Competition between maternal and paternal X chromosomes in human biology and cancer

虽然通常认为单个有机体中的基因是对齐的 利益-最大化有机体的健康-在某些情况下， 个体中的不同基因可能受益于不同的权衡 有机体的特征。在这种“基因组内冲突”下，不同的基因可能 进化到以不同的方式影响有机体，并对抗 其他基因。虽然这一事实的重要性在分子中是很好地理解的 进化生物学家、生物医学研究人员在很大程度上没有意识到这些 这意味着什么。在拟议的工作中，我们将探索长期以来被低估的作用 基因组内冲突中的X染色体，并阐明这种冲突对 人类生物学。预计X染色体将经历特别高水平的 基因组内冲突既是因为它的非典型遗传模式(主要是 从雌性遗传)，因为它的半合子经验(允许单一的 具有超大影响的等位基因)。这项研究计划的长期目标是 了解基因组内冲突如何影响人类健康，并设计冲突- 有重点的干预战略。这项提案的短期目标是确定 冲突驱动X染色体对调节、转录和细胞的影响 生物学。我们将通过(I)研究基因组冲突的影响来实现这些目标 在X染色体microRNA调控网络上；(Ii)识别 在X染色体上的差异表达取决于它们是哪个亲本 以及(Iii)使用单细胞RNA-seq数据来识别细胞类型和 母系和父系遗传基因差异表达对转录的影响 人类组织中的X染色体。

While generally the genes in a single organism are thought of as having aligned interests – maximizing the fitness of the organism – under some circumstances, different genes in an individual may benefit from different tradeoffs between an organism’s characteristics. Under such “intragenomic conflict,” different genes may evolve to influence the organism in different ways, and to antagonize the actions of other genes. While the importance of this fact is well-understood among molecular evolutionary biologists, biomedical researchers have largely failed to appreciate these implications. In the proposed work, we will explore the long-underappreciated role of the X chromosome in intragenomic conflict, and elucidate the impacts of this conflict on human biology. The X chromosome is expected to experience particularly high levels of intragenomic conflict both because of its atypical inheritance pattern (being primarily inherited from females) and because of its hemizygous experience (allowing a single allele to have outsize influence). The long term goals of this research programme are to understand how intragenomic conflict influences human health and to devise conflict- focused strategies for interventions. The short-term goals of this proposal are to identify the regulatory, transcriptomic and cellular impacts of conflict-drive X chromosomal biology. We will pursue these goals through (i) studying the impact of genomic conflict on X chromosomal microRNA regulatory networks; (ii) identifying genes that are differentially expressed on X chromosomes depending on which parent they are inherited from; and (iii) using single-cell RNA-seq data to identify the cell-type and transcriptomic impacts of differential expression of maternally- and paternally-inherited X chromosomes in human tissues.