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.

通常，单个生物中的基因被认为是对齐的 利益 - 在某些情况下最大化生物体的适应性， 个体中不同的基因可能会受益于 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生物，并与 其他基因。尽管这一事实的重要性在分子中得到了充分理解 进化生物学家，生物医学研究人员在很大程度上未能欣赏这些 含义。在拟议的工作中，我们将探讨久经考验的作用 基因组内冲突中的X染色体，并阐明了这场冲突的影响 人类生物学。 X染色体预计会特别高 基因组冲突既是由于其非典型遗传模式（主要是主要的） 从女性那里继承），并且由于其半合子经验（允许一个人 等位基因具有超大影响）。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 - 专注于干预措施的策略。该提议的短期目标是确定 冲突驱动X染色体的调节，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追求这些目标 在X染色体microRNA调节网络上； （ii）识别基因 根据X染色体的差异表达，具体取决于他们是哪个父 继承; （iii）使用单细胞RNA-seq数据识别细胞类型和 母体和父亲伴侣的差异表达的转录组影响 X人体组织中的X染色体。