Recombination rate variation and evolution in primates

灵长类动物的重组率变化和进化

• 批准号: 7352010
• 负责人: MOLLY F PRZEWORSKI
• 金额: $ 29.17万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-17 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7352010
• 关键词: Address; American; Aneuploidy; Biology; Chromosomal Rearrangement; Chromosome Mapping; Chromosome abnormality; Chromosomes; Chromosomes, Human, Pair 21; Chromosomes, Human, Pair 22; Data; Developmental Disabilities; Embryo; Ensure; European; Event; Evolution; Female; Fertility; Founder Generation; Genetic; Genetic Recombination; Genome; Genomics; Genotype; Goals; Heritability; Homologous Gene; Human; Human Genetics; Individual; Lead; Life; Linkage Disequilibrium; Location; Maps; Medical; Meiosis; Meiotic Recombination; Mind; Modeling; Molecular; Natural Selections; Numbers; Ovum; Pan Genus; Pan troglodytes; Placement; Pongidae; Population; Population Genetics; Predisposition; Primates; Process; Range; Rate; Regulation; Relative (related person); Research; Research Design; Resolution; Role; Shapes; Single Nucleotide Polymorphism; Spontaneous abortion; Surveys; Testing; Time; Variant; Work; abstracting; base; comparative; design; genetic pedigree; human disease; human female; human male; hutterite; improved; insight; male; research study; sex; spatial temporal variation; sperm cell; tool; transmission process

DESCRIPTION (provided by applicant): Abstract: Errors in the meiotic recombination process underlie a variety of chromosomal abnormalities, which are associated with spontaneous miscarriages and a wide range of human diseases. In spite of the crucial importance of recombination in meiosis, recent studies have revealed tremendous variation in rates among human females, and a rapid evolution of fine-scale recombination rates in apes. These observations raise important questions about recombination rate variation within and between species and its determinants. Addressing these questions is a key medical challenge, as well as an important step in understanding how natural selection acts on recombination rates. Here, we propose a unique combination of experimental and computational approaches to: i) Quantify variation in recombination rates among human males and females, using dense genotyping data collected in a large pedigree of a founder population (the Hutterites). These data will be used to evaluate the reliability of linkage-disequilibrium based maps, and garner new insights into the genetic basis of recombination rate variation and its possible effects on fertility. ii) Characterize the evolution of broad-scale recombination rates by building a genome-wide genetic map for common chimpanzees, the closest living evolutionary relative of humans. By comparing the map to what is seen in humans, we can assess the evolutionary constraints acting on recombination over different genetic scales, and ask whether the same determinants of recombination are at work in the two species. iii) Test hypotheses about the evolution of recombination hotspots, and delimit the rate at which they evolve, by performing sperm-typing experiments in two human populations and in common chimpanzees. In summary, we propose to combine molecular and population genetics tools to address outstanding questions about selective constraints on human recombination, with important implications for human genetics and evolutionary biology. Project Summary: A substantial fraction of human embryos are aneuploid (i.e., have an abnormal number of chromosomes) and, as a result, do not survive to full term or have severe developmental disabilities. Most cases of aneuploidy are caused by errors in the meiotic recombination process. This work aims to characterize variation in the human recombination process and to understand its determinants, thereby improving our understanding of the susceptibility to aneuploidy.

描述（由申请人提供）：摘要：减数分裂重组过程中的错误是各种染色体异常的基础，这些异常与自发流产和广泛的人类疾病有关。尽管重组在减数分裂中的重要性至关重要，但最近的研究表明，人类女性率的差异很大，以及猿类的细规重组率的快速发展。这些观察结果提出了有关物种及其决定因素内部和决定因素之间的重组率变化的重要问题。解决这些问题是一个关键的医学挑战，也是了解自然选择如何对重组率的行动的重要步骤。在这里，我们提出了实验和计算方法的独特组合：i）使用在建立者人群（Hutterites）的大量谱系中收集的密集基因分型数据来量化人类和女性重组率的变化。这些数据将用于评估基于连锁的基础图的可靠性，并获得对重组率差异及其对生育能力的可能影响的遗传基础的新见解。 ii）通过为人类最接近的生命进化亲戚建立一个全基因组的遗传图来表征广泛重组率的演变。通过将地图与人类所见的地图进行比较，我们可以评估在不同遗传尺度上作用于重组的进化约束，并询问在这两个物种中是否起作用相同的重组决定因素。 iii）测试假设关于重组热点的演变，并通过在两个人群和常见的黑猩猩中进行精子型实验来划定它们进化的速率。总而言之，我们建议将分子和种群遗传学工具结合起来，以解决有关人类重组选择性限制的杰出问题，对人类遗传学和进化生物学的重要意义。 项目摘要：大部分人类胚胎是非整倍体（即具有异常数量的染色体），因此，无法生存到完整期限或患有严重的发育障碍。大多数非整倍性病例是由减数分裂重组过程中的错误引起的。这项工作旨在表征人类重组过程中的变化并了解其决定因素，从而提高我们对非整倍性易感性的理解。