Recombination rate variation and evolution in vertebrates

脊椎动物的重组率变化和进化

• 批准号: 10544798
• 负责人: MOLLY F PRZEWORSKI
• 金额: $ 44.13万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 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 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10544798
• 关键词: ATAC-seq; Address; Affinity; Alleles; Binding; Binding Sites; Biological Assay; Birds; Candidate Disease Gene; Cells; ChIP-seq; Chromatin; Chromosome Mapping; DNA Binding; Data; Double Strand Break Repair; Event; Evolution; Fishes; Frequencies; Genes; Genetic; Genetic Recombination; Genome; Genomic approach; Genomics; Germ Cells; Histones; Learning; Linkage Disequilibrium; Linkage Disequilibrium Mapping; Location; Mammals; Maps; Meiosis; Meiotic Recombination; Modeling; Mus; N-terminal; Northern Pike; Orthologous Gene; Pattern; Phenotype; Phylogenetic Analysis; Phylogeny; Population Dynamics; Population Genetics; Process; Production; Research Personnel; Role; Snakes; Sorting; Specific qualifier value; Testing; Testis; Variant; Vertebrates; Work; Zinc Fingers; bioinformatics pipeline; candidate identification; comparative; data integration; egg; genome wide association study; genome-wide; genomic data; histone modification; interest; male; novel; predictive modeling; promoter; recruit; repaired; single cell analysis; sperm cell; transcriptome sequencing; zebra finch

PROJECT SUMMARY Meiotic recombination is a fundamental genetic and evolutionary process, initiated by the deliberate infliction of numerous double strand breaks (DSBs) on the genome. In most mammals, these DSBs are specified by PRDM9, which binds DNA through a zinc finger (ZF) array and makes two histone modifications that together serve to recruit the DSB machinery. In these species, the ZF binding affinity is rapidly-evolving. Intriguingly, PRDM9 is not only found in mammals but throughout vertebrates, and may be directing meiotic recombination there too. Despite its broad phylogenetic distribution, the gene has been lost independently many times; in these cases, the determinants of DSB location are less well understood but are associated with promoter features. We propose four analyses that address these gaps in our understanding: Aim 1. Do non-mammalian species with an intact PRDM9 use it to direct recombination? We will test this hypothesis in corn snakes, a vertebrate species that carries a complete and rapidly-evolving PRDM9. We will infer a genetic map from linkage disequilibrium (LD) data as well as by End- seq, a recently-developed approach to assay meiotic DSB frequencies in the genome. We will also collect genomic data about salient histone marks, chromatin accessibility and expression levels. These data will help us to establish if PRDM9 is used to direct recombination. The generality of our findings will be evaluated by building and examining an LD-based map in a fish species with an intact PRDM9, the Northern pike. Aim 2. What mechanisms direct the location of DSBs in species lacking an intact PRDM9? Here, we will focus on two vertebrates: zebra finches, which (like other birds) lack PRDM9 entirely, and swordtail fish, which lack the two N-terminal domains. We will combine existing LD-based genetic maps with data that we will collect on DSB frequencies, salient histone marks, chromatin accessibility, and expression levels. We will then ask which genomic features influence local recombination rates and if they also play a role in species with an intact PRDM9. Aim 3. What genes co-evolve with PRDM9? We will test 246 candidate genes for their co-evolution with PRDM9 across the vertebrate phylogeny. As a byproduct, we will make available a pipeline to identify orthologs of interest. Aim 4. What drives the evolution of PRDM9 binding? To answer this question, we developed a generative model, from PRDM9 binding to population dynamics. We will extend our model, notably to characterize conditions for the loss of PRDM9, and test key predictions with genomic and comparative data. Thus, we will combine population genetic, phylogenetic and experimental approaches in four vertebrate species to learn how DSBs are localized in the genome and how and why the mechanism differs among taxa.

项目摘要 减数分裂重组是一个基本的遗传和进化过程，由减数分裂启动。 在基因组上故意造成许多双链断裂（DSB）。在大多数哺乳动物中， 这些DSB由PRDM 9指定，其通过锌指（ZF）阵列结合DNA， 使两个组蛋白修饰一起用于招募DSB机制。在这些 物种，ZF结合亲和力是快速发展的。有趣的是，PRDM 9不仅存在于 哺乳动物，但整个脊椎动物，并可能指导减数分裂重组有太多。 尽管其广泛的系统发育分布，该基因已经独立丢失了很多次;在 在这些情况下，DSB位置的决定因素还不太清楚，但与 启动子特征我们提出了四个分析来解决我们理解中的这些差距： 1.具有完整PRDM 9的非哺乳动物物种使用它来指导重组吗？我们将测试 玉米蛇是一种脊椎动物，携带着一种完整的、快速进化的基因， PRDM9.我们将从连锁不平衡（LD）数据以及末端不平衡数据推断遗传图谱。 seq是最近开发的测定基因组中减数分裂DSB频率的方法。我们还将 收集关于显著组蛋白标记、染色质可及性和表达水平的基因组数据。 这些数据将帮助我们确定PRDM 9是否用于指导重组。的一般性的 我们的研究结果将通过建立和检查一个鱼类的基于LD的地图进行评估， 一条完整的PRDM 9，北方梭子鱼目标二。哪些机制指导争端解决机构的定位， 缺少完整PRDM 9的物种？在这里，我们将重点介绍两种脊椎动物：斑胸草雀， (like其他鸟类）完全缺乏PRDM 9，而剑尾鱼缺乏两个N-末端 域.我们将联合收割机结合现有的基于LD的遗传图谱和我们将在DSB上收集的数据 频率、显著组蛋白标记、染色质可及性和表达水平。然后我们将 询问哪些基因组特征影响局部重组率，以及它们是否也在 PRDM 9基因完整的物种目标3.哪些基因与PRDM 9共同进化？我们将测试246 在脊椎动物胚胎发育中与PRDM 9共同进化的候选基因。作为 副产品，我们将提供一个管道，以确定感兴趣的直系同源物。目标4。什么驱使 PRDM 9结合的演变为了回答这个问题，我们开发了一个生成模型， 从PRDM 9结合到种群动态。我们将扩展我们的模型，特别是描述 PRDM 9丢失的条件，并使用基因组和比较数据测试关键预测。 因此，我们将结合联合收割机群体遗传学，系统发育和实验方法在四个脊椎动物 物种，以了解DSB如何定位在基因组中，以及如何和为什么机制不同的类群。