Evolution of Homologous Recombination Mechanisms

同源重组机制的演变

基本信息

批准号：
10589833
负责人：
Galina Petukhova
金额：
$ 31.02万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10589833
关键词：
Address Alleles Aneuploidy Animals Area Automobile Driving Back Binding Sites Birds Canis familiaris ChIP-seq Chromatin Chromosome Segregation Chromosomes Conflict (Psychology)Congenital Abnormality CpG Islands DNA DNA Binding DNA Methylation Data Defect Didelphidae Early Diagnosis Electrophoretic Mobility Shift Assay Elements Enhancers Event Evolution Failure Fertility Fishes Frequencies Gametogenesis Generations Genes Genetic Recombination Genetic Variation Genome Genomic Segment Haplotypes Health Human Individual Induced Mutation Infertility Inherited Investigation Knock-out Linkage Disequilibrium Location Mammals Maps Measures Meiosis Mus Pattern Plants Population Positioning Attribute Prevention Process Proteins Rattus Resolution Role Site Specificity Spontaneous abortion Sterility Structure Time Yeasts bisulfite sequencing chromatin remodeling follow-up functional genomics genetic information genome-wide homologous recombination interest methylation pattern mutant novel pressure promoter segregation subfertility

项目摘要

ABSTRACT Homologous recombination reshuffles genetic information between parental chromosomes generating genetic diversity and driving evolution. Recombination predominantly occurs at recombination hotspots, the narrow genomic regions where recombination frequency exceeds the frequency in the adjacent areas by up to three orders of magnitude. In some species, hotspots localize opportunistically to the regions with open chromatin configuration, such as promoters, enhancers and CpG islands. In others, including humans and mice, hotspots are routed away from these functional elements by the PRDM9 protein, protecting them from mutagenic effects of recombination. Deletion of the Prdm9 gene results in relocation of hotspots from PRDM9 binding sites back to promoters, leading to sterility or subfertility in mice and rats, but seemingly not in humans. This means that recombination-induced mutations in functional genomic elements will be passed to progeny. Furthermore, since locations of recombination hotspots change dramatically in Prdm9 mutants, the established patterns of linkage disequilibrium will be broken, leading to novel allele combinations. Therefore, investigation of the consequences of the Prdm9 loss in species that naturally lost Prdm9 through evolution is of particular interest. In this study we will map recombination hotspots in three species that lost canonical Prdm9 and examine three specific mechanisms that may define recombination landscape in such species.

抽象的同源重组对产生遗传的父母染色体之间的遗传信息多样性和驱动进化。重组主要发生在重组热点处，狭窄重组频率超过相邻区域的频率的基因组区域最多三个数量级。在某些物种中，热点在开放染色质的区域中进行了机会主义的位置配置，例如启动子，增强剂和CPG岛。在其他人，包括人和老鼠，热点 PRDM9蛋白可以远离这些功能元素，保护它们免受诱变作用重组。 PRDM9基因的删除导致prdm9结合位点的热点迁移给促进者，导致小鼠和大鼠的不育或不育，但似乎不在人类中。这意味着重组诱导的功能基因组元素突变将传递给后代。此外，由于重组热点的位置在PRDM9突变体中发生了巨大变化，因此已建立的模式连锁不平衡将被打破，从而导致新的等位基因组合。因此，调查 PRDM9在物种中自然损失PRDM9通过进化而产生的后果特别令人感兴趣。在这项研究中，我们将在三个丢失规范PRDM9的物种中绘制重组热点，并检查三个可能定义此类物种重组景观的特定机制。