Molecular and evolutionary characterization of male recombination and its reversal in the D. nasuta species subgroup

D. nasuta 物种亚群雄性重组及其逆转的分子和进化特征

基本信息

批准号：
10251849
负责人：
Heng Chin Kevin Wei
金额：
$ 9.22万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-02 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10251849
关键词：
Address Alleles Aneuploidy Behavior Biochemical CRISPR/Cas technology Chromosome Segregation Chromosomes Coupled Disease Dissection Down Syndrome Drosophila genus Electron Microscopy Engineering Ensure Evaluation Evolution Female Filament GTP-Binding Protein alpha Subunits, Gs Gene Expression Profile Genes Genetic Genetic Materials Genetic Polymorphism Genetic Recombination Genetic Variation Genome Genome Scan Haplotypes Homologous Gene Human Hybrids Immunofluorescence Immunologic Immunoprecipitation Individual Mammals Maps Mass Spectrum Analysis Meiosis Meiotic Recombination Microscopy Modeling Modification Molecular Mutation Natural Selections Organism Ovary Pathway interactions Phenotype Phylogenetic Analysis Process Protein C Proteins Reagent Recombinants Resolution Ribosomes Scanning Scheme Sex Chromosomes Sex Ratio Sister Son Source Spontaneous abortion Structure Subgroup Synaptonemal Complex Tertiary Protein Structure Testing Testis Transgenic Organisms Y Chromosome base causal variant chromosome fusion cost dimorphism fitness fly genome sequencing genomic tools insight interest male novel offspring pressure sample fixation sex sexual dimorphism transcriptome transmission process whole genome

项目摘要

PROJECT SUMMARY/ABSTRACT Meiotic recombination is the exchange of genetic material between homologous chromosomes and is universally found in sexually reproducing organisms. By creating novel allelic combinations through chromosomal crossovers, meiotic recombination promotes genetic diversity and the efficacy of natural selection. When recombination is absent, like on the Y chromosome, deleterious mutations irreversibly accumulate in a process known as degeneration. The synaptonemal complex, which is required for the formation of crossovers, tethers homologues together and facilitates their proper disjunction in meiosis. Disruptions to to the process result in aneuploidy, which is the leading cause of Down syndrome and spontaneous abortions. Despite its essential functions, aspects of meiotic recombination are unexpectedly prone to change. Many genes involved are rapidly evolving under positive selection and, similarly, recombination rate can drastically differ between closely related species, and even between sexes. In fact, many distinct taxa, including Drosophila, lost the ability to recombine in males altogether, a.k.a. male achiasmy. While much of the mechanistic details are well characterized particularly in model species, it remains unclear as to why recombination is so labile. This proposal aims to address this question by focusing on D. nasuta, which, unique among Drosophila, has male recombination, and its sister species D. albomicans, which reverted to male achiasmy less than 100 thousand years ago. The reversal in D. albomicans occurred after fixation of two chromosomal fusions creating a pair of young neo-sex chromosomes. I previously showed that, prior to the reversal, male recombination produced multiple neo-Y haplotypes that now have different extent of degeneration. These two species offer an unique opportunity to determine the genetic, evolutionary, and molecular bases underlying the transition to and from achiasmy. I propose to identify the causal locus underlying the reversal to male achiasmy in D. albomicans, combining genomic tools and a classical phenotype mapping scheme (Aim 1). Candidates will be confirmed via transgenic manipulation with CRIPSR-Cas9. I will investigate the evolution of known genes involved in meiotic recombination in these two as well as closely related species, reasoning that male recombination in D. nasuta likely required activation of and adaptive modifications to the existing recombination machineries (Aim2). The resulting molecular and mechanistic changes during D. nasuta male meiosis will then be characterized with high resolution microscopy (Aim 2). Finally, I will determine the evolutionary pressure causing the reversal to male achiasmy in D. albomicans by testing the hypothesis that male recombination incurs a fitness cost due to the presence of the neo-Y chromosome (Aim 3). Execution of these aims will provide significant insight on the causes and consequences underlying the dichotomy between functional conservation and lability of recombination.

项目概要/摘要减数分裂重组是同源染色体之间遗传物质的交换，是普遍存在的存在于有性生殖生物体中。通过染色体创建新颖的等位基因组合交叉、减数分裂重组促进遗传多样性和自然选择的功效。什么时候不存在重组，就像在 Y 染色体上一样，有害突变在一个过程中不可逆地积累称为退化。联会复合体，是形成交叉、系链所必需的同源物聚集在一起并促进它们在减数分裂中的正确分离。过程中断会导致非整倍体，这是唐氏综合症和自然流产的主要原因。尽管它必不可少减数分裂重组的功能和方面出乎意料地容易发生变化。许多涉及的基因迅速在正选择下进化，同样，密切相关的重组率可能有很大差异物种之间，甚至性别之间。事实上，许多不同的类群，包括果蝇，失去了重组的能力全部为男性，又名男性异性。虽然许多机械细节都得到了很好的表征特别是在模式物种中，目前尚不清楚为什么重组如此不稳定。本提案旨在通过关注 D. nasuta 来解决这个问题，D. nasuta 在果蝇中是独一无二的，具有雄性重组，及其姊妹种 D. albomicans，恢复雄性不对称性小于 100 千年前。 D. albomicans 的逆转发生在两条染色体融合体固定后一对年轻的新性染色体。我之前表明，在逆转之前，雄性重组产生了多种新Y单倍型，这些单倍型现在具有不同程度的退化。这两个物种提供了确定过渡到和的遗传、进化和分子基础的独特机会来自阿奇亚斯米。我建议确定 D. albomicans 中雄性失对称逆转的因果轨迹，结合基因组工具和经典表型作图方案（目标 1）。候选人将通过以下方式确认使用 CRIPSR-Cas9 进行转基因操作。我将研究参与减数分裂的已知基因的进化这两个以及密切相关的物种中的重组，推断 D. nasuta 中的雄性重组可能需要激活现有的重组机制并对其进行适应性修改（目标2）。这 D. nasuta 雄性减数分裂期间产生的分子和机制变化将具有高特征分辨率显微镜（目标 2）。最后，我将确定导致男性逆转的进化压力通过检验雄性重组会由于以下原因而产生适应度成本的假设：新 Y 染色体的存在（目标 3）。这些目标的执行将提供对原因的重要洞察以及功能保守和重组不稳定性之间二分法背后的后果。