Recombination Rate Variation and Evolution in Primates

灵长类动物的重组率变化和进化

• 批准号: 8506818
• 负责人: MOLLY F PRZEWORSKI
• 金额: $ 35.77万
• 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 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8506818
• 关键词: Address; Age; Aneuploidy; Back; Chromosome Mapping; Chromosome Segregation; Chromosomes; Chromosomes, Human, Pair 21; Conceptions; DNA Sequence Rearrangement; Development; Developmental Disabilities; Drosophila genus; Ensure; Event; Evolution; Fathers; Female; Fertility; Genes; Genetic Recombination; Genome; Genomics; Genotype; Germ-Line Mutation; Grant; Human; Human Gene Mapping; Individual; Lead; Length; Link; Location; Maternal Age; Meiosis; Mothers; Mus; Mutagenesis; Mutation; Nuclear Family; Parents; Pattern; Phenotype; Play; Population; Primates; Process; Property; Reproductive Health; Research; Resolution; Risk; Role; Sampling; Source; Specific qualifier value; Spontaneous abortion; Testing; Variant; Woman; Work; base; fitness; genetic pedigree; genome sequencing; genome wide association study; insight; interest; male; offspring; public health relevance; segregation; sex; stem; transmission process

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.

描述（由申请人提供）： 在人类中，重组在减数分裂中起着至关重要的作用。重组过程中的错误会导致非整倍性，这是自发流产和严重发育障碍的主要原因，也会导致有害的基因组重排，并可能导致突变。然而，尽管重组的作用受到高度限制，但在每个研究尺度上，人类之间的重组都存在巨大差异。我们的长期研究兴趣在于表征这种变异，确定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的遗传变异，有助于发现 PRDM9（一种在指定小鼠和人类热点位置中至关重要的基因）。这个案例展示了重组变异的研究如何能够深入了解机制。我们还记录了重组率对女性生育力的影响，尤其是高龄母亲。一起，我们的发现 来自其他群体的专家强调了了解重组率变化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，我们建议分析大量人类谱系，以检查个体之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 多个已进行基因分型的核心家庭，以前所未有的分辨率构建精细规模的性别特异性基因图谱，并表征性别特异性热点。在目标 2 中，我们将使用同一组核心家族进行一项强有力的全基因组关联研究，以确定有助于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变化如何影响非整倍体的风险。在目标 3.i 中，我们将评估无交叉情况下四分体正确分离的证据，即不交叉染色体备用机制的存在。在目标 3.ii 中，我们将描述危及真析取的重组模式。为此，我们将收集并分析女性及其受孕三体产物的样本，将这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进行对比。最后，在目标 4 中，我们将通过收集和分析两个大核心家族的基因组序列来测试重组是否会以不可忽略的速率引入种系突变。这项工作将为重组率变异的决定因素及其对人类生殖健康和基因组进化的影响提供重要的新见解。