Fossil Free Sequencing of Archaic Genomes

描述(由申请人提供)： 到目前为止，对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，而且受到可用标本数量的限制。然而，最近的发现表明，基因流动发生在古人群体之间，如尼安德特人和丹尼索瓦人，以及解剖学上的现代人，这表明了一种用于古生物基因组测序的无化石方法。为此，拟议项目的目标是为古人类祖先的基因分析开发一种创新的新范式，古人类祖先的DNA存在于现代人的基因组中。在目标1中，我们将开发新的和计算高效的方法来识别导入的DNA序列。这些方法将不依赖于古参考序列的可用性，因此将有助于发现以前未知的古人类，如果这些群体与现代人交换基因的话。我们将在各种人口统计模型和混合情景下，通过广泛的联合模拟，严格评估新开发的统计数据的威力和错误发现率。在目标2中，我们将利用我们对几个大规模测序项目的访问，并将这些新方法应用于从超过11,000个不同地理位置的个人中收集的全基因组和外显子组序列。我们还将开发方法来综合分析重建的古代元基因组的群体遗传学特征，并检验诸如杂交的适合度效应、基因流动的性别偏见模式以及导入序列是否受到正选择等假说。该项目的成功完成将扩大我们对古人类和现代人之间混合事件的理解，提供对导入如何塑造人类基因组多样性现有模式的洞察，并可能促进对以前未知的古代群的分子发现和表征，这些古代群对现代基因库做出了贡献。总体而言，我们预计，对古生代基因组进行无化石测序将是新兴的古基因组学领域的重大进步，使迄今为止无法进行的遗传分析成为可能。

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.