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

研究综述 着丝粒卫星及其绑定伙伴正在进行一场进化军备竞赛， 每一方都在不断进化，以赢得这场比赛。因此，着丝粒是最具分歧的 种群中的基因组元素，最终停止交换遗传物质，形成两个谱系。 携带基因座的重复着丝粒卫星的高度顽固性一直是阻碍 研究着丝粒进化的作用。这项拟议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的血统分离2) 地理上分离的和部分繁殖隔离的家鼠血统，这是一个理想的 研究世系分离的系统3)基于候选的进化引导的方法来描绘 世系分离的遗传复杂过程。 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有所不同，尽管 他们分开后很短的进化时间。这表明这两种着丝粒的快速分化 进化中的物种已经获得了功能差异，这是可以衡量的。这项工作表明 着丝粒卫星和着丝粒蛋白的快速进化的亚种特有变体导致 家鼠血统之间的着丝粒功能变异。这一假说预测， 这些谱系在杂交减数分裂中由于“着丝粒”而产生染色体分离不对称。 不兼容“。利用可测量的功能差异，本提案旨在确定 导致杂交失败的特定的着丝粒特征。我们的多学科进化 指导性方法结合了基因组学、细胞生物学和遗传学来研究 杂交种中不同血统的着丝粒。 这项拟议的研究不仅有助于理解着丝粒进化在血统中的作用 分离，但也将提供对着丝粒进化和遗传机制的洞察。会的 也增强了我们对着丝粒受损引起的广泛的染色体疾病的理解 功能。癌细胞的着丝粒代谢涉及卫星阵列的扩张和过度表达 着丝粒蛋白质和模拟自然界着丝粒进化。我们的研究结果将因此 提供对癌症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.