Characterization of Normal Genomic Variability

正常基因组变异的表征

• 批准号: 9551260
• 负责人: Andrew Singleton
• 金额: $ 80.1万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9551260
• 关键词: Africa; Africa South of the Sahara; Base Pairing; Biological; Biological Assay; Brain; Cataloging; Catalogs; Copy Number Polymorphism; DNA Methylation; DNA Resequencing; Data; Data Analyses; Disease; Employee Strikes; Epigenetic Process; Foundations; Founder Effect; Generations; Genetic; Genetic Variation; Genomics; Genotype; Geography; Goals; Haplotypes; Human; Human Genetics; Individual; Linkage Disequilibrium; Messenger RNA; Methylation; Pathway interactions; Pattern; Phase; Population; Quantitative Trait Loci; Regulation; Sampling; Single Nucleotide Polymorphism; Site; Structure; Surveys; Tissues; Transcriptional Regulation; Variant; Work; age related; brain tissue; epigenome; exome sequencing; genetic variant; genome-wide; genomic variation; interest; trait; transcriptome sequencing; whole genome

Using more than 500 samples from 31 distinct worldwide human populations we performed very dense genome wide single nucleotide polymorphism (SNP) genotyping at 550,000 loci. We analyzed these data and the distribution of genotypes, haplotypes and copy number variants across populations. We showed that these data were able to assign individuals to populations and that the resulting predictions supported fine-scale inferences about population structure. Increasing linkage disequilibrium was observed with increasing geographic distance from Africa, as expected under a serial founder effect for the out-of-Africa spread of human populations. We extended upon this work to use the data from these populations to determine whether imputation of unknown genotypes is feasible and the best approach to this prediction. This particular aspect of work has now been expanded to include numerous sub-populations in sub-saharan Africa, particularly from the people of the San. To understand the effects of genetic variability on DNA methylation we have performed genome wide genotyping, exome sequencing and epigenome wide DNA methylation typing in 500 brain samples. These data show a striking effect of genetic variation on DNA methylation levels and show clearly that such variation is likely to be physically close the the DNA methylation site under influence. Further we show that these effects are generally consistent across tissues, although there are some notable exceptions to this noted as tissue specific methylation Quantitative Trait Loci. We have extended these analyses to reveal age related DNA methylation changes that occur across various tissues, including brain. We are still involved in ongoing work to perform a more dense genetic and epigenetic survey of these tissues, including exome sequencing, assay of 500,000 DNA methylation sites and mRNA sequencing. Further we are generating RNAseq data with the aim of integrating these data with the genetic and epigenetic data in order to better understand genetic control of transcription. In addition we have performed resequencing of disease related loci in these samples in an effort to understand the effects of rare genetic variability on biological traits. Most recently this work has included the generation of whole genome sequence.

利用来自全球31个不同人群的500多个样本，我们在550,000个座位上进行了非常密集的全基因组单核苷酸多态(SNP)基因分型。我们分析了这些数据以及基因类型、单倍型和拷贝数变异在人群中的分布。我们表明，这些数据能够将个体分配给种群，由此产生的预测支持关于种群结构的精细推断。随着距离非洲的地理距离的增加，观察到越来越多的连锁不平衡，正如在人口向非洲以外扩散的连续创始人效应下所预期的那样。在这项工作的基础上，我们使用来自这些人群的数据来确定未知基因类型的归因是否可行，以及这种预测的最佳方法。这一特定方面的工作现已扩大到包括撒哈拉以南非洲的许多亚人口，特别是来自桑人的人口。 为了了解遗传变异对DNA甲基化的影响，我们对500个大脑样本进行了全基因组基因分型、外显子组测序和表观基因组全DNA甲基化分型。这些数据显示了遗传变异对DNA甲基化水平的显著影响，并清楚地表明这种变异很可能在物理上接近受影响的DNA甲基化位点。此外，我们还表明，这些效应在组织中大体上是一致的，尽管有一些值得注意的例外，称为组织特异性甲基化数量性状基因座。 我们已经扩展了这些分析，以揭示发生在包括大脑在内的各种组织中的与年龄相关的DNA甲基化变化。我们仍在参与正在进行的工作，以对这些组织进行更密集的遗传和表观遗传学调查，包括外显子组测序、500,000个DNA甲基化位点的分析和mRNA测序。此外，我们正在生成RNAseq数据，目的是将这些数据与遗传和表观遗传数据相结合，以便更好地了解基因对转录的控制。此外，我们还对这些样本中与疾病相关的基因座进行了重新测序，以努力了解罕见的遗传变异对生物特征的影响。最近，这项工作包括了全基因组序列的生成。