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。重组过程中的错误导致非整倍性，这是自发性流产和严重发育障碍的主要原因，以及有害基因组重排，可能是突变。然而，尽管它具有高度限制的角色，但在每个研究的规模上，重组的重组都是巨大的。我们的长期研究兴趣在于表征这种差异，确定其决定因素并理解其生物医学和进化含义。特别是，我们的工作揭示了不同个体使用的一组重组热点的遗传变化，这有助于发现PRDM9（在指定小鼠和人类中的热点位置的核心重要性）。该病例证明了重组变异的研究如何产生对机制的见解。我们还记录了重组率对女性生育能力的影响，尤其是在年长的母亲中。在一起，我们的发现 来自其他群体的人强调了理解重组率差异及其效果的决定因素的生物医学重要性。在这种竞争性更新中，我们建议分析一大批人类的谱系，以检查个体之间重组率差异的基础以及对非整倍性风险和诱变的后果。在AIM 1中，我们专注于性别之间的差异。我们建议通过分析已经被基因型的3000多个核心家庭，以前所未有的分辨率建立一个精细的，性别特异性的遗传图并表征性别特异性的热点。在AIM 2中，我们将进行全基因组的关联研究，以确定使用相同的一组核家族有助于重组表型变化的新基因座。在AIM 3中，我们计划研究重组率和产妇年龄的变化如何影响非整倍性的风险。在AIM 3.i中，我们将评估无跨界四分之一的适当分离的证据，即是否存在具有抗牙性染色体的备用机制。在AIM 3.II中，我们将表征危害适当分离的重组模式。为此，我们将收集和分析妇女及其构想产物的样本，在这种情况下，重组的对比模式与可行的，非晶状体的后代相匹配。最后，在AIM 4中，我们将通过收集和分析两个大核家族的基因组序列来测试重组是否以不可忽略的速率引入种系突变。这项工作将为重组率变化的决定因素以及对人类生殖健康和基因组进化的影响而产生重要的新见解。