Mapping the Full Spectrum of Human Genetic Variation and Archaic Hominin Introgression in Oceania

绘制大洋洲人类遗传变异和古人类基因渗入的全谱图

• 批准号: 10501175
• 负责人: Serena Tucci
• 金额: $ 41.88万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10501175
• 关键词: Address; Admixture; Anthropology; Complex; Computational Biology; DNA; Disease susceptibility; Evolution; Genetic; Genetic Drift; Genetic Variation; Genetic study; Genome; Genomics; Geography; Goals; Graph; Human; Human Genetics; Human Genome; Inherited; Knowledge; Maps; Modernization; Molecular Biology; Natural Selections; Oceania; Oceans; Pattern; Phase; Phenotype; Play; Population; Population Heterogeneity; Recording of previous events; Research; Resolution; Role; Single Nucleotide Polymorphism; Variant; fitness; genome sequencing; genome-wide; genomic variation; human pangenome; improved; insight; migration; novel; population genetic structure; programs

Project Summary/Abstract: Large-scale population genomic studies have failed to provide a full picture of the genetic variation harbored in human populations, largely overlooking entire regions of the world. Indeed, of the human genomes currently available, only ~3% are from Oceania, a region that harbors unique population-specific genetic variation, including the largest amounts of DNA inherited from archaic hominin such as Neanderthals and the enigmatic Denisovans. Thus, a fundamental knowledge gap exists regarding human genetic variation and archaic hominin introgression in Oceania. A better understanding of the full spectrum of human genomic variation in Oceania is critical for reconstructing our evolutionary past and disentangling the genetic basis of phenotypic variation and disease susceptibility. In this context, my lab aims to discover and characterize human genetic variation in Oceania at unprecedented resolution. Upon establishing my lab in July 2020, we have spearheaded two large- scale genome sequencing projects which aim to characterize the full spectrum of human genetic variation in Oceania, from single nucleotide polymorphisms to large, complex structural variants. Using an integrative approach that combines insights from population genomics, molecular biology, genome sequencing, computational biology and anthropology, my lab seeks to understand how migrations, admixture, genetic drift, cultural barriers, and natural selection influence patterns in population genetic structure. One fundamental question we seek to address is how archaic hominin introgression contributes to phenotypic variation. While several lines of evidence exist for both adaptive and deleterious effects of Neandertal introgressed variants, our understanding of the impact of Denisovan introgression on fitness in modern humans is limited by the few available Oceanic genomes available. Our proposal offers an unprecedented opportunity to map Denisovan introgressed variants that remain undiscovered at present and make inference about their fitness and functional consequences. Importantly, motivated by the recent discovery of Oceanic-specific adaptive introgressed structural variants (SVs), my lab will explore the role that SVs played in human evolution and adaptation by generating the first panel of fully phased de novo assemblies of Oceanic genomes, and will comprehensively characterize SVs by integrating them into the latest human pangenome graph. Overall, my research program will empower the discovery of previously unknown human genetic variation, including novel candidates for adaptive introgression, and address fundamental questions about our evolutionary history.

项目摘要/摘要： 大规模的群体基因组研究未能提供遗传变异的全貌。 人口，很大程度上俯瞰世界整个地区。事实上，目前的人类基因组 现有的，只有约 3% 来自大洋洲，该地区拥有独特的人群特异性遗传变异， 包括从尼安德特人和神秘人等古代人族遗传而来的最大量 DNA 丹尼索瓦人。因此，关于人类遗传变异和古人类存在基本知识差距 大洋洲的基因渗入。更好地了解大洋洲人类基因组变异的全谱是 对于重建我们的进化历史和解开表型变异的遗传基础至关重要 疾病易感性。在这种背景下，我的实验室旨在发现和表征人类遗传变异 大洋洲以前所未有的分辨率。在 2020 年 7 月建立我的实验室后，我们率先开展了两项大型项目： 规模基因组测序项目，旨在表征人类遗传变异的全谱 大洋洲，从单核苷酸多态性到大型复杂的结构变异。使用综合 结合了群体基因组学、分子生物学、基因组测序的见解的方法， 计算生物学和人类学，我的实验室致力于了解迁移、混合、遗传漂变、 文化障碍和自然选择影响种群遗传结构的模式。一个基本的 我们寻求解决的问题是古人类基因渗入如何导致表型变异。尽管 存在多种证据表明尼安德特人基因渗入变异体的适应性和有害影响，我们的 对丹尼索瓦人基因渗入对现代人类健康影响的了解仅限于少数人 可用 可用的海洋基因组。我们的提案为绘制丹尼索瓦人地图提供了前所未有的机会 目前尚未发现的基因渗入变体，并对它们的适应性和功能进行推断 结果。重要的是，受到最近发现的海洋特异性适应性基因渗入的推动 结构变异（SV），我的实验室将通过以下方式探索 SV 在人类进化和适应中所发挥的作用 生成第一组完全定相的海洋基因组从头组装，并将全面 通过将 SV 整合到最新的人类泛基因组图中来表征 SV。总的来说，我的研究计划 将有助于发现以前未知的人类遗传变异，包括新的候选者 适应性基因渗入，并解决有关我们进化历史的基本问题。