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

• 批准号: 10606493
• 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
• 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
• 来源: https://reporter.nih.gov/project-details/10606493
• 关键词: Address; Admixture; African; Anatomy; CRISPR/Cas technology; Characteristics; Communities; Complex; DNA; DNA Sequence; Data; Data Set; Development; Disease; Event; Funding; Gene Exchanges; Gene Pool; Genes; Genetic Variation; Genome; Genomics; Geography; Human; Human Genetics; Human Genome; Individual; Inherited; Large-Scale Sequencing; Maps; Methodology; Methods; Modeling; Modernization; Molecular; Nature; Pattern; Phenotype; Population; Population Genetics; Population Heterogeneity; Population Study; Recording of previous events; Research; Sex Bias; Shapes; Statistical Methods; Survival Analysis; System; Technology; Testing; Variant; Work; design; detection method; experimental analysis; experimental study; fitness; functional genomics; improved; insight; novel; reference genome; segregation; user friendly software; whole genome

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.

总结 在过去的十年中，古DNA（aDNA）的进展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合，如 尼安德特人和丹尼索瓦人。在上一轮融资中，我们开创了识别和解释 在现代人类的基因组中仍然分离的渗入的人类DNA。分析这些幸存者 古代谱系表明，人类之间的混合是常见的，既有阳性的，也有阴性的。 适合度对基因流的影响，渗入序列具有功能和表型效应。 尽管有这些见解，但仍有许多根本性的重要问题有待解决。的 更全面地了解古人类混合体的主要障碍包括需要 进一步发展计算上有效的方法来发现渗入序列，它们的应用， 更多的全球多样化的人群，以及实验研究，以描绘分子和功能 基因流的后果我们将在更新项目中解决这些问题。具体而言，在目标1中， 我们将扩展和改进鉴定基因渗入DNA序列的方法。这种进一步的方法 为了提高能力、降低误报率并提高计算效率，有必要进行开发 足以分析大量的测序数据集。在目标2中，我们将利用我们对几个 大规模测序项目，并将这些新的方法应用于全基因组序列数据， 100，000个不同地域的个体。重要的是，通过专门构建一个多样化的小组， 个体，特别是来自未充分研究的人群，我们将能够对古代的 人类混合物以前不可能。我们还将制定方法，全面分析 渐渗序列的群体遗传学特征和检验假设，如适合度效应 基因流的性别偏见模式，以及与未知（或“幽灵”）血统的混合。最后在 目标3，我们将进行第一次系统和全面的实验分析，自适应渗入 使用尖端的基因编辑和功能基因组学技术。圆满完成 拟议的项目将扩大我们对古代和现代人类之间混合事件的理解， 深入了解基因渗入如何塑造人类基因组多样性的现存模式， 分子发现和表征以前未知的古老群体，有助于 现代基因库