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

人类生物学和癌症中母本和父本 X 染色体之间的竞争

• 批准号: 10629780
• 负责人: Scott Roy
• 金额: $ 15.5万
• 依托单位: SAN FRANCISCO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-16 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629780
• 关键词: Aging; Alleles; Behavior; Biology; Cells; Characteristics; Code; Conflict (Psychology); Data; Disease; Exhibits; Female; Foundations; Future; Gene Expression; Genes; Genetic Transcription; Genome; Genomic Imprinting; Genomics; Goals; Growth; Health; Human; Human Biology; Individual; Inheritance Patterns; Inherited; Intervention; Link; Malignant Neoplasms; Mammals; MicroRNAs; Molecular; Molecular and Cellular Biology; Motivation; Noise; Organism; Outcome Study; Parents; Pattern; Phenotype; Proteins; Regulation; Regulator Genes; Research; Research Personnel; Resources; Role; Shapes; Signal Transduction; Source; Testing; Tissues; Work; X Chromosome; X Inactivation; autosome; cell type; differential expression; experience; fitness; gene regulatory network; genome-wide; human disease; human tissue; imprint; insight; interest; link protein; male; programs; single-cell RNA sequencing; transcriptome; transcriptome sequencing; transcriptomics

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.

虽然通常认为单个生物体中的基因是对齐的 利益——最大化有机体的适应性——在某些情况下， 个体中的不同基因可能会受益于基因之间的不同权衡 有机体的特征。在这种“基因组内冲突”下，不同的基因可能 进化以不同的方式影响有机体，并对抗有机体的行为 其他基因。虽然这一事实的重要性在分子生物学界已得到充分理解 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 影响。在拟议的工作中，我们将探讨长期被低估的作用 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。 X 染色体预计会经历特别高水平的 基因组内冲突既是因为其非典型遗传模式（主要是 从女性遗传）并且由于其半合子经验（允许单个 等位基因具有巨大的影响）。该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- 重点干预策略。该提案的短期目标是确定 冲突驱动的 X 染色体的调控、转录组和细胞影响 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 X染色体microRNA调控网络； (ii) 鉴定基因 X 染色体上的差异表达取决于其亲本 继承自； (iii) 使用单细胞 RNA-seq 数据来识别细胞类型和 母系和父系遗传差异表达的转录组影响 人体组织中的 X 染色体。