Recombination rate variation and evolution in primates

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各种人类疾病有关。尽管重组在减数分裂中至关重要，但最近的研究揭示了人类女性之间重组率的巨大差异，以及猿类中精细重组率的快速进化。这些意见提出了重要的问题，重组率的变化内和物种之间及其决定因素。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，我们提出了一个独特的实验和计算方法的组合：i）量化人类男性和女性之间的重组率的变化，使用密集的基因分型数据收集在一个大谱系的创始人人口（哈特派）。这些数据将被用来评估的可靠性连锁不平衡为基础的地图，并获得新的见解重组率变异的遗传基础及其对生育力的可能影响。ii）通过为普通黑猩猩（与人类最接近的现存进化亲属）构建全基因组遗传图谱来表征大规模重组率的进化。通过将该图谱与人类的图谱进行比较，我们可以评估在不同遗传尺度上影响重组的进化约束，并询问在这两个物种中是否存在相同的重组决定因素。iii）通过在两个人类群体和普通黑猩猩中进行精子分型实验，检验关于重组热点进化的假设，并界定它们进化的速率。总之，我们建议结合联合收割机分子和群体遗传学工具，以解决悬而未决的问题，人类重组的选择性限制，人类遗传学和进化生物学的重要影响。 项目概述：相当一部分人类胚胎是非整倍体（即，染色体数目异常），因此不能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。这项工作的目的是在人类重组过程中的变化的特点，并了解其决定因素，从而提高我们对非整倍体的易感性的理解。

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.