Recombination Rate Variation and Evolution in Primates

描述(由申请人提供)： 在人类中，重组在减数分裂中起着关键作用。重组过程中的错误导致非整倍体，这是自发流产和严重发育障碍的主要原因，以及有害的基因组重排和可能的突变。然而，尽管重组的作用受到高度限制，但在所考察的每一种尺度上，重组在人类中都是非常不同的。我们的长期研究兴趣在于描述这种变异的特征，识别其决定因素，并了解其生物医学和进化意义。特别是，我们的工作揭示了不同个体使用的重组热点集合中的可遗传变异，有助于发现PRDM9(一种在指定小鼠和人类热点位置方面具有核心重要性的基因)。这个案例展示了对重组变异的研究如何能够产生对机制的洞察。我们还记录了重组率对女性生育力的影响，特别是在年长的母亲中。总而言之，我们的发现 来自其他小组的研究强调了了解重组率变异的决定因素及其影响的生物医学重要性。在这次竞争性更新中，我们建议分析一组庞大的人类家系，以检查个体间重组率差异的基础以及非整倍体风险和突变的后果。在目标1中，我们关注性别之间的差异。我们建议通过分析3000多个已经进行基因分型的核心家庭，以前所未有的分辨率构建一个精细的、性别特定的遗传图谱，并描述特定性别的热点。在目标2中，我们将使用相同的核心家族进行一项强大的全基因组关联研究，以确定导致重组表型变异的新基因座。在目标3中，我们计划研究重组率和母亲年龄的差异如何影响非整倍体的风险。在目标3.i中，我们将评估在没有交叉的情况下四分体适当分离的证据，也就是说，存在着相互融合的染色体的备份机制。在目标3.ii中，我们将描述危及适当分离的重组模式。为此，我们将收集和分析来自女性和她们的三体受孕产物的样本，将这一组中的重组模式与年龄匹配的可存活的非三体后代的传播模式进行对比。最后，在目标4中，我们将通过收集和分析两个大的核心家族的基因组序列，来测试重组是否以不可忽视的速度引入生殖系突变。这项工作将对重组率变异的决定因素以及对人类生殖健康和基因组进化的影响产生重要的新见解。

DESCRIPTION (provided by applicant): In humans, recombination plays a critical role in meiosis. Errors in the recombination process lead to aneuploidy, the leading cause of spontaneous miscarriages and of severe developmental disabilities, as well as to deleterious genome rearrangements and possibly to mutations. Yet in spite of its highly constrained roles, recombination is tremendously variable among humans, at every scale examined. Our long-term research interests lie in characterizing this variation, identifying its determinants and understanding its biomedical and evolutionary implications. In particular, our work revealed heritable variation in the set of recombination hotspots used by different individuals, contributing to the discovery of PRDM9 (a gene of central importance in specifying hotspot locations in mice and humans). This case demonstrates how studies of variation in recombination can yield insight into mechanism. We also documented an effect of recombination rates on female fertility, notably in older mothers. Together, our findings and those from other groups underscore the biomedical importance of understanding the determinants of recombination rate variation and their effects. In this competitive renewal, we propose to analyze a huge set of human pedigrees in order to examine the basis for differences in recombination rates among individuals and the consequences for aneuploidy risk and mutagenesis. In Aim 1, we focus on differences between sexes. We propose to build a fine-scale, sex-specific genetic map at unprecedented resolution and characterize sex-specific hotspots, by analyzing over 3000 nuclear families that have already been genotyped. In Aim 2, we will conduct a well-powered genome-wide association study to identify new loci that contribute to variation in recombination phenotypes, using the same set of nuclear families. In Aim 3, we plan to examine how variation in recombination rates and maternal age influence the risk of aneuploidy. In Aim 3.i, we will assess the evidence for proper segregation of tetrads without a crossover, i.e., for the presence of a back-up mechanism for achiasmatic chromosomes. In Aim 3.ii, we will characterize the recombination patterns that endanger proper disjunction. To this end, we will collect and analyze samples from women and their trisomic products of conception, contrasting patterns of recombination in this set to age-matched transmissions to viable, non-trisomic offspring. Finally, in Aim 4, we will test whether recombination introduces germline mutations at non-negligible rates, by collecting and analyzing genome sequences for two large nuclear families. This work will yield important new insights into the determinants of recombination rate variation and the implications for human reproductive health and genome evolution.