R35 Investigating rapidly evolving centromeres and their role in the reproductive isolation in mammals

R35 研究快速进化的着丝粒及其在哺乳动物生殖隔离中的作用

• 批准号: 10501334
• 负责人: Jitendra Thakur
• 金额: $ 38.82万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-19 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10501334
• 关键词: Binding; Binding Proteins; Cancerous; Cells; Cellular biology; Centromere; Chromosome Segregation; Complex; Congenital chromosomal disease; Elements; Evolution; Failure; Genetic; Genetic Materials; Genomics; Geography; House mice; Hybrids; Impairment; Infertility; Malignant Neoplasms; Mammals; Measurable; Measures; Meiosis; Metabolism; Nature; Population; Process; Proteins; Race; Research; Role; Side; System; Testing; Time; Variant; Work; arms race; base; forging; insight; male; multidisciplinary; overexpression; reproductive

RESEARCH SUMMARY Centromeric satellites and their binding partners are engaged in an ongoing evolutionary arms race such that each side is continuously evolving to win the race. As a result, centromeres are one of the most divergent genomic elements in populations, which ultimately stop exchanging genetic material and become two lineages. Highly intractable nature of repetitive centromeric satellite harboring loci has been an impediment to investigating the role of centromere evolution. The proposed research will test the role of centromere evolution in lineage separation by utilizing 1) a state-of-the-art genomics-based approach to study satellite evolution 2) geographically separated and partially reproductively isolated house mouse lineages, which serve as an ideal system to study lineage separation 3) a candidate based evolutionarily guided approach to delineate genetically complex process of the lineage separation. Interestingly, binding of centromeric proteins at centromeric satellites varies between these lineages despite the short evolutionary time after their split. This suggests that rapid divergence of centromeres in these two evolving species have acquired functional differences, which can be measured. This work proposes that rapidly evolving subspecies-specific variants of centromeric satellites and centromeric proteins result in functional centromere variation between house mouse lineages. This hypothesis predicts that a cross between these lineages generates chromosome segregation asymmetries in the hybrid meiosis due to “centromere incompatibilities”. Taking advantage of the measurable functional divergence, this proposal aims to identify lineage specific centromere features that contribute to the hybrid failure. Our multidisciplinary evolutionary guided approach combines genomics, cell biology, and genetics to study incompatibilities between centromeres of diverging lineages in the hybrid. The proposed research will not only help in understanding the role of centromere evolution in lineage separation but will also provide insights into the mechanisms of centromere evolution and inheritance. It will also enhance our understanding of widespread chromosomal disorders resulting from impaired centromere function. Centromere metabolism in cancerous cells involves expansion of satellite arrays and over-expression of centromeric proteins and mimics centromere evolution in nature. Findings from our research will thus provide insights into the process of centromere microevolution in cancers.

研究摘要 Centromeric卫星及其约束伙伴参与正在进行的进化武器竞赛，以至于 双方都在不断发展以赢得比赛。结果，centromeres是最不同的 人群中的基因组元素，最终停止改变遗传物质并成为两个谱系。 重复性的中心卫星的高度棘手的性质是藏有基因座的障碍 研究着丝粒进化的作用。拟议的研究将测试Centromere Evolution的作用 在谱系分离中，使用1）基于最先进的基因组学方法研究卫星进化2） 地理分离并部分再现了孤立的房屋小鼠谱系，这是理想的 研究谱系分离的系统3）基于候选的进化指导方法来描述 谱系分离的遗传复杂过程。 有趣的是，在这些谱系目的地之间，丝粒卫星处的丝粒蛋白的结合在 他们分裂后的短暂进化时间。这表明这两个中心粒的迅速发散 不断发展的物种获得了可以测量的功能差异。这项工作的建议 快速发展的丝粒卫星和丝粒蛋白的亚种特异性变体导致 房屋小鼠谱系之间的功能性共粒差异。这个假设的预测是 这些谱系在杂种减数分裂中产生染色体隔离不对称，因为 不兼容”。利用可测量的功能差异，该建议旨在确定 谱系特定的中心粒特征，导致杂种衰竭。我们的多学科进化 指导方法结合了基因组学，细胞生物学和遗传学来研究之间的不相容性 杂种中分歧谱系的centromeres。 拟议的研究不仅将有助于理解中心粒演变在谱系中的作用 分离，但还将提供有关Centromere进化和继承机制的见解。会 还增强了我们对Centromere受损的宽度染色体疾病的理解 功能。取消细胞中的Centromere代谢涉及卫星阵列的扩展和过表达 自然界中的丝粒蛋白质和模仿着丝粒进化。因此，我们的研究结果将 提供有关癌症中心粒微粒进化过程的见解。