Evolution of homologous recombination mechanisms

同源重组机制的进化

• 批准号: 10798573
• 负责人: Galina Petukhova
• 金额: $ 3.29万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10798573
• 关键词: Address; Alleles; Aneuploidy; Animals; Antibodies; Automobile Driving; Binding; Binding Sites; Birds; Canis familiaris; ChIP-seq; Chromatin; Chromosomal Rearrangement; Chromosome Segregation; Chromosomes; Conflict (Psychology); Congenital Abnormality; CpG Islands; Cross-Linking Reagents; Custom; DNA; DNA Binding; DNA Methylation; Data; Defect; Detection; 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; Histone H3; Human; Individual; Infertility; Inherited; Knock-out; Knockout Mice; Location; Lysine; Mammals; Maps; Marsupialia; Measures; Meiosis; Methylation; Monodelphis Domestica; Mus; Nematoda; Nucleotides; Plants; Population; Positioning Attribute; Prevention; Process; Proteins; Rattus; Resolution; Role; Site; Specificity; Spontaneous abortion; Structure; Time; Yeasts; bisulfite sequencing; chromatin remodeling; experimental study; follow-up; functional genomics; genetic information; genome-wide; genomic locus; homologous recombination; improved; improved outcome; mutant; pressure; promoter; segregation

ABSTRACT Homologous recombination reshuffles genetic information between parental chromosomes generating genetic diversity and driving evolution. Recombination predominantly occurs at a set of genomic locations called recombination hotspots. In most mammals, including humans, hotspot locations are defined by the sequence- specific binding of the PRDM9 protein, which trimethylates lysine 4 of the histone H3 at the sites where recombination is later initiated. In Prdm9 knockout mice DSBs are targeted to gene promoters and enhancers, which also carry the H3K4 trimethylation mark. Therefore, PRDM9 directs recombination away from functional genomic elements. This role is important as data indicate mutagenic effects of recombination both on the local nucleotide level and in gross chromosomal rearrangements. Nevertheless, some species do not have the Prdm9 gene or have lost canonical Prdm9 through evolution. In most of such species, recombination hotspots still exist, but they form at the H3K4me3-marked gene promoters and other genomic regions with accessible DNA. In contrast, nematodes and dipterans do not have recombination hotspots. Why promoters are not targeted by the DSB machinery in such species is not understood. In this study we propose to answer this question with the example of the marsupial Monodelphis Domestica, the first vertebrate species that, according to our preliminary data, lacks recombination hotspots. In addition to the prominent role of homologous recombination in evolution, recombination per se is essential for proper segregation of homologous chromosomes during gametogenesis. Recombination defects are invariably associated with infertility, miscarriage and aneuploidy-related birth defects. Defining the mechanisms that control genetic recombination will eventually aid in detection, prevention and/or treatment of aneuploidy-related infertility and birth defects.

摘要 同源重组亲本染色体之间的遗传信息， 多样性和推动进化。突变主要发生在一组基因组位置， 重组热点在包括人类在内的大多数哺乳动物中，热点位置由以下序列定义- PRDM 9蛋白的特异性结合，其使组蛋白H3的赖氨酸4在以下位点三甲基化： 随后开始重组。在Prdm 9敲除小鼠中，DSB靶向基因启动子和增强子， 其还带有H3 K4三甲基化标记。因此，PRDM 9引导重组远离功能性的 基因组元件。这一作用是重要的，因为数据表明重组对局部细胞的诱变作用， 核苷酸水平和总染色体重排。然而，有些物种没有 Prdm 9基因或通过进化失去了典型的Prdm 9。在大多数这样的物种中，重组热点 仍然存在，但它们形成于H3 K4 me 3标记的基因启动子和其他基因组区域， DNA.相反，线虫和双翅目昆虫没有重组热点。为什么发起人不 DSB机制在这些物种中的靶向作用尚不清楚。在这项研究中，我们试图回答这个问题。 以有袋动物Monodelphis Domestica为例，这是第一个脊椎动物物种，根据 根据我们的初步数据，缺乏重组热点。除了同源的突出作用外， 重组在进化中，重组本身对于同源基因的正确分离是必不可少的。 配子发生过程中的染色体生殖缺陷总是与不育有关， 流产和非整倍体相关的出生缺陷。定义控制基因重组的机制 最终将有助于检测、预防和/或治疗非整倍体相关的不孕症和出生缺陷。