Human population genomics in time and space: comparing ancient and modern genomes

时间和空间上的人类基因组学：比较古代和现代基因组

• 批准号: 8524625
• 负责人: Meredith Lauren Carpenter
• 金额: $ 4.92万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8524625
• 关键词: Address; Age; Agriculture; Amino Acid Sequence; Area; Autistic Disorder; Biological Preservation; Bulgaria; Civilization; Complex; Computing Methodologies; Copper; DNA; Data; Databases; Deltastab; Disease; Ensure; Etiology; Farming environment; Frequencies; Genetic; Genome; Genomics; Genotype; Goals; Haplogroup; Human; Human Genome; Individual; Iron; Lactase; Libraries; Light; Location; Methods; Middle East; Mitochondria; Modeling; Movement; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Pattern; Phenotype; Play; Population; Population Explosions; Population Genetics; Process; Quality Control; Relative (related person); Role; Sampling; Sequence Analysis; Single Nucleotide Polymorphism; Site; Technology; Testing; Theoretical model; Time; Tooth structure; Variant; base; disease-causing mutation; genetic analysis; genome sequencing; human DNA; human disease; human population growth; migration; protein structure; public health relevance; research study; theories

DESCRIPTION (provided by applicant): The goal of this project is to compare patterns of functional variation in the genomes of ancient and modern human populations. DNA from at least 50 ancient human individuals from a range of time periods (6300 BC- 400 BCE, with at least 10 individuals from each time period) and locations in Bulgaria will be extracted from teeth and sequenced using a recently developed method for targeted whole-genome capture followed by whole-genome sequencing. This will be the first study to obtain genome sequences from populations of ancient individuals from a range of time periods. The results will be analyzed to determine the genetic relationships of these individuals to other ancient individuals and to modern populations. In addition, functional variation in these genomes will be examined to test the hypothesis that variation, including the load of deleterious mutations, has increased over the last 10,000 years as a result of the human population explosion produced by the invention of agriculture. This hypothesis, predicted by population genetic theory, can be most directly tested using ancient DNA. I will accomplish these goals through three specific aims: First, I will sequence ancient DNA from the teeth of 50 individuals from different geographical areas and time periods in Bulgaria. The extracted DNA will first be subjected to targeted whole-genome capture to enrich for endogenous sequences, and the resulting library will be sequenced at low coverage using Illumina technology to assess the levels of human DNA in the samples. DNA from at least 50 samples that pass strict quality control criteria will then be sequenced to higher levels of coverage. Secondly, I will use autosomal, mitochondrial, and Y-chromosomal variation to trace population identities and movements over time. I will determine the mitochondrial and Y-chromosomal haplogroups of the ancient individuals and compare them to those of modern populations. In addition, I will use the whole-genome sequencing data to analyze autosomal variation in these ancient genomes by comparing to reference panels including 1,000 Genomes, the Population Reference Sample (POPRES), and the Human Genome Diversity Panel (HGDP). Finally, I will compare patterns of functional variation in ancient and modern human genomes. I will categorize variation in ancient and modern genomes using three criteria: impact on the amino acid sequence; functional prediction by computational methods based on evolutionary conservation and effect on protein structure; and presence in databases of human disease mutations. I will then compare the relative frequency of putatively damaging vs. putatively neutral variants in the ancient vs. modern genomes to assess whether, as predicted by theory, modern-day populations have accumulated a disproportionate number of deleterious variants. The results of these analyses could shed light on the demographic processes that determined the spectrum of functional variation in modern and ancient human populations. !

描述（由申请人提供）：该项目的目的是比较古代和现代人口基因组中功能变化的模式。来自至少50个古代人物的DNA（公元前6300年，公元前6300年，每个时间段至少有10个个体）和保加利亚的位置将从牙齿中提取，并使用最近开发的方法对靶向全基因组捕获进行测序，然后由全基因组测序进行。这将是第一项从一段时间内从古代个体种群中获得基因组序列的研究。将对结果进行分析，以确定这些人与其他古代个体和现代人群的遗传关系。此外，将检查这些基因组的功能变化，以检验以下假设：由于农业发明所产生的人口爆炸，在过去的10，000年中，包括有害突变的负载（包括有害突变的负载）增加了。通过人口遗传理论预测的这一假设可以使用古代DNA进行最直接测试。我将通过三个特定的目标来实现这些目标：首先，我将从保加利亚的不同地理区域和时间段的50个个体的牙齿中对古代DNA进行序列。提取的DNA首先将受到靶向全基因组捕获的量，以富集内源序列，并使用Illumina技术在低覆盖范围内对所得的库进行测序，以评估样品中人类DNA的水平。从至少50个样品中，通过严格质量控制标准的DNA将被测序为较高 覆盖水平。其次，我将使用常染色体，线粒体和Y染色体变异来追踪人口身份和运动。我将确定古代个体的线粒体和Y染色体单倍群，并将其与现代人群进行比较。此外，我将使用全基因组测序数据来分析这些古代基因组中的常染色体变异，并与包括1,000个基因组，人口参考样本（POPRE）和人类基因组多样性面板（HGDP）在内的参考面板进行比较。最后，我将比较古代和现代人类基因组中功能变化的模式。我将使用三个标准对古代和现代基因组的变异进行分类：对氨基酸序列的影响；基于进化保护和对蛋白质结构的影响的计算方法的功能预测；以及在人类疾病突变数据库中的存在。然后，我将比较古代与现代基因组中预性破坏的相对频率与预性中性变体的相对频率，以评估现代人口是否积累了不成比例的有害变体。这些分析的结果可能阐明了确定现代和古代人口功能差异范围的人口过程。呢