Recombination rate variation and evolution in primates

描述(申请人提供)：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一系列人类疾病有关。尽管重组在减数分裂中至关重要，但最近的研究显示，人类雌性之间的重组比率存在巨大差异，类人猿中细小规模的重组比率迅速进化。这些观察结果提出了关于物种内和物种之间的重组率差异及其决定因素的重要问题。解决这些问题是一个关键的医学挑战，也是理解自然选择如何影响重组率的重要一步。在这里，我们提出了一种独特的实验和计算方法的组合：i)使用在创始人群体(哈特利派)的大量家系中收集的密集基因分型数据，量化人类男性和女性之间的重组率差异。这些数据将被用来评估基于连锁不平衡的图谱的可靠性，并获得对重组率变异的遗传基础及其对生育的可能影响的新见解。Ii)通过构建普通黑猩猩的全基因组遗传图谱来描述大规模重组率的演变，普通黑猩猩是人类现存的最接近的进化亲戚。通过将该图谱与在人类中看到的进行比较，我们可以评估在不同遗传尺度上作用于重组的进化约束，并询问重组的相同决定因素是否在两个物种中发挥作用。Iii)通过在两个人类种群和普通黑猩猩身上进行精子分型实验，测试关于重组热点进化的假设，并界定它们的进化速度。综上所述，我们建议结合分子遗传学和群体遗传学工具来解决关于人类重组的选择性限制的突出问题，这对人类遗传学和进化生物学具有重要意义。 项目摘要：相当一部分人类胚胎是非整倍体(即染色体数量异常)，因此不能存活到足月或有严重的发育障碍。大多数非整倍体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异并了解其决定因素，从而提高我们对非整倍体易感性的理解。

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.