Identification and interpretation of introgressed hominin DNA in modern human genomes

摘要 在过去的十年里，古代dna(Adna)的进步为人类提供了惊人的新见解。 历史，包括确凿的证据表明，现代人与现已灭绝的古人类混杂在一起，例如 尼安德特人和丹尼索瓦人。在上一轮融资中，我们首创了识别和解释 在现代人的基因组中仍然分离的人的DNA。对这些幸存下来的人的分析 古老的谱系表明，人类之间的混合很常见，既有积极的，也有消极的 适应度对基因流动的影响，以及引入的序列具有功能和表型效应。 尽管有这些见解，但仍有许多根本性的重要问题有待解决。这个 更全面地理解古人混合物的主要障碍包括需要 进一步发展计算高效的方法来寻找渐入序列，它们应用于 更具全球多样性的种群，以及描绘分子和功能的实验研究 基因流动的后果。我们将在重建项目中逐一解决这些问题。具体来说，在目标1中， 我们将扩展和改进识别导入DNA序列的方法。这种进一步的方法论 为了提高处理能力、降低误检率并提高计算效率，开发是必要的 足以分析庞大的测序数据集。在目标2中，我们将利用我们对几个 大规模测序项目，并将这些新方法应用于来自澳大利亚的全基因组序列数据 10万个地理上不同的人。重要的是，通过专门构建一个多样化的小组 个体，特别是来自未被研究的种群的个体，我们将能够对古老的 人类混合物以前是不可能的。我们还将开发方法来全面分析 导入序列的群体遗传学特征及适应度效应等检验假设 混杂、性别偏见的基因流动模式，以及与未知(或“幽灵”)血统的混杂。最后，在 目的3.首次系统、全面地对自适应内向学习进行实验分析 使用尖端基因编辑和功能基因组学技术的基因座。成功地完成了 拟议的项目将扩大我们对古人类和现代人之间混合事件的理解， 洞察渗入如何塑造人类基因组多样性的现存模式，并促进 对以前未知的古类群的分子发现和表征，这些古类群对 现代基因库。

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.