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

研究综述 着丝粒卫星和它们的结合伙伴参与了一场持续的进化军备竞赛， 每一方都在不断进化以赢得比赛。因此，着丝粒是最具分歧性的 种群中的基因组元素，最终停止交换遗传物质，成为两个谱系。 具有重复着丝粒卫星的基因座的高度难治性已经成为 研究着丝粒进化的作用。这项拟议中的研究将测试着丝粒进化的作用 通过利用1）最先进的基于基因组学的方法来研究卫星进化2） 地理上分离和部分生殖隔离的家鼠谱系，这是一个理想的 系统研究谱系分离3）候选人为基础的进化指导的方法来划定 血统分离的复杂遗传过程。 有趣的是，着丝粒蛋白在着丝粒卫星上的结合在这些谱系之间变化， 它们分裂后的短暂进化时间。这表明，这两个物种的着丝粒的快速分化 进化中的物种获得了可以测量的功能差异。这项工作提出， 快速进化的着丝粒卫星和着丝粒蛋白质的亚种特异性变体导致 家鼠谱系之间的功能性着丝粒变异。这一假说预测， 这些谱系在杂种减数分裂中由于“着丝粒”而产生染色体分离不对称性 不兼容性”。利用可衡量的功能差异，本建议旨在确定 导致杂交失败的谱系特异性着丝粒特征。我们的多学科进化 引导方法结合了基因组学、细胞生物学和遗传学，以研究 杂种中分歧谱系的着丝粒。 这项研究不仅有助于理解着丝粒进化在谱系中的作用， 分离，但也将提供深入了解着丝粒进化和遗传的机制。它将 也增强了我们对着丝粒受损导致的广泛染色体疾病的理解 功能癌细胞中的着丝粒代谢涉及卫星阵列的扩展和过度表达 着丝粒蛋白质和模仿自然界中的着丝粒进化。因此，我们的研究结果将 提供了对癌症中着丝粒微进化过程的见解。

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.