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

项目概要/摘要： 大规模的群体基因组研究未能提供基因变异的全貌， 人类的人口，在很大程度上俯瞰整个地区的世界。事实上，目前人类的基因组 只有约3%来自大洋洲，这是一个拥有独特种群特异性遗传变异的地区， 包括最大数量的遗传自古人类的DNA，如尼安德特人和神秘的 丹尼索瓦人因此，关于人类遗传变异和古人类， 在大洋洲渐渗。更好地了解大洋洲人类基因组变异的全谱， 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， 疾病易感性在这种情况下，我的实验室旨在发现和描述人类遗传变异， 以前所未有的分辨率。在2020年7月成立我的实验室后，我们率先推出了两个大型- 大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结构变异。使用综合 这种方法结合了人口基因组学、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 我们试图解决的问题是古人类基因渗入如何导致表型变异。而 尼安德特人渐渗变体的适应性和有害影响存在几条证据，我们 对丹尼索瓦人基因渗入对现代人类健康的影响的理解受到少数人的限制， 可用的海洋基因组可用。我们的提议提供了一个前所未有的机会 渗入的变异，目前仍未发现，并作出推断，他们的健身和功能 后果重要的是，由于最近发现的海洋特异性适应性基因渗入， 结构变异（SV），我的实验室将探索SV在人类进化和适应中发挥的作用， 产生第一组完全分阶段的大洋基因组从头组装，并将全面 通过将它们整合到最新的人类泛基因组图中来表征SV。总的来说，我的研究项目 将有助于发现以前未知的人类遗传变异，包括新的候选人， 适应性基因渗入，并解决有关我们的进化历史的基本问题。

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.