Identification and interpretation of introgressed hominin DNA in modern human genomes

现代人类基因组中渗入的古人类 DNA 的鉴定和解释

基本信息

批准号：
10211454
负责人：
Joshua Michael Akey
金额：
$ 33.37万
依托单位：
PRINCETON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2025-03-31
项目状态：
未结题

项目摘要

Summary Over the past decade, advances in ancient DNA (aDNA) have provided striking new insights into human history, including conclusive proof that modern humans admixed with now extinct hominins, such as Neandertals and Denisovans. In the last cycle of funding, we pioneered methods to identify and interpret introgressed hominin DNA that still segregates in the genomes of modern humans. Analyses of these surviving archaic lineages shows that admixture among hominins was common, there was both positive and negative fitness consequences to gene flow, and introgressed sequences have functional and phenotypic effects. Despite these insights, there are many fundamentally important questions that remain to be addressed. The major barriers to a more comprehensive understanding of archaic hominin admixture include the need for further development of computationally efficient methods to find introgressed sequences, their application to more globally diverse populations, and experimental studies to delineate the molecular and functional consequences of gene flow. We will address each of these issues in the renewal project. Specifically, in Aim 1, we will extend and refine methods for identifying introgressed DNA sequences. Such further methodological development is necessary to improve power, reduce false positive rates, and be computationally efficient enough to analyze massively large sequencing data sets. In Aim 2, we will leverage our access to several large-scale sequencing projects and apply these novel methods to whole-genome sequence data from over 100,000 geographically diverse individuals. Importantly, by specifically constructing a diverse panel of individuals, particularly from understudied populations, we will be able to make inferences about archaic hominin admixture not previously possible. We will also develop methods to comprehensively analyze the population genetics characteristics of introgressed sequences and test hypotheses such as the fitness effects of admixture, sex-biased patterns of gene flow, and admixture with unknown (or “ghost”) lineages. Finally, in Aim 3, we will perform the first systematic and comprehensive experimental analysis of adaptively introgressed loci using cutting-edge gene editing and functional genomics technologies. The successful completion of the proposed project will extend our understanding of admixture events between archaic and modern humans, provide insight into how introgression has shaped extant patterns of human genomic diversity, and facilitate the molecular discovery and characterization of previously unknown archaic groups that have contributed to the modern gene pool.

概括在过去的十年中，古代DNA（ADNA）的进步为人类提供了惊人的新见解历史，包括现代人类现在已经灭绝的人类的结论性证据，例如尼安德特人和丹尼索沃斯人。在资金的最后一个周期中，我们开创了识别和解释的方法仍在现代人类基因组中分离的侵入性纯种DNA。这些幸存的分析档案谱系表明，植物中的混合是常见的，既有正面又有负面对基因流的适应性后果和渗入序列具有功能和表型效应。尽管有这些见解，但仍有许多重要的问题要解决。对古老的人类混合的更全面理解的主要障碍包括需要进一步开发计算高效的方法以查找侵入序列，其应用于全球多样的人群以及描述分子和功能的实验研究基因流的后果。我们将在续签项目中解决这些问题。具体来说，在AIM 1中，我们将扩展和完善用于识别渗入DNA序列的方法。这种进一步的方法论开发对于提高功率，降低误报率并提高计算效率是必要的足以分析大型测序数据集。在AIM 2中，我们将利用我们对几个的访问权限大规模测序项目，并将这些新方法应用于整个基因组序列数据 100,000个地理不同的人。重要的是，专门构建了一个潜水面板个人，尤其是从可理解的人群中，我们将能够推断出有关档案以前无法进行hominin混合。我们还将开发用于全面分析的方法渗透序列和检验假设（例如健身效应）的种群遗传学特征混合物，基因流的性偏见模式以及具有未知（或“幽灵”）谱系的混合物。最后，在 AIM 3，我们将对自适应渗透的第一个系统和全面的实验分析使用尖端基因编辑和功能基因组学技术的基因座。成功完成拟议的项目将扩展我们对档案和现代人类之间的混合事件的理解，提供有关渗入如何影响人类基因组多样性模式的洞察力，并促进以前未知的古群的分子发现和表征有助于现代基因池。