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

项目摘要/摘要： 大规模的种群基因组研究未能提供蕴藏在人类基因组中的遗传变异的全貌 人类人口，在很大程度上俯瞰世界的整个地区。事实上，目前人类基因组的 目前，只有~3%的人来自大洋洲，这是一个拥有独特群体特有遗传变异的地区， 包括从古人类遗传的最大量的DNA，如尼安德特人和神秘的 丹尼索瓦人。因此，关于人类基因变异和古人类的基本知识鸿沟存在 大洋洲的海侵。更好地了解大洋洲人类基因组变异的全谱是 对于重建我们进化的过去和解开表型变异的遗传基础和 疾病易感性。在这种情况下，我的实验室旨在发现和表征人类基因变异 大洋洲以前所未有的决心。在2020年7月建立我的实验室后，我们带头开展了两个大型- 大规模基因组测序计划，旨在描述人类基因变异的全谱 大洋洲，从单核苷酸多态到大型复杂结构变体。使用集成式 结合了群体基因组学、分子生物学、基因组测序、 计算生物学和人类学，我的实验室试图理解迁徙，混合，遗传漂移， 文化障碍和自然选择影响种群遗传结构的模式。一个基本原则 我们试图解决的问题是古人类基因导入是如何导致表型变异的。而当 有几条证据表明尼安德特人的导入变体既有适应作用，也有有害影响，我们的 对丹尼索瓦的渗透对现代人体能的影响的了解受到少数人的限制 可利用的海洋基因组。我们的提案提供了一个前所未有的机会来绘制丹尼索万地图 目前仍未发现的导入变体并对其适用性和功能性进行推断 后果。重要的是，受最近发现的海洋特有的适应性引入的激励 结构变异(SVS)，我的实验室将通过以下方式探索SVS在人类进化和适应中所起的作用 产生第一组完全阶段性的海洋基因组从头开始组装，并将全面 通过将SVS整合到最新的人类痛苦组图中来描述SVS。总体而言，我的研究计划 将使以前未知的人类基因变异的发现成为可能，包括新的候选 适应性引入，并解决关于我们进化史的基本问题。

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.