enroll 1000 individuals who will be evaluated for personal health status and family history.The project aims to:",
"We (Hein, Schierup and Wiuf) have published a 300 page book on molecular population genetics titled \u201cGene Genealogies, Sequence Variation and Evolution\u201d Oxford University Press, and are presently developing a tutorial in association mapping that we hope to publish as a booklet in 2006 and are also involved in a very large EU collaboration (Holland, Denmark, Iceland and UK) to find susceptibility genes for breast and prostate cancer. In comparative genomics, the most fundamental investigation is to find genes in a pair of aligned genomes.",
"Key bioinformatic steps to take a genetic study from an initial linkage or association to laboratory genotyping are illustrated. The reader should note the role of genomic sequence as a common thread through every stage regions in man (see Chapter 5). Similar issues also exist in the establishment of true orthology between genes in different species, where one is identified to play a role in a disease model. If two genes are truly orthologous, their evolution closely follows patterns of speciation (Fitch, 2000).",
"In general terms, the approaches we describe can be applied to sequence data from any collection of organisms, but our emphasis here is primarily on Bioinformatics for Geneticists, Second Edition. Edited by Michael R. Barnes 2007 John Wiley & Sons, Ltd ISBN 978-0-470-02619-9 (HB) ISBN 978-0-470-02620-5 (PB) \u2402 C 106 CH 6 COMPARATIVE GENOMICS questions of relevance to human genetics. We begin, in Section 6.2 by presenting an overview of genome structure and content, providing a context for the subsequent discussions.",
"4 Assembling a View of the Human Genome Colin A. M. Semple Bioinformatics, MRC Human Genetics Unit, Edinburgh EH4 2XU, UK 4.1 Introduction The miraculous birth of the draft human genome sequence took place against the odds. It was only made possible by parallel revolutions in the technologies used to produce, store and analyse the sequence data, and by the development of new, large-scale consortia to organize and obtain funding for the work (Watson, 1990). The initial flood of human sequence has subsided as the sequencing centres have sequenced genomes from other mammalian orders and beyond.",
"This fully indexed but semi-intelligible Bioinformatics for Geneticists, Second Edition. Edited by Michael R. Barnes 2007 John Wiley & Sons, Ltd ISBN 978-0-470-02619-9 (HB) ISBN 978-0-470-02620-5 (PB) \u2402 C 4 CH 1 BIOINFORMATICS CHALLENGES FOR THE GENETICIST \u2018book of life\u2019 immediately began to serve as a valuable framework for integration of genetic and biological data. However, knowledge of the genome sequence did not immediately clarify the nature and structure of human genetic variation.",
"Methods for DNA sequencing are constantly being improved, with the ultimate goal of sequencing a human genome in a single day for a cost of about US $1,000, an end that appears to be in sight (Hayden, 2014).In the very near future, whole-genome sequencing will be routinely available for clinical purposes, perhaps even beginning at birth.The major challenge ahead is the interpretation of this information.How do our genes interact with each other, and how does the environment contribute to the development of health and disease?What are the individual and societal implications of knowing our genome sequence?The answers to these and other important questions will unfold in the years ahead.Thus, we are truly in an era where precision medicine may soon become a reality.",
"Characteristics of genotyping and sequencing technologies",
"Key bioinformatic steps to take a genetic study from an initial linkage or association to laboratory genotyping are illustrated. The reader should note the role of genomic sequence as a common thread through every stage regions in man (see Chapter 5). Similar issues also exist in the establishment of true orthology between genes in different species, where one is identified to play a role in a disease model. If two genes are truly orthologous, their evolution closely follows patterns of speciation (Fitch, 2000).",
"In general terms, the approaches we describe can be applied to sequence data from any collection of organisms, but our emphasis here is primarily on Bioinformatics for Geneticists, Second Edition. Edited by Michael R. Barnes 2007 John Wiley & Sons, Ltd ISBN 978-0-470-02619-9 (HB) ISBN 978-0-470-02620-5 (PB) \u2402 C 106 CH 6 COMPARATIVE GENOMICS questions of relevance to human genetics. We begin, in Section 6.2 by presenting an overview of genome structure and content, providing a context for the subsequent discussions.",
"4 Assembling a View of the Human Genome Colin A. M. Semple Bioinformatics, MRC Human Genetics Unit, Edinburgh EH4 2XU, UK 4.1 Introduction The miraculous birth of the draft human genome sequence took place against the odds. It was only made possible by parallel revolutions in the technologies used to produce, store and analyse the sequence data, and by the development of new, large-scale consortia to organize and obtain funding for the work (Watson, 1990). The initial flood of human sequence has subsided as the sequencing centres have sequenced genomes from other mammalian orders and beyond.",
"Introduction Since the first human genome was sequenced at an estimated cost of $150 million, several advanced high-throughput techniques \u2013 some with lower costs - have come up. At the same time, this resulted in a data deluge and a critical need to connect the heterogeneous sequencing data and associated annotations \u2013 structural and functional with the basic tenets of biology or molecular basis of development and disease.",
"Key bioinformatic steps to take a genetic study from an initial linkage or association to laboratory genotyping are illustrated. The reader should note the role of genomic sequence as a common thread through every stage regions in man (see Chapter 5). Similar issues also exist in the establishment of true orthology between genes in different species, where one is identified to play a role in a disease model. If two genes are truly orthologous, their evolution closely follows patterns of speciation (Fitch, 2000).",
"In general terms, the approaches we describe can be applied to sequence data from any collection of organisms, but our emphasis here is primarily on Bioinformatics for Geneticists, Second Edition. Edited by Michael R. Barnes 2007 John Wiley & Sons, Ltd ISBN 978-0-470-02619-9 (HB) ISBN 978-0-470-02620-5 (PB) \u2402 C 106 CH 6 COMPARATIVE GENOMICS questions of relevance to human genetics. We begin, in Section 6.2 by presenting an overview of genome structure and content, providing a context for the subsequent discussions.",
"4 Assembling a View of the Human Genome Colin A. M. Semple Bioinformatics, MRC Human Genetics Unit, Edinburgh EH4 2XU, UK 4.1 Introduction The miraculous birth of the draft human genome sequence took place against the odds. It was only made possible by parallel revolutions in the technologies used to produce, store and analyse the sequence data, and by the development of new, large-scale consortia to organize and obtain funding for the work (Watson, 1990). The initial flood of human sequence has subsided as the sequencing centres have sequenced genomes from other mammalian orders and beyond.",
"Ample time was allotted to answer questions and a copy of \"A Guide to Your Genome\" (National Human Genome Research Institute 2007) was provided to further assist participants' understanding and ability to communicate results with family members or others.",
"Whether within 10 or 12 (or 8) years, such inexpensive sequencing will change both research and clinical care, and progress does not need to wait even that long.The National Human Genome Research Institute (NHGRI) plans to focus a significant portion of the sequencing capacity that it supports on medical sequencing.For instance, the NHGRI and the National Cancer Institute are actively considering a Human Cancer Genome Project, 22 which would use DNA sequencing and a host of other genome technologies to gather information about the mutations and functional abnormalities found in multiple samples from many major types of cancer.Medical sequencing should also provide important insight into many other diseases.For example, sequencing all exons in X-linked mental retardation syndromes may reveal much about their etiology.Sequencing candidate genes in the extremes of the distribution of quantitative traits should also reveal much of importance about common diseases, such as coronary atherosclerosis. 23With further technological advances, other previously unimaginable research approaches will become real.",
"Key bioinformatic steps to take a genetic study from an initial linkage or association to laboratory genotyping are illustrated. The reader should note the role of genomic sequence as a common thread through every stage regions in man (see Chapter 5). Similar issues also exist in the establishment of true orthology between genes in different species, where one is identified to play a role in a disease model. If two genes are truly orthologous, their evolution closely follows patterns of speciation (Fitch, 2000).",
"In general terms, the approaches we describe can be applied to sequence data from any collection of organisms, but our emphasis here is primarily on Bioinformatics for Geneticists, Second Edition. Edited by Michael R. Barnes 2007 John Wiley & Sons, Ltd ISBN 978-0-470-02619-9 (HB) ISBN 978-0-470-02620-5 (PB) \u2402 C 106 CH 6 COMPARATIVE GENOMICS questions of relevance to human genetics. We begin, in Section 6.2 by presenting an overview of genome structure and content, providing a context for the subsequent discussions.",
"4 Assembling a View of the Human Genome Colin A. M. Semple Bioinformatics, MRC Human Genetics Unit, Edinburgh EH4 2XU, UK 4.1 Introduction The miraculous birth of the draft human genome sequence took place against the odds. It was only made possible by parallel revolutions in the technologies used to produce, store and analyse the sequence data, and by the development of new, large-scale consortia to organize and obtain funding for the work (Watson, 1990). The initial flood of human sequence has subsided as the sequencing centres have sequenced genomes from other mammalian orders and beyond."
],
[
"In birds, where erythrocyte telomere length (ETL) is measured, the majority of species sampled have shown no sex difference (36).Nonetheless, bird telomere dynamics are complex and, as with humans, may be affected by environment and stress.For example, a longitudinal study of black-tailed gulls (Larus crassitostris) over 2-5 years found no correlation between ETL and age or sex.Rather, ETL attrition was correlated with reduced food availability and environmental stressors (55).In a captive zebra finch (Taeniopygia guttata) population, male and female mean telomere length decreased with increasing age of the animals, but did differ between sexes (56).As these examples illustrate, the relationship between telomere length, lifespan, and sex is likely to be complex in other vertebrates.",
"Comparative studies of age-related telomere attrition in other species also reveal a variety of patterns.Barrett and Richardson (36) recently summarized the comparative data available on sex differences in telomere length.They found a strong correlation between male-biased mortality and either shorter telomeres or greater telomere attrition in males across bird and mammal taxa.However, telomere length did not differ between males and females in species where females are shorter-lived than males (36), suggesting that telomere shortening is not associated with species-specific longevity in a simple linear fashion.These studies generally suffer from relatively small sample sizes and are largely cross-sectional.Further, the use of diverse assays, different tissues (eg, leukocytes in mammals vs erythrocytes in birds), and lack of standardized benchmarks for accuracy makes comparisons between studies difficult.",
"In some organisms, there is no clear relationship between telomere length and lifespan.Age-related telomere attrition could not be detected in Daphnia pulex (57) or sea urchin species (Strongylocentrotus franciscanus and Lytechinus variegatus) (58).Studies in C. elegans examining natural variation in telomere length and experimentally manipulated telomere length detect no correlation with lifespan (59,60), and in Drosophila, which uses a telomerase-independent mechanism for telomere maintenance, there is a similar lack of correlation between longevity and telomere length (61).Similarly, data on sex differences in age-related telomere shortening are mixed.For example, in the ant species Lasius niger, the rate of telomere shortening is more rapid in short-lived males compared to longer-lived females.But, mean telomere length does not differ between the two types of females, queens and workers, despite the fact that queens live much longer than workers (up to 28 years vs 2-3 months) (62).These findings suggest that the question of how telomere shortening affects aging across species and how sex affects telomere attrition rates are complex.",
"With new methodologies to assess relative telomere length by Q-PCR, studies were designed to address the impact of telomere length on aging, aging associated pathologies, and mortality.One such study has correlated shorter leukocyte telomere lengths at age 60 with a three times higher risk of heart disease and an eightfold increase in risk of infection-related death (36), thereby associating measured relative cellular aging with disease and life expectancy.In a similar way, chronic stress was shown to correlate with short leukocyte telomere length, a phenomenon attributed to higher levels of oxidative stress at the cellular level (70).More recent studies have linked telomere length in smooth muscle cells with senescence and disease severity in patients with atherosclerosis (141,150).Leukocyte telomere length was also short in a cohort of similar patients and associated with a higher risk of developing occult cardiovascular disease (71).More data are needed to understand and validate the use of leukocyte telomere length as a biomarker for cardiovascular and other diseases.",
"Shortening of the telomeres at the ends of chromosomes has been associated with age-related disease and mortality [16][17][18].A recent study identified a common haplotype of four SNPs in the human telomerase reverse transcriptase gene (hTERT) that is enriched in centenarians and associated with longer telomere length [19].It was also shown that centenarians and their offspring maintain longer telomeres compared with controls and that longer telomeres are associated with protection from age-related diseases, better cognitive function and lipid profiles of healthy ageing [19].",
"New research has indicated how social factors, such as subordination, may translate into biological effects (epel et al. 2004;Chae et al. 2014).In a now classic study, epel et al. ( 2004) examined the telomere lengths of fifty-eight healthy premenopausal women who either had a healthy child (n = 19) or were giving care to a chronically ill child (n = 39. )They measured perceived stress, years of caregiving, telomere length, and oxidative stress.They found highly statistically significant differences in telomere length between women taking care of chronically ill children and those who had healthy children.They found highly statistically significant negative correlations between telomere length and perceived stress and years of caregiving.Telomerase activity had highly statistically significant negative correlations with perceived stress and years of caregiving.Oxidative stress was highly positively correlated with perceived stress and years of caregiving.They concluded that the telomere length shortening was equivalent to 9 to 17 years of aging in the high stress group.Telomere length is considered a biomarker of aging (Finch and Kirkwood 2000).Thus, this study showed that caregiver stress had essentially aged these women 9 to 17 years compared to women who had healthy children.",
"The single, consistent predictor of the rate of telomere attrition shown in multiple adult and the few child longitudinal studies is the baseline measurement of telomere length at the start of each study.This suggests the importance of understanding predictors of telomere length prior to adulthood, as it determines in part the rate of change (Revesz et al. 2014a, b;Nordfjall et al. 2009).Moreover, longitudinal studies in adults have had found that telomere attrition rate is dependent on baseline telomere length independent of any phenotypic predictors of shortening, such as disease or demographic variables (Nordfjall et al. 2009), attesting to the importance of studies to evaluate risk factors for shortening prior to adulthood.",
"Rates of decline in childhood may be particularly relevant for later chronic disease risk as shorter telomere length has been implicated in disease progression through exposure to cellular senescence, inflammatory cytokines and adipocyte hypertrophy (Raschenberger et al. 2015;Willeit et al. 2014;Monickaraj et al. 2012;Fyhrquist et al. 2013).",
"Adult studies have also found a negative correlation with baseline telomere length, suggesting a negative feedback regulation of leukocyte telomere length (Farzaneh-Far et al. 2010;Aviv et al. 2009;Epel et al. 2008;Nordfjall et al. 2009).It is possible that while our follow-up period was shorter than Shalev et al. 2013 and adult studies, which had a minimum of 5 year intervals with the exception of Puterman et al. (2015) who followed for a one-year time period, there may be biological regulation of telomere length at 4 and 5 years of age such that shorter telomeres are more robustly maintained, whereas longer telomeres have greater rates of decline, over a short period of one year.It is unlikely that this relationship is due to assay error or regression to the mean given the consistency of our findings across studies.We have had similar findings of longer telomeres having greater rates of decline and shorter telomeres being maintained in our different studies (Farzaneh-Far et al. 2010;Epel et al. 2008;Puterman et al. 2015).",
"We found primarily maintenance and lengthening from 4 to 5 years of age in children, with minimal telomere attrition, indicating that most of the telomere loss happens in the first 4 years, plateauing by age 4. Lastly, we found close to 10 % of the variance in rate of change in children shared by mothers.While some of this shared variance is genetic, there are likely environmental factors that need to be further identified that impact rate of telomere length change.",
"Abstract Telomeres are the protective complexes at the end of chromosomes, required for genomic stability.Little is known about predictors of attrition in young children or the relationship between parental and child patterns of telomere change.Telomere length was assessed twice over one year, at 4 and at 5 years of age, in Latino preschool children (n = 77) and their mothers (n = 70) in whole blood leukocytes.Maternal and child rates of attrition during the same time period were compared in 70 mother-child pairs.More children showed lengthened telomeres over one year compared to their mothers and very few children showed attrition (2.6 %).Approximately 31 % of children and 16 % of mothers displayed lengthening over one year while 66 % of children showed maintenance in contrast with 74 % of mothers.The strongest predictor for child telomere length change was child's baseline telomere length (r = \u22120.61,p < 0.01).Maternal rate of change was associated with child rate of change (r = 0.33, p < 0.01).After controlling for child baseline telomere length, the relationship between child and maternal rate of change trended towards significance (Coeff = 0.20, 95 % CI \u22120.03 to 0.43; p = 0.08).",
"Blackburn and Epel, a health psychologist who did original research on how specific lifestyle and psychological habits can protect telomeres, published The Telomere Effect (Blackburn & Epel, 2017), in which they suggested that individuals with shorter telomeres developed diseases earlier in life (a shorter \"disease span\").What follows is the evidence from these authors, their colleagues, and other researchers describing how length of telomeres contributes to mind-body connection and healthy longevity.",
"As early as at the time of birth, each of the 92 telomeres of the human genome has its own characteristic length.Additionally, each telomere shortens by its individual attrition rate.In general, longer telomeres at birth are associated with higher age-dependent attrition rates and vice versa.Overall, telomere shortening appears more dynamic in males.",
"In conclusion, a combination of overall and chromosomespecifi c shorter telomeres and more pronounced age-dependent telomere erosion could be observed in males.There is a prospective clinical study strongly suggesting that longer telomeres decrease the risk of dying (Cawthon et al., 2003).With this in mind, the telomere length discrepancies between the sexes may indeed be a factor infl uencing the differences in their life expectancy.",
"In every chromosome a linear decline of telomere length with age was observed, being more pronounced in men independent of the examined chromosome arm.This might suggest that telomere length on single chromosome arms may be infl uenced by the same factors which determine overall telomere length.",
"S. Mayer a S. Br\u00fcderlein a S. Perner a I. Waibel a A. Holdenried a N. Ciloglu a C. Hasel a T. Mattfeldt a K.V. Nielsen b P. M\u00f6ller a a Institute of Pathology, University of Ulm, Ulm (Germany); b DakoCytomation A/S, Glostrup (Denmark) follow uniformity.In previous studies, sex-specifi c differences in telomere length and attrition rate of men and women were found (Benetos et al., 2001;Cawthon et al., 2003;Nawrot et al., 2004), suggesting gender differences in behavior of telomeres.In individual chromosome arms, telomere length was also shown not to be homogeneous (Lansdorp et al., 1996;Benn, 1997;Martens et al., 1998;Surralles et al., 1999;Hao and Tan, 2001;Londono-Vallejo et al., 2001;Graakjaer et al., 2003), some telomeres being signifi cantly shorter, others longer than the average length.",
"To date, these characteristics in telomere lengths could not be set in a biological context, as only a few groups have provided detailed information about chromosome-specifi c patterns of telomere distribution (Lansdorp et al., 1996;Graakjaer et al., 2003).Whether accumulation of short telomeres (Martens et al., 2000;Londono-Vallejo et al., 2001) or rather the shortest telomere of one specifi c chromosome arm (Hemann et al., 2001) elicits senescence, remains an open question so far.",
"In recent literature, there are hints that the average telomere length may be higher in women and that their annual shortening rate may be somewhat lower (Vaziri et al., 1993;Rufer et al., 1998;Jeanclos et al., 2000), but these reported differences failed to reach statistical signifi cance except for one study (Jeanclos et al., 2000).Here, we provide compelling evidence that this is indeed the case.",
"It is generally accepted that telomeres shorten during DNA replication both in vitro and in vivo.In individuals, short telomeres are considered to be a sign of advanced age.Cawthon and coworkers (2003) showed that telomere shortening in humans likely contributes to mortality, supporting the hypothesis that they might act as a mitotic clock (Allsopp et al., 1992).Telomere length dynamics, however, does not seem to Abstract.During aging, telomeres are gradually shortened, eventually leading to cellular senescence.By T/C-FISH (telomere/centromere-FISH), we investigated human telomere length differences on single chromosome arms of 205 individuals in different age groups and sexes.For all chromosome arms, we found a linear correlation between telomere length and donor age.Generally, males had shorter telomeres and higher attrition rates.Every chromosome arm had its individual age-specifi c telomere length and erosion pattern, resulting in an unexpected heterogeneity in chromosomespecifi c regression lines.This differential erosion pattern, however, does not seem to be accidental, since we found a correlation between average telomere length of single chromosome arms in newborns and their annual attrition rate.Apart from the above-mentioned sex-specifi c discrepancies, chromosome arm-specifi c telomere lengths were strikingly similar in men and women.This implies a mechanism that arm specifi cally regulates the telomere length independent of gender, thus leading to interchromosomal telomere variations.",
"Shortening of the telomeres at the ends of chromosomes has been associated with age-related disease and mortality [16][17][18].A recent study identified a common haplotype of four SNPs in the human telomerase reverse transcriptase gene (hTERT) that is enriched in centenarians and associated with longer telomere length [19].It was also shown that centenarians and their offspring maintain longer telomeres compared with controls and that longer telomeres are associated with protection from age-related diseases, better cognitive function and lipid profiles of healthy ageing [19]."
],
[
"Selection could occur at multiple levels, from germ cell generation and propagation to fertilization and early embryonic growth.Chromosomal abnormalities, including aneuploidy, were found in 10-20% of spermatozoa and oocytes (20) and in the cleaved embryo, with a 21% rate of abnormalities in preimplantation embryos (21).These findings led to a model for natural selection against chromosome abnormalities (21).Selection extends to the end of gestation: Only approximately 30% of all conceptions result in a live birth, with more than half of aborted fetuses containing chromosomal abnormalities (22), a number likely to be an underestimate because of technological limitations in measuring all possible mutations.But even in the very small fraction of germ cell duos that survive this withering genome attack and result in a live birth, a number of severe de novo mutations will still be found (23).The data on gross chromosomal alterations suggest that overall, mutation frequency early in life is very high.The functional consequence, however, is limited because of selection.Somewhat surprisingly, this picture points toward an initial decline in genomic alterations, allowing the adult individual to acquire a somatic genome optimally equipped to provide function.",
"The phenotype of the F1 hybrids is compared to those of the parental inbred strains to reveal dominance or semi-dominance relationships between the alleles that a\u00a1ect the phenotype. Phenotypic di\u00a1erences between reciprocal F1 hybrids indicate that one or more of the following factors may a\u00a1ect the trait: (1) sex linkage (X- or Ylinked traits), (2) genomic imprinting of QTLs that a\u00a1ect the phenotype, (3) prenatal maternal e\u00a1ects (e\u00a1ects of intrauterine environment), and/or (4) postnatal maternal or paternal e\u00a1ects (e\u00a1ects of maternal and/or paternal parenting behaviour on o\u00a1spring).",
"Sex brings harmful alleles together into the same genetic background, allowing selection to more efficiently purge them from the population and potentially producing some offspring that are fitter than either parent. However, the benefit of recombining deleterious mutations may depend on the nature of the epistatic interactions between them. The mutational deterministic hypothesis (Kondrashov 1988) depends partly on this epistasis.",
"In most plants and animals, sex is a necessary component of reproduction, and the question for evolutionary biologists is why reproductive mechanisms have evolved that way. In one of the experiments described next, evolutionary geneticists have nevertheless devised a way to compare evolution with and without recombination in the obligately sexual fruit fly.",
"This disparity in investment is the basis for the twofold cost: asexual females hypothetically could transmit twice as many alleles at the same cost. In most plants and animals, mates tend to be unrelated, leading to outcrossing. But sex usually also involves the basic process of physical recombination: the breakage and reunion of two different DNA or RNA molecules. Of these two processes, recombination is clearly the more widespread feature of sexual reproduction. A variety of reproductive systems, such as selfing and automixis, involve recombination but not outcrossing. In contrast, relatively few reproductive systems have outcrossing without recombination.",
"Crossing over-The swapping of genetic material that occurs in the germline.During the formation of egg and sperm cells, also known as meiosis, paired chromosomes from each parent align so that similar DNA sequences from the paired chromosomes cross over one another.Crossing over results in a shuffling of genetic material and is an important cause of the genetic variation seen among offspring.This process is also known as meiotic recombination.",
"The reason for the rarity of these mutations is natural selection: If the mutations result in disorders that decrease health and reproductive fitness, they will eventually be eliminated from a population.In exceptional cases, mutations may cause both beneficial and detrimental consequences, resulting in opposing forces of positive selection and negative selection that may cause the mutations to be preserved at nonrare frequencies in a population.For example, the HbS mutation in the HBB gene (which produces the \u03b2 subunit of hemoglobin) causes sickle cell disease when present in both alleles, a detrimental consequence, but protects against malaria when present in 1 allele, a beneficial consequence, ensuring that the mutation persists in populations in areas of the world where malaria is endemic.Genes are passed from parents to offspring via the process of meiosis by which gametes, the egg cells in the mother and the sperm cells in the father, are generated.Ordinarily, each cell has 23 pairs of chromosomes; the gametes have 23 unpaired chromosomes.In meiosis, the 23 pairs are split so that each gamete receives 1 chromosome from each pair (Figures 8 and 9).Two gametes (egg and sperm) ultimately join into a single cell, the zygote, which has the full complement of 23 chromosome pairs restored.If all goes well, the zygote gives rise to a live offspring.",
"Recombination (meiotic recombination)-The swapping of genetic material that occurs in the germline.During the formation of egg and sperm cells, also known as meiosis, paired chromosomes from each parent align so that similar DNA sequences from the paired chromosomes recombine with one another.Recombination results in a shuffling of genetic material and is an important cause of the genetic variation seen among offspring.Also known as crossing over.",
"In the generation of gametes, crossing over regularly occurs, and genetic information is swapped between members of a chromosome pair.That doesn't matter within inbred animals, because the swapped parts are identical.In an F 1 animal, however, the chromosomes of a particular pair are genetically different, one each having come from each parent.Each gamete produced will be unique, as will be each F 2 zygote formed by uniting of the gametes from two F 1 parents.An F 2 group thus provides for expression of some genetic variability.This variability is limited to the allelic differences existing between the parent strains of the F 1 s, so that another F 2 , derived from different inbred strains, will express different genetic differences.",
"Sex brings harmful alleles together into the same genetic background, allowing selection to more efficiently purge them from the population and potentially producing some offspring that are fitter than either parent. However, the benefit of recombining deleterious mutations may depend on the nature of the epistatic interactions between them. The mutational deterministic hypothesis (Kondrashov 1988) depends partly on this epistasis.",
"In most plants and animals, sex is a necessary component of reproduction, and the question for evolutionary biologists is why reproductive mechanisms have evolved that way. In one of the experiments described next, evolutionary geneticists have nevertheless devised a way to compare evolution with and without recombination in the obligately sexual fruit fly.",
"This disparity in investment is the basis for the twofold cost: asexual females hypothetically could transmit twice as many alleles at the same cost. In most plants and animals, mates tend to be unrelated, leading to outcrossing. But sex usually also involves the basic process of physical recombination: the breakage and reunion of two different DNA or RNA molecules. Of these two processes, recombination is clearly the more widespread feature of sexual reproduction. A variety of reproductive systems, such as selfing and automixis, involve recombination but not outcrossing. In contrast, relatively few reproductive systems have outcrossing without recombination.",
"Aberrant recombination patterns on chromosomes that have missegregated have also been identified as an important factor, in both male and female gametes (Table I).This is because recombination together with cohesion of sister chromatids establish the unique 'bivalent' chromosome structure where homologous partner chromosomes are tethered together, a configuration that is critical for their accurate segregation in meiosis I (Fig. 2A).The remarkable feature is that recombination occurs in foetal oocytes whereas chromosome segregation takes place decades later (Fig. 2A).Since mammalian oocytes are arrested at the G2/M transition (or dictyate stage), this raises the intriguing question of how the bivalent is maintained until the meiotic divisions.",
"Traditionally, it has been agreed that the \ufb01nal sex of an individual (phenotypic sex) depends on two sequential processes: the sex determination system of the species and the gonad differentiation process (Valenzuela, 2008). However, recently, these two seemingly distinct processes are viewed as part of a general process leading to gonad formation and sex ratios (Sarre et al. , 2004; Quinn et al. , 2011; Uller and Helantera\u0308, 2011).",
"However, we expect that only at this level, the most signi\ufb01cant contributions brought by integrating epigenetics will be made. Concluding Remarks and Future Prospects Fish sex ratios are the result of a complex interaction between genetic, biochemical, and environmental interactions. The ultimate result of these interactions at the individual level is gender: male or female. However, at the population level, the combination of sex determination and differentiation sets the sex ratio. In turn, sex ratios de\ufb01ne the reproductive capacity of populations and, if sex growth dimorphism exists, also the growth characteristics, something very important in an aquaculture context.",
"Obehav is, in turn, influenced by offspring genes and environment (Ogene and Oenvir respectively). Hence, indirect genetic effects (blue arrows) and direct genetic effects (red arrow) are important influencers of behaviour. B) Parentoffspring conflict theory predicts that parental resource investment and offspring solicitation behaviours are influenced by the fitness benefit to a focal individual (O), cost to a social partner such as a sibling (S1 and S2) or parent (P), and by their coefficient of relatedness (black arrows). 42 Figure 2: Genomic imprinting can result in divergent phenotypes from the same genotype. A) A paternally imprinted gene, i.e. maternally expressed.",
"Because of the small contribution, through the sperm, of the paternal transcriptome to the fertilized zygote, and because of the stronger maternal contribution to child rearing in most model organisms, parental effects are typically thought of as synonymous with maternal effects, although true paternal effects are known to exist (Rando, 2012). Maternal effects have been shown to be important during embryonic development, leading to differences in the birth weight of mice depending on the genotype of the mother (Cowley et al. , 1989; Wolf et al. , 2011).",
"Therefore, the resulting phenotypic patterns lag a generation behind the genetic transmission of the causal variants. The most well-studied parental genetic effects are caused by deposition of maternal transcripts into the egg prior to fertilization, resulting in differences in early embryonic development depending on the genotype of the mother. Certain genes have also been shown to respond to maternal influence after birth through genetically defined maternal behaviors (Weaver et al. , 2004).",
"The phenotype of the F1 hybrids is compared to those of the parental inbred strains to reveal dominance or semi-dominance relationships between the alleles that a\u00a1ect the phenotype. Phenotypic di\u00a1erences between reciprocal F1 hybrids indicate that one or more of the following factors may a\u00a1ect the trait: (1) sex linkage (X- or Ylinked traits), (2) genomic imprinting of QTLs that a\u00a1ect the phenotype, (3) prenatal maternal e\u00a1ects (e\u00a1ects of intrauterine environment), and/or (4) postnatal maternal or paternal e\u00a1ects (e\u00a1ects of maternal and/or paternal parenting behaviour on o\u00a1spring).",
"It was believed by many that for each trait variant we should expect to find a corresponding genetic change, or \u201egene for\u201f that trait. Through historical happenstance the relationship between genes and traits was set up and treated as if it were one-to-one. But the production of a trait involves not only genes, but also their interactions with each other and the environment, and chance."
],
[
"distinguishing prenatal from postnatal maternal effects, see below). Maternal effects can account for a large proportion of phenotypic variance, especially during early life, and for some traits explain more variation than direct genetic effects [33, 97, 99, 100, 102\u2013115]. However, maternal and offspring genotype are correlated (i.e. half their genes are shared), and in inbred lines they are fully confounded, thus separating the effects of their respective genotypes is difficult. To remove this confounding effect cross-fostering has been used, both in the laboratory and in the field [119, 131].",
"Using genetic markers, the pattern of inheritance can be tracked through families. For example, by analyzing a marker linked to the eye color gene in several generations, it is possible to determine from which grandparents a child has inherited its eye color alleles. More importantly, \ufb01nding a marker linked to a disease can lead to location of the faulty gene causing the disease. Finding the gene is very valuable in the search for the cure. The distance between two loci can be expressed either as physical or genetic distance.",
"Although autosomal SNPs are commonly used as genetic markers to infer ancestry or race/ethnicity membership, haploid such as mitochondria, Y-DNA, and X-lined markers are also important to provide separate stories of ancestry of individuals from paternal and maternal sides [42,43].Therefore, genetic structure created due to autosomal markers could be different from those of lineage markers (often influenced by political, social, and migration history of individuals/populations).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.",
"a) Autosomal DNA (testing both sexes) markers: autosomal DNA tests utilize DNA from the 22 pairs of autosomal chromosomes.Autosomal DNA is inherited from both parents.Autosomal testing provides percentages of ethnicity using autosomal DNA SNP test (i.e., ancestry informative markers), and it is the most commonly used test to infer ancestry across diploid genome.b) Y-DNA or Y-SNPs (paternal line testing) markers: a haploid Y-DNA is the paternally inherited non-recombining portion of the Y chromosome, and it tests only for males.The Y-DNA testing tests the Y chromosome which is passed intact from father to son with no DNA from the mother.Y-DNA testing can then be used to trace direct paternal line.Y-DNA remains the same in each generation, allowing us to compare surname from different regions to see if we are from the same family.Y-line testing does not indicate anything about the contributions of the other ancestors in a family tree.In other words, you could be 3/4th Native American, with only the direct paternal line being European, and this test would tell you nothing at all about those other three Native lines.When testing the Y-chromosome, there are two types of tests, short tandem repeat (STR) and SNP markers.STR tests are best for recent ancestry while SNP tests tell about more ancient ancestry.c) Mitochondrial DNA (maternal line testing) markers:",
"Additional information about past breeding practices can be gleaned by quantifying the number of reproductive males and females in a population.This can be achieved by comparing levels of genetic diversity between sex chromosomes, autosomes and mtDNA 99 .In cattle, for example, gene flow from aurochs is evident in the autosomes but is absent in mtDNA 41 .This has been interpreted as a management strategy that may have involved allowing insemination of domesticated females by wild bulls 41,100 .In horses, a comparison of the levels of diversity of the Y chromosome and the autosomal chromosomes demonstrated that some cultures allowed fewer males to breed and instead selected specific stallion bloodlines 55 .This male-oriented breeding strategy was not practised by the Romans and only became increasingly prominent in the past 1,000 years as a result of the growing influence of Oriental stallions (Arabian, Persian and Turkmen) 101 .",
"Dr Ring: What makes the maternal gene so peculiar compared to the paternal?Dr Cookson: If you look in the epidemiologic sense, many studies show that there is increased risk of allergic disease if the mother is affected.However, very few studies have actually set out to test that formally and most of them might suffer from some sort of selection bias because the mother is more likely to be aware of her symptoms and feel guilty, and so on.It is very difficult to explain.Is it genomic imprinting, where the gene is only active when transmitted through the mother?I do not think all of these genes would be imprinted, though it is possible.It also seems that there are effects of the maternal phenotype.The maternal phenotype, if the mother is affected or unaffected, determines the strength of the maternal effect.Again, if a gene was imprinted, you would not expect maternal phenotype to be important.So, I think that this has something to do with maternal/fetal interaction, either through the placenta or shortly after birth.There is the issue of immune conflict between mother and child.At the same time, the mother is trying to prime the infant's immune system.",
"Genetic and Genomic Discovery Using Family Studies Ingrid B. Borecki, PhD; Michael A. Province, PhD G enetic studies traditionally have been performed on sets of related individuals, that is, families.Mendel's early studies in sweet peas (Pisum sativum) on the inheritance patterns of discrete traits from parents with specific mating types to offspring has shed light on the basic mechanisms of inheritance, including the fundamental laws of segregation of discrete factors (genes) from parents to offspring and the cosegregation of genes that are closely located on a chromosome (linkage).The distribution of traits within families exhibited mathematical segregation ratios in offspring from known mating types.These expected segregation ratios have been used as an important discovery tool in the study of human diseases in pedigrees, providing evidence for a multitude of single-gene disorders.Furthermore, in some cases, trait cosegregation with genetic markers with known positions provides mapping information that enables localization and, ultimately, identification of the relevant causative gene.",
"In fact, this idea has been pursued before in the context of signatures of reproductive isolation and shown to reveal patterns consistent with epistatic gene interactions that arise in the shape of Dobzhansky-Muller incompatibilities [10,11]. In contrast to the mouse data, the available human genotypes were derived from outbred, ethnically distinct populations. In this case pairs of functionally interacting genes can be detected following a slightly different approach.",
"Family Structure The first re-identification method (FAMILY) employs genealogical data accompanying genomic data.Genealogies, rich in depth and structure, permit the construction of complex familial relationships.Consider a simple family structure of two parents and one child.Since the parental genders are guaranteed, there exist 2 variants of this structure, since the child's gender is either male or female.When disease status is taken into account, it is represented as a Boolean variable; either an individual afflicted or not afflicted.In this aspect, all three family members can be represented as three attributes {Father, Mother, Child}, and there exist (father's disease status)*(mother's disease status)*(child's disease status)*(child's gender) = 2*2*2*2 = 16 possible family-disease combinations.In reality, pedigrees are much more robust than a simple nuclear family.For example, a three-generation family of two children per family permits on the order of 10 5 distinct variants of the family-disease structure and 10 6 individuals that could be uniquely characterized.The number of combinationsk is larger when supplementary information, such as living status or medical/genetic features, is considered. 16e ability to determine unique family structures is only one part of the re-identification process.These structures must be linked to identifiable information, which, in many instances, is publicly available in the form of various genealogical databases.These databases are accessible both offline and via the World Wide Web.For example, genealogical records are available in many public databases, including ,Ancestry.com>,,Infospace.com>,,RootsWeb.com>,,GeneaNet.com>,,FamilySearch.org>, and ,Genealogy.com>. {From such data, it is not difficult to construct family structures and, with such information in hand, an adversary can link disease-labeled family structures to named individuals.",
"Fig. 3. Illustrations of the three CEU pedigrees (black) showing how genetic information from distant patrilineal relatives (arrow; red, patrilineal lines) can identify individuals.Filled squares represent sequenced individuals.To respect the privacy of these families, only abbreviated versions are presented.The sex of the CEU grandchildren was randomized.The numbers of grandchildren are not given.",
"When I was in high school, I remember often trying to match my friends to their parents at various school functions and being surprised at how easy this was.As human geneticists, in spite of the enormous advances being made in our field, we still cannot answer many of the everyday questions that we are asked, such as: \"Why does he look just like his mother? \"Max Perutz [1], in a recent editorial comment in the New Scientist entitled \"The Molecular Biology of the Future,\" suggested some questions, for, as he put it, \"an examination in some future century. \"Here are two of them: (1) \"The time has come\" the Walrus said, \"To talk of many things ...And why the sea is boiling hot And whether pigs have wings. \"Calculate the amount of genetic information this would require in megacricks.",
"Using genetic markers, the pattern of inheritance can be tracked through families. For example, by analyzing a marker linked to the eye color gene in several generations, it is possible to determine from which grandparents a child has inherited its eye color alleles. More importantly, \ufb01nding a marker linked to a disease can lead to location of the faulty gene causing the disease. Finding the gene is very valuable in the search for the cure. The distance between two loci can be expressed either as physical or genetic distance.",
"In contrast, genomic imprinting is due to epigenetic changes within the individual causing differential gene expression characterized by either complete or partial silencing of one parental allele (Barlow, 2011; Abramowitz and Bartolomei, 2012; Ashbrook and Hager, 2013). As both mothers and fathers had contact with the pups in our study, our observed PGEs could come from either parent. Among quantitative USV traits only peak amplitude of call displayed a possible parent-of-origin effect. For call number, call duration, mean peak frequency, and all morphological traits, there were no significant parent-of-origin effect in reciprocal F1 females. In contrast, Thornton et al.",
"Another way of avoiding stratification is to use family-based samples.This approach has several theoretical advantages: as well as being immune to stratification 114 , these samples can be used to determine whether an allele has different effects on disease when it is inherited maternally or paternally 115 , and DISCORDANT SIB designs [116][117][118] can control for the effects of shared environment.Furthermore, more complex family-based designs are possible 119 that might allow combined association and linkage analysis 120 , and family-based association tests have also been developed for quantitative traits [94][95][96][97][98] .However, pure sibship-based association studies are underpowered relative to case-control studies 107,116,117 , and the requirement for living parents might introduce an age-of-onset bias towards younger patients for diseases that usually arise late in life.Furthermore, family-based samples are often much more difficult to collect, particularly if larger pedigrees are sought.Finally, the most commonly used family-based design, the TRANSMISSION DISEQUILIBIRIUM TEST (TDT; see REF. 114) is susceptible to technical artefacts (see below).",
"Because mtDNA is not subjected (as far as we know) to sexual recombination and crossover at the time of nuclear meiosis, nature must call on other means to ensure that inevitable germ plasm mtDNA mutations (Medvedev, 1981) are not transmitted.These mutations among primary oocytes, on the face of it, can be expected to increase with time, that is with maternal age.Empirical data on this question are incomplete and conflicting, being mostly confined so far to searches for deletions rather than point mutations (Chen et al., 1995;Keefe et al., 1995).It is inevitable, however, that there will be such mutations and that there must therefore be a reliable physiological mechanism (a) for giving an opportunity for back-mutations to occur, (b) for selecting in favor of those back-mutations (thus preserving the genome) and in favor of rare advantageous mutations, and (c) for preventing the spread of persistent harmful mutations through the population -mutations that are too slight (or too late in origin) to have escaped intraovarian culling.The sheer conservation of the mitochondrial genome over 0.5 billion years or more, despite a mutation rate estimated at 10 -20 times that of nuclear DNA, is ample reason to conclude that such a physiological purification process must exist.",
"To scrutinize the polygenic networks underlying complex diseases, however, mouse resources that are optimized to study the actions of isolated genetic loci on a fixed background will be insufficient on their own. For example, predisposition to the metabolic syndrome is inherited in a non-Mendelian fashion stressing genetic heterogeneity and multigenetic pathogenesis (Nandi et al. , 2004). With the reawakening as to the extraordinary genetic resources and phenotypic diversity archived in extant inbred strains, however, a foundation is in place for tracking down these complex traits and quantitative trait loci (QTL).",
"Otherwise, tens of thousands or markers will appear significant in the genome-wise association studies using up to one million genetic markers. Approaches to control for stratification include using of self report of ancestry or genetically derived principle components in the analysis. For studies using inbred mouse lines, a cladogram which is a hierarchical grouping based on phylogenetic analysis of strain relatedness can be created to subdivide inbred strains into more genetically homogenous subgroups.",
"Although bilateral descent is the norm in Western societies, it is not universal and there is 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 father's brother's children are members of your family, but not your father's sisters (Kottak, 2007).They are members of their husband's group or family.Efforts to create a family pedigree may be hampered if the participant is not familiar with her mother's relatives, but her mother's brother's 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., 1997;Wertz, 1997).One cannot assume that the named proband is in a position to speak for the extended family in agreeing to participate in any genetic research (DudokdeWit et al., 1997).",
"In particular in polygynous species, a female\u2019s offspring may have different fathers and are thus more closely related through the maternal than the paternal line. Therefore, any fitness cost to mothers, such as increased provisioning and care, affect maternally derived genes more strongly than paternally derived genes, leading to the silencing of the maternal copy (i.e. paternal expression) of genes that increase resource transfer. 5. Coadaptation between offspring and maternal traits The genetics of the co-evolution of parental and offspring traits has been investigated using quantitative genetics models and in several empirical studies (Agrawal et al.",
"In this scenario, genes expressed in parents will be selected for their effects on parental behaviour while genes expressed in offspring will be selected for their effects on influencing parental behaviour. At the genetic level the predicted conflict between paternal and maternal genomes is thought to have led to the evolution of genomic imprinting (monoallelic gene expression). Genomic imprinting effects are good examples of offspring genetic effects on maternal care because of the impact on the quality of maternal care and level of resource provisioning (e.g. Li et al. , 1999)."
],
[
"Genetic mapping in mouse strains enhances the power of detecting modifier genes and identifying complex genetic interactions. Genomewide quantitative trait locus (QTL) analysis, as described in more detail below, represents a promising approach to detect genetic variants that are associated with specific phenotypes and interact with each other. 16 ACCEPTED MANUSCRIPT In experimental crosses of two (inbred) strains the first generation (F1) of offsprings is genetically heterozygous but equal. Then in the next generation (F2) the PT strain-specific genetic information is distributed across the genomes of their progeny and RI each offspring is genetically unique.",
"Second, and perhaps more important, is the difference in the size and types of the genetic reference populations. In our previous study, we mapped the QTL with 36 F2 mice that were genotyped at 82 markers. In the current study, by comparison, we were able to map QTLs after examining 342 mice from 55 strains that were genotyped at approximately 4000 markers.",
"This contrast can be exploited to identify subregions that underlie the trans-QTLs [67]. SNPs were counted for all four pairs of parental haplotypes\u2014B vs D, B vs H, B vs C, and L vs S\u2014and SNP profiles for the four crosses were compared (figure 6). Qrr1 is a highly polymorphic PLoS Genetics | www.plosgenetics.org 8 November 2008 | Volume 4 | Issue 11 | e1000260 QTL Hotspot on Mouse Distal Chromosome 1 Figure 5. QTL for aminoacyl-tRNA synthetases in distal Qrr1.",
"The traditional approach to QTL mapping is to use two strains that differ maximally in the phenotype as parental strains for genetic crosses, with the following caveats. QTL analysis based on a single cross will most likely reflect only a small portion of the net genetic variation, and QTL detection will be limited to regions where the two progenitor strains have functional polymorphisms. Data from multiple crosses, or from an HS, will overcome this limitation and can also be used to reduce QTL intervals [5,30].",
"These candidate genes are then sequenced in the two parental inbred strains looking for sequence di\u00a1erences in coding or regulatory regions. After \u00a2ne mapping the QTL interval and shortening the list of plausible candidate polymorphisms, the major challenge remains \u2401 proving de\u00a2nitively which nucleotide polymorphism underlies the QTL. The most direct proof would be replacing one strain\u2019s allele with another strain\u2019s allele (creating a FIG. 1. Intercross breeding strategy for mapping quantitative trait loci (QTLs). On the right, the parental, F1 hybrid, and intercross (F2) mouse generations are depicted.",
"Furthermore, splicing QTLs (sQTLs) rather than eQTLs could comprise the molecular mechanism linking DNA variants with YFP53; thus, sQTL analysis could uncover genes that would not normally be detected at the level of differential gene expression (DGE),53 and thus, a differentially 181 182 Molecular-Genetic and Statistical Techniques for Behavioral and Neural Research Figure 8.5 Schematic for immediate, rapid \ufb01ne mapping in select F2 recombinants of the RCC-F2 cross. Top panel: Genome-wide signi\ufb01cant QTL (green trace; red dashed line \u00bc signi\ufb01cance threshold; blue vertical lines \u00bc Bayes credible interval).",
"Interval-specific haplotype analysis Approximately 97% of the genetic variation between inbred mouse strains is ancestral [22], so regions of identity by descent (IBD) between two strains used to detect a QTL are highly unlikely to contain the causal genetic polymorphism underlying the QTL [28]. For example, a cross between C57BL/6J and A/J mice detected www.sciencedirect.com a blood pressure QTL on Chr 1 [7].",
"Interval-specific haplotype analysis Approximately 97% of the genetic variation between inbred mouse strains is ancestral [22], so regions of identity by descent (IBD) between two strains used to detect a QTL are highly unlikely to contain the causal genetic polymorphism underlying the QTL [28]. For example, a cross between C57BL/6J and A/J mice detected www.sciencedirect.com a blood pressure QTL on Chr 1 [7].",
"At present, the BXD panel is composed of 80 different strains that all have been fully genotyped.26 Variation in any quantifiable trait can be associated with the segregation of parental alleles, and linkage genetics can map this variation to quantitative trait loci (QTLs), thereby identifying the genomic region(s) affecting that trait. An overview of the QTL mapping approach is depicted in Figure 2. Classical QTL analysis has permitted the identification of loci that are associated with variation in HSC traits.",
"In general, linking genetic variation with trait variation identifies QTL and a significant linkage of phenotype and genotype suggest that the DNA status helps to determine trait expression. As stated above, mouse QTL studies provide distinct advantages over human studies in the examination of genetic causes of a quantitative trait (e.g. alcoholism), even in the absence of specific hypotheses regarding its aetiology or candidate genes.",
"The progenitor mouse strains should have sufficient variation for the traits of interest and they should be genetically diverse enough to enable genetic mapping (BENNETT et al. 2006; FLINT 2003; GRISEL 2000). The sample size required for the identification of QTL depends largely on the effect size that a QTL contributes to phenotypes on interest. Inference about QTL can be made if one or more genetic markers are over- or underrepresented in the analysed individuals. Genotyping is often done by means of microsatellite markers, which contains mono, di-, tri-, or tetranucleotide tandem repeats flanked by specific sequences (Figure 4a).",
"This comparison gives information about the reliability of the observed genotype information: The more the marker locations differ between the two maps (which signifies variation in marker positions), the higher the possibility of genotyping errors. QTL mapping was done in several stages to identify loci acting individually and QTL that interacted, either additively or epistatically. To determine individually-acting QTL, a singleQTL genome scan was conducted with the function scanone.",
"Importantly, whereas these studies required substantial labor, time, and resources, X-QTL is a quick and easy approach to achieve a comparable level of genetic dissection. The levels of complexity observed here (e.g. 14 loci explaining 70% of the genetic variance for 4-NQO resistance) are still dramatically lower than those seen in for some human traits in GWAS (e.g. 40 loci explaining 5% of the variance for height 2,5). One obvious explanation is the difference in experimental designs (line crosses vs. population association studies), but differences in genetic architectures among species and traits may also contribute.",
"The method uses two pieces of information: mapping data from crosses that involve more than two inbred strains and sequence variants in the progenitor strains within the interval containing a quantitative trait locus (QTL). By testing whether the strain distribution pattern in the progenitor strains is consistent with the observed genetic effect of the QTL we can assign a probability that any sequence variant is a quantitative trait nucleotide (QTN). It is not necessary to genotype the animals except at a skeleton of markers; the genotypes at all other polymorphisms are estimated by a multipoint analysis.",
"The method uses two pieces of information: mapping data from crosses that involve more than two inbred strains and sequence variants in the progenitor strains within the interval containing a quantitative trait locus (QTL). By testing whether the strain distribution pattern in the progenitor strains is consistent with the observed genetic effect of the QTL we can assign a probability that any sequence variant is a quantitative trait nucleotide (QTN). It is not necessary to genotype the animals except at a skeleton of markers; the genotypes at all other polymorphisms are estimated by a multipoint analysis.",
"Genotyping all the individual progeny for markers that show allelic variation between the parental strains (either single nucleotide polymorphisms or simple sequence repeats) will allow the detection of associations between trait values and marker genotype, and in this way demonstrate to which set of markers a QTL is linked. To reduce the genotyping effort, selective genotyping of the individuals at the extremes of the phenotypic spectrum can be performed (20,23). Although these three approaches are in general considered to be the best to detect and map QTL, they have several disadvantages for quantitative traits involving HSC.",
"So, how do you go about planning and performing a QTL study, and how 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 a mutant (or genetically engineered) strain onto several inbred strains.",
"QTL Theory and Planning The theory behind the most basic form of QTL mapping is based upon intercrossing two inbred strains. The mouse genome consists of 19 pairs of autosomes (non sex-determining chromosome) and the X and Y chromosomes. In the example shown in Fig. 18.1, we are intercrossing stain A (shown with a black chromosome pair) with strain B (shown with a white chromosome pair). The initial F1 (filial generation 1) mice are true hybrids, with each individual From: Molecular Biomethods Handbook, 2nd Edition.",
"These candidate genes are then sequenced in the two parental inbred strains looking for sequence di\u00a1erences in coding or regulatory regions. After \u00a2ne mapping the QTL interval and shortening the list of plausible candidate polymorphisms, the major challenge remains \u2401 proving de\u00a2nitively which nucleotide polymorphism underlies the QTL. The most direct proof would be replacing one strain\u2019s allele with another strain\u2019s allele (creating a FIG. 1. Intercross breeding strategy for mapping quantitative trait loci (QTLs). On the right, the parental, F1 hybrid, and intercross (F2) mouse generations are depicted.",
"QTL mapping studies then seek to detect the polymorphisms underlying the complex traits of interest by scanning for alleles that co-vary with the traits. Similar experiments also can be conducted with special derivatives of inbred strains known as recombinant inbred (RI) mice. These animals are derived by cross-breeding two or more distinct parental strains (which often diverge widely for the trait of interest), followed by inbreeding of the offspring for several generations (Bailey 1971). Given the correct breeding strategy, this method 1 This is an issue faced by GWASs researchers when classifying samples as cases or controls."
]
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