Evolution of the Genome-wide Recombination Rate in Mice

小鼠全基因组重组率的演变

• 批准号: 9896869
• 负责人: Bret A Payseur
• 金额: $ 59.04万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-15 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9896869
• 关键词: Animal Model; Biological; Chromosomes; Cytology; DNA; DNA Double Strand Break; Defect; Developmental Disabilities; Disease; Ensure; Evolution; Female; Gametogenesis; Generations; Genetic; Genetic Enhancement; Genetic Polymorphism; Genetic Recombination; Genetic Variation; Genome; Genomics; Geography; Health; Heritability; House mice; Human; Immunofluorescence Immunologic; Individual; Lead; Link; Measures; Meiosis; Molecular; Mus; Mutation; Natural Selections; Nature; Oogenesis; Pathway interactions; Pattern; Phenotype; Population; Portraits; Process; Regulation; Research; Role; Spermatogenesis; Spontaneous abortion; Synaptonemal Complex; Testing; Variant; biological sex; egg; experience; fetal loss; genetic profiling; genome-wide; inter-individual variation; male; pressure; repaired; sex; sperm cell; trait

PROJECT SUMMARY Recombination during meiosis serves multiple biological roles. Recombination diversifies genomes by shuffling combinations of mutations, thereby increasing genetic variation and enhancing the efficiency of natural selection. In many species, recombination also ensures that chromosomes segregate properly during gametogenesis. Although these roles should impose strong selective constraints on recombination, recombination rate varies among individuals. This unexpected result raises a major unanswered question: what processes govern variation in recombination rate in nature? Importantly, we still lack a basic picture of how the heritable component of recombination rate varies within and between species – information that is required for understanding how any phenotype evolves. Two clues about potential determinants of natural variation come from recent studies targeting recombination mechanisms. First, the two sexes present contrasting recombination landscapes and meiotic constraints, raising the prediction that males and females will display discordant patterns of inter-individual variation. Second, there is new evidence that the number of DNA double-strand breaks and the proportion of breaks repaired as crossovers also show differences among individuals, suggesting that these traits could explain natural variation in recombination rate. The proposed research will provide a much-needed portrait of natural genetic variation in recombination rate across multiple evolutionary scales. The contributions of sex and key meiotic processes to variation in recombination rate among individuals will be evaluated. In Aim 1, we will measure polymorphism and divergence in the genome-wide recombination rate during oogenesis and spermatogenesis by applying immunofluorescence cytology to individual mice. Sex-specific, genetic variation in the total number of crossovers will be quantified on geographically global and local scales using a panel of house mice and their relatives. The prediction that recombination rate experiences distinctive evolutionary pressures in the two sexes will be tested through controlled comparisons between females and males across common genomic backgrounds. In Aim 2, we will use immunofluorescence cytology to profile natural genetic variation in molecular processes that lead to crossovers, including the generation of double-strand breaks, the regulation of recombination intermediates, and the assembly of the synaptonemal complex. By linking these traits to the total number of crossovers in the same set of strains, we will test the hypothesis that the decision between crossover and non-crossover repair is a primary factor in recombination rate evolution. Defects in recombination are a leading cause of fetal loss and a leading genetic cause of developmental disabilities in humans. By examining heritable variation in recombination rate and its potential determinants in natural populations of the house mouse – a model organism for recombination-related disorders – this project is relevant to human health.

项目总结 减数分裂过程中的重组具有多种生物学作用。重组通过改组使基因组多样化 突变组合，从而增加遗传变异并提高自然 选择。在许多物种中，重组还确保染色体在 配子发生。尽管这些角色应该对重组施加很强的选择性约束， 重组率因个体而异。这个意想不到的结果提出了一个重大的悬而未决的问题： 本质上，是什么过程支配着重组率的变化？ 重要的是，我们仍然缺乏关于重组率的可遗传成分在和 物种之间-了解任何表型如何进化所需的信息。关于两条线索 自然变异的潜在决定因素来自最近针对重组机制的研究。 首先，两性呈现出截然不同的重组格局和减数分裂限制，提高了 预测男性和女性将表现出不协调的个体间差异模式。第二，有 新的证据表明DNA双链断裂的数量和断裂修复的比例 杂交还显示出个体之间的差异，这表明这些特征可以解释自然变异。 重组率。 拟议中的研究将为自然基因重组率的变异提供急需的描述。 跨越多个进化尺度。性别和关键减数分裂过程对变异的贡献 将评估个体间的重组率。在目标1中，我们将测量多态和 卵子发生和精子发生过程中全基因组重组率的差异 免疫荧光细胞学检测小鼠个体。因性别而异的遗传变异总数 交叉将在全球和本地范围内使用一组室内老鼠和他们的 亲戚。预测重组率在两者中经历了不同的进化压力 性别将通过共同基因组中雌性和雄性之间的受控比较来进行测试 背景。在目标2中，我们将使用免疫荧光细胞学来描述自然遗传变异 导致交叉的分子过程，包括双链断裂的产生，调节 重组中间体和联会复合体的组装。通过将这些特征与 在同一组菌株中的总交叉次数，我们将检验假设之间的决定 交叉修复和非交叉修复是重组率进化的主要因素。 重组缺陷是胎儿丧失的主要原因，也是发育的主要遗传原因 人类的残疾。通过研究重组率及其潜在决定因素的可遗传变异 家鼠的自然种群--重组相关疾病的模式生物--这个项目 与人类健康有关。