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(申请人提供)：该项目的目标是比较古人类和现代人基因组的功能变异模式。来自保加利亚不同时期(公元前6300年-公元前400年，每个时期至少10个人)和不同地点的至少50个古人类个体的DNA将从牙齿中提取出来，并使用最近开发的一种定向全基因组捕获方法进行测序，然后进行全基因组测序。这将是第一次从一系列时间段的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，以确定这些个体与其他古代个体和现代种群的遗传关系。此外，还将研究这些基因组中的功能变异，以检验这样一种假设，即由于农业发明导致的人口爆炸，变异，包括有害突变的负载，在过去10,000年里有所增加。这一假设是由种群遗传学理论预测的，可以用古代DNA进行最直接的检验。我将通过三个具体目标来实现这些目标：第一，我将从保加利亚不同地理区域和不同时期的50个人的牙齿中测序古代DNA。提取的DNA将首先进行有针对性的全基因组捕获，以丰富内源序列，并使用Illumina技术在低覆盖率下对所得文库进行测序，以评估样本中人类DNA的水平。从至少50个通过严格质量控制标准的样本中提取的DNA将被测序至更高级别 覆盖范围的级别。其次，我将使用常染色体、线粒体和Y染色体变异来追踪种群的身份和随时间的变化。我将测定古代个体的线粒体和Y染色体单倍群，并将它们与现代群体的单倍群进行比较。此外，我将使用全基因组测序数据，通过与包括1000个基因组的参考小组、种群参考样本(POPRES)和人类基因组多样性小组(HGDP)进行比较，来分析这些古老基因组中的常染色体变异。最后，我将比较古代和现代人类基因组的功能变异模式。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；基于进化保守和对蛋白质结构影响的计算方法进行功能预测；以及存在于人类疾病突变数据库中。然后，我将比较古代和现代基因组中推定的破坏性和推定的中性变异的相对频率，以评估是否像理论预测的那样，现代人口积累了不成比例的有害变异。这些分析的结果可能有助于揭示决定现代人和古代人功能变异频谱的人口统计过程。好了！