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

点击翻译按钮获取中文摘要

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.