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

研究概要 着丝粒卫星及其结合伙伴正在进行一场持续的进化军备竞赛，使得 每一方都在不断发展以赢得比赛。因此，着丝粒是最不同的之一 群体中的基因组元件，最终停止交换遗传物质并成为两个谱系。 重复着丝粒卫星窝藏位点的高度棘手性质一直是一个障碍 研究着丝粒进化的作用。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 2) 进行谱系分离 地理上分离且部分生殖隔离的家鼠谱系，这是理想的 研究谱系分离的系统3）基于候选的进化引导方法来描绘 谱系分离的遗传复杂过程。 有趣的是，着丝粒卫星上着丝粒蛋白的结合在这些谱系之间存在差异，尽管 他们分裂后短暂的进化时间。这表明这两个细胞中着丝粒的快速分歧 进化的物种已经获得了可以测量的功能差异。这项工作提出 着丝粒卫星和着丝粒蛋白快速进化的亚种特异性变体导致 家鼠谱系之间的功能着丝粒变异。该假设预测两者之间的交叉 由于“着丝粒”，这些谱系在杂交减数分裂中产生染色体分离不对称 不兼容”。利用可测量的功能差异，该提案旨在确定 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 杂种中不同谱系的着丝粒。 拟议的研究不仅有助于理解着丝粒进化在谱系中的作用 分离，但也将提供对着丝粒进化和遗传机制的见解。它将 还增强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 着丝粒蛋白并模拟自然界中着丝粒的进化。因此，我们的研究结果将 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.