Characterization of Normal Genomic Variability

正常基因组变异的表征

• 批准号: 10251688
• 负责人: Andrew Singleton
• 金额: $ 0.86万
• 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/10251688
• 关键词: Africa; Africa South of the Sahara; Aging; American; Base Pairing; Biological; Brain; Cataloging; Catalogs; Cells; Copy Number Polymorphism; DNA Methylation; Data; Data Analyses; Data Set; Disease; Epigenetic Process; Foundations; Founder Effect; Genetic; Genetic Transcription; Genetic Variation; Genomics; Genotype; Geography; Goals; Haplotypes; Human; Human Genetics; Individual; Linkage Disequilibrium; Methylation; Pathway interactions; Pattern; Phase; Population; Quantitative Trait Loci; Regulation; Role; SNP genotyping; Sampling; Site; Structure; Tissues; Variant; Work; brain tissue; epigenome; epigenome-wide association studies; exome sequencing; genetic variant; genome sequencing; 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 have previously 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, RNA 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. These data are now being used to understand genetic aging in different tissues and as a reference data set for epigenome wide association studies. We have generated whole genome sequencing across our reference data set, the North American Brain Expression Consortium, and have in parallel performed whole transcriptome sequencing. Current analyses are focussing on expression quantitative trait locus identification, expression outlier analysis (to establish the role of rare variability on expression and biological traits in general). We are generating pilot data in these samples that aim to identify epigenetic and transcriptional changes at the single-cell level.

使用来自31个不同的全球人群的500多个样本，我们在550，000个位点进行了非常密集的全基因组单核苷酸多态性（SNP）基因分型。我们之前已经分析了这些数据以及基因型、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到种群中，并且由此产生的预测支持关于种群结构的精细尺度推断。随着与非洲的地理距离的增加，观察到越来越多的连锁不平衡，正如预期的那样，在非洲以外的人口传播的一系列创始人效应。我们在这项工作的基础上扩展到使用这些人群的数据来确定未知基因型的插补是否可行以及这种预测的最佳方法。这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，特别是桑人。 为了了解遗传变异对DNA甲基化的影响，我们在500个脑样本中进行了全基因组基因分型、外显子组测序、RNA测序和表观基因组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可能在物理上接近受影响的DNA甲基化位点。此外，我们表明，这些影响在组织中通常是一致的，尽管有一些值得注意的例外，如组织特异性甲基化数量性状基因座。这些数据现在被用于了解不同组织中的遗传衰老，并作为表观基因组广泛关联研究的参考数据集。 我们已经在我们的参考数据集北美脑表达联盟中生成了全基因组测序，并平行进行了全转录组测序。目前的分析集中在表达数量性状基因座鉴定，表达离群值分析（以确定罕见变异对表达和生物性状的作用）。我们正在这些样本中生成试点数据，旨在确定单细胞水平的表观遗传和转录变化。