Population dynamics and medical consequences of sex chromosome evolution

性染色体进化的种群动态和医学后果

• 批准号: 10623638
• 负责人: Melissa A Wilson
• 金额: $ 45.37万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-11 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10623638
• 关键词: Accounting; Address; Affect; Africa; African; Animals; Biology; Chromosomes; Collaborations; Demography; Development; Disease; Diverse Workforce; Evolution; Gene Expression; Genomics; Health; Human; Human Genome; Learning; Link; Macaca mulatta; Medical; Methodological Studies; Methodology; Methods; Mitochondrial DNA; Organ; Outcome Study; Pattern; Placenta; Ploidies; Population; Population Dynamics; Population Study; Pregnancy Outcome; Recording of previous events; Research; Research Project Grants; Self Efficacy; Sex Bias; Sex Chromosomes; Students; Testing; Tissues; Training; Variant; Work; X Chromosome; X Inactivation; Y Chromosome; autosome; gene expression variation; genome-wide; genomic variation; improved; instructor; migration; novel; sex; skills; tool

PROJECT SUMMARY Sex-bias exists in the human genome in DNA content and gene expression. The human X and Y chromosomes are useful tools for inferring human demography, and crucial for our understanding of human health. However, despite the genomics era, X and Y chromosomes are still vastly underutilized, especially in a genome-wide context. Most established genomics methods and analyses fail to explicitly incorporate sex chromosomes, missing more than 5% of typical genomic variation, and ignoring regions known to contribute to disease. The study of sex chromosome evolution therefore addresses deficits in conventional approaches with critical implications for human health and biology. My research has focused on the integration of these chromosomes to build comprehensive analyses of human history and utilizing an evolutionary approach to characterize sex-bias in gene expression. This project will utilize multiple approaches for studying sex chromosome variation across human and non-human species. First, we will focus on development and extensive testing of novel methodology for accurately accounting for technical variation that affects alignment and variant calling on the sex chromosomes. Current alignment pipelines do not account for the shared homology between the X and Y chromosome, resulting in mis-mapping of reads between the sex chromosomes and reduced power for variant calling. We will incorporate sex chromosome biology to improve alignment and variant calling on the sex chromosomes. Second, we will study the evolution of sex chromosomes and X-inactivation in non-human animals, focused on our close evolutionary relative, the rhesus macaque. Third, we will study gene expression variation (with an emphasis on X-linked gene expression and X-inactivation) between the sexes, and between human populations in the human placenta. The placenta is the one organ routinely expelled from the body that also provides a crucial interface during development, and is not studied in current large-scale tissue expression projects. In collaboration with a long-term pregnancy outcome study we will generate and comprehensively analyze population-specific sex-bias in the human placenta. Fourth, we will study truly genome-wide patterns of variation (autosomes, X chromosome, Y chromosome, and mtDNA) in African populations. Populations in Africa are the most diverse in the world, and representation of that diversity is conspicuously absent from global population studies. In collaboration with anthropologists, who are studying, cultural variation, we will use patterns of variation across the sex chromosomes and autosomes to infer recent and ancient demography, informed by sex-biased migration and demography. Finally, we will contribute novel training materials for instructors and study student learning and self-efficacy as they learn genomics research skills. This work will improve methodology for studying sex-linked variation, provide estimates of sex-biased human demography, elucidate sex-biased expression in the human placenta, and utilize these research projects to improve training and inclusion of a diverse workforce.

项目摘要 人类基因组在DNA含量和基因表达方面存在性别偏见。人类的X和Y 染色体是推断人类人口统计学的有用工具，对于我们理解人类的进化至关重要。 健康然而，尽管进入了基因组学时代，X和Y染色体仍然被大大地利用不足，特别是在一个 全基因组背景。大多数已建立的基因组学方法和分析未能明确纳入性别 染色体，缺失超过5%的典型基因组变异，并忽略了已知的区域， 疾病因此，性染色体进化的研究解决了传统方法的缺陷， 对人类健康和生物学的重要影响。我的研究主要集中在整合这些 染色体建立人类历史的全面分析，并利用进化的方法， 描述基因表达中的性别偏见。这个项目将利用多种方法来研究性 人类和非人类物种的染色体变异。一是坚持以发展为中心， 对新方法进行广泛测试，以准确说明影响对准的技术变化 和性染色体上的变异。目前的对齐管道不考虑共享的 X和Y染色体之间的同源性，导致性别之间读取的错误映射 染色体和降低的变异识别能力。我们将结合性染色体生物学， 性染色体上的排列和变异。第二，我们将研究性的进化 非人类动物的染色体和X染色体失活，重点是我们的近亲，恒河猴 猕猴。第三，我们将研究基因表达变异（重点是X连锁基因表达， X-失活）之间，以及人类胎盘中的人类群体之间。胎盘是 这是一个经常从身体排出的器官，在发育过程中也提供了一个关键的界面， 在目前的大规模组织表达项目中没有研究。与长期妊娠的合作 结果研究，我们将产生和全面分析人口特异性性别偏见，在人类 胎盘第四，我们将研究真正的全基因组变异模式（常染色体、X染色体、Y染色体 染色体和mtDNA）。非洲的人口是世界上最多样化的， 在全球人口研究中，这种多样性显然缺乏代表性。协同 研究文化差异的人类学家，我们将使用跨性别的差异模式， 染色体和常染色体来推断最近和古代的人口统计学，由性别偏见的迁移和 人口统计学最后，我们将为教师提供新颖的培训材料，并研究学生的学习情况， 自我效能感，因为他们学习基因组学研究技能。这项工作将改进研究性连锁的方法 变异，提供性别偏见的人类人口统计学的估计，阐明性别偏见的表达，在人类 胎盘，并利用这些研究项目，以改善培训和包容的多元化劳动力。