Fossil Free Sequencing of Archaic Genomes

古老基因组的无化石测序

• 批准号: 9250792
• 负责人: Joshua Michael Akey
• 金额: $ 8.71万
• 依托单位: UNIVERSITY OF WASHINGTON
• 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 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9250792
• 关键词: Admixture; African; Anatomy; Bioinformatics; Biological Preservation; Characteristics; DNA; DNA Sequence; Data; Data Set; Disease; Event; Evolution; Fossils; Gene Pool; Genes; Genetic Variation; Genetic study; Genome; Genomics; Geography; Goals; Human; Human Genetics; Hybrids; Individual; Inherited; Large-Scale Sequencing; Metagenomics; Methods; Modeling; Modernization; Molecular; Nature; Pattern; Population; Population Genetics; Population Sizes; Recording of previous events; Sample Size; Sex Bias; Specimen; Statistical Methods; Testing; Time; design; exome; exome sequencing; fitness; gene discovery; genetic analysis; genome sequencing; innovation; insight; metagenome; novel; public health relevance; simulation; statistics; whole genome

DESCRIPTION (provided by applicant): To date, the genetic analysis of extinct archaic hominins has required the isolation and sequencing of ancient DNA obtained from fossilized remains, which is technologically challenging and limited by the number of available specimens. However, the recent discovery that gene flow occurred between archaic groups, such as Neanderthals and Denisovans, and anatomically modern humans suggests a fossil free approach for the sequencing of archaic genomes. To this end, the goals of the proposed project are to develop an innovative new paradigm for the genetic analysis of archaic human ancestors, whose DNA lives on in the genomes of modern humans. In Aim 1, we will develop novel and computationally efficient methods for identifying introgressed DNA sequences. These methods will not depend on the availability of an archaic reference sequence and will therefore facilitate the discovery of previously unknown archaic hominins, if such groups exchanged genes with modern humans. We will rigorously evaluate the power and false discovery rates of newly developed statistics through extensive coalescent simulations under a wide variety of demographic models and admixture scenarios. In Aim 2, we will leverage our access to several large-scale sequencing projects and apply these novel methods to whole-genome and exome sequences collected in over 11,000 geographically diverse individuals. We will also develop methods to comprehensively analyze the population genetics characteristics of the reconstructed archaic metagenomes and to test hypotheses such as the fitness effects of hybridization, sex-biased patterns of gene flow, and whether introgressed sequences have been subject to positive selection. 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 may facilitate the molecular discovery and characterization of previously unknown archaic groups that have contributed to the modern gene pool. Overall, we anticipate that fossil free sequencing of archaic genomes will be a significant advancement for the burgeoning field of paleogenomics, allowing genetic analyses that have heretofore not been possible.

描述（由申请人提供）： 迄今为止，对已灭绝的古人类进行遗传分析需要对从化石遗骸中获得的古代DNA进行分离和测序，这在技术上具有挑战性，并且受到可用标本数量的限制。然而，最近发现基因流动发生在尼安德特人和丹尼索瓦人等古代群体与解剖学上的现代人类之间，这表明了一种无需化石的方法即可对古代基因组进行测序。为此，该项目的目标是开发一种创新的新范式，对远古人类祖先进行遗传分析，其 DNA 存在于现代人类的基因组中。在目标 1 中，我们将开发新颖且计算高效的方法来识别基因渗入的 DNA 序列。这些方法将不依赖于古代参考序列的可用性，因此将有助于发现以前未知的古代人类，如果这些群体与现代人类交换基因的话。我们将通过在各种人口模型和混合场景下进行广泛的合并模拟，严格评估新开发的统计数据的功效和错误发现率。在目标 2 中，我们将利用对多个大规模测序项目的访问权，并将这些新颖的方法应用于从 11,000 多个不同地理位置的个体中收集的全基因组和外显子组序列。我们还将开发方法来全面分析重建的古老宏基因组的群体遗传学特征，并测试诸如杂交的适应性效应、基因流的性别偏向模式以及渐渗序列是否受到正选择等假设。该项目的成功完成将扩展我们对古代人类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有模式，并可能促进对现代基因库做出贡献的先前未知的古代群体的分子发现和表征。总的来说，我们预计古代基因组的无化石测序将成为古基因组学新兴领域的重大进步，使迄今为止不可能的遗传分析成为可能。