Recombination rate variation and evolution in primates

摘要：减数分裂重组过程中的错误是多种染色体异常的基础，这些染色体异常与自然流产和多种人类疾病有关。尽管重组在减数分裂中起着至关重要的作用，但最近的研究表明，人类女性的重组率存在巨大差异，类人猿的精细重组率也在迅速进化。这些观察结果提出了关于物种内部和物种之间的重组率变化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结合：i)量化人类男性和女性之间重组率的变化，使用在一个创始人群体（Hutterites）的大型谱系中收集的密集基因分型数据。这些数据将用于评估基于连锁不平衡图谱的可靠性，并为重组率变异的遗传基础及其对生育的可能影响提供新的见解。ii)通过构建普通黑猩猩（与人类进化关系最近的现存黑猩猩）的全基因组遗传图谱，描述大范围重组率的进化特征。通过将这张图谱与人类的对比，我们可以评估在不同基因尺度上影响重组的进化限制，并询问在这两个物种中是否有相同的重组决定因素在起作用。iii)通过在两个人类种群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，并划定它们进化的速度。综上所述，我们建议结合分子和群体遗传学工具来解决关于人类重组的选择性约束的突出问题，这对人类遗传学和进化生物学具有重要意义。

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.