Patterns of cis regulatory variation in diverse human populations.
Patterns of cis regulatory variation in diverse human populations.
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DOI：
10.1371/journal.pgen.1002639
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Dermitzakis ET
中科院分区：
文献类型：
--
作者：
Stranger BE;Montgomery SB;Dimas AS;Parts L;Stegle O;Ingle CE;Sekowska M;Smith GD;Evans D;Gutierrez-Arcelus M;Price A;Raj T;Nisbett J;Nica AC;Beazley C;Durbin R;Deloukas P;Dermitzakis ET
基因表达变异的遗传基础长期以来一直是研究的对象，其目的不仅是了解调控变异的全貌，而且最近还用于协助疾病信号的解读和阐明。到目前为止，许多研究针对特定组织和基于人群的样本进行，但对调控变异在不同人群间的变异程度评估有限。我们分析了来自国际人类基因组单体型图计划（HapMap3）中8个全球人群共726个个体的淋巴母细胞系的全基因组基因表达，并将基因表达水平与位于基因顺式位置的HapMap3单核苷酸多态性（SNP）相关联。我们描述了血统对这些不同人群内部和之间基因表达水平的影响，并揭示了其对基因表达全局模式的不可忽视的影响。我们进一步剖析了人群之间存在差异的特定功能通路。在控制了非遗传因素和人群混合之后，我们还确定了5691个表达数量性状位点（eQTL），并观察到一半的顺式eQTL在一个或多个人群中得到了重复。我们强调了人群之间eQTL共享的模式，这种模式部分由人群遗传相关性决定，并且发现亚洲人、欧洲混血人群和非洲亚人群之间eQTL效应存在显著共享。具体而言，我们观察到eQTL的效应大小和效应方向在人群中高度保守。我们发现随着人群之间eQTL共享的增加，eQTL与转录起始位点的距离越来越近，这突出表明靠近转录起始位点的变异具有更强的效应，因此更有可能在更广泛的人群中被检测到。这些结果共同提供了人类人群在功能调控变异方面差异程度的独特图景和资源，并对复杂性状变异在人群间的可转移性进行了估计。
个体之间基因表达程度（即开启或关闭）的差异是所有物种都表现出的一个特征，并且研究已经确定了基因组中包含影响基因表达水平的遗传变异的区域。为了评估人类调控变异在不同人群间的变异程度，我们描述了对基因表达水平有功能影响的基因组区域的定位。我们分析了来自726个无亲缘关系个体的人类细胞系的全基因组基因表达，这些个体代表了8个全球人群，并且已经由国际人类基因组单体型图计划进行了良好的遗传特征分析。我们描述了血统对这些不同人群内部和之间基因表达水平的影响，并揭示了其对基因表达全局模式的不可忽视的影响。我们确定了约5700个基因，其表达水平与在物理位置上靠近该基因的遗传变异相关联，并且我们观察到在亚洲人、欧洲混血人群和非洲亚人群之间存在显著的关联共享，这种共享部分取决于人群遗传相关性。我们确定了受调控变异影响的生物学功能，并描述了人群特异性和人群共享关联的共同和独特特征。这些结果提供了人类人群在功能调控变异方面差异程度的独特图景和资源。
The genetic basis of gene expression variation has long been studied with the aim to understand the landscape of regulatory variants, but also more recently to assist in the interpretation and elucidation of disease signals. To date, many studies have looked in specific tissues and population-based samples, but there has been limited assessment of the degree of inter-population variability in regulatory variation. We analyzed genome-wide gene expression in lymphoblastoid cell lines from a total of 726 individuals from 8 global populations from the HapMap3 project and correlated gene expression levels with HapMap3 SNPs located in cis to the genes. We describe the influence of ancestry on gene expression levels within and between these diverse human populations and uncover a non-negligible impact on global patterns of gene expression. We further dissect the specific functional pathways differentiated between populations. We also identify 5,691 expression quantitative trait loci (eQTLs) after controlling for both non-genetic factors and population admixture and observe that half of the cis-eQTLs are replicated in one or more of the populations. We highlight patterns of eQTL-sharing between populations, which are partially determined by population genetic relatedness, and discover significant sharing of eQTL effects between Asians, European-admixed, and African subpopulations. Specifically, we observe that both the effect size and the direction of effect for eQTLs are highly conserved across populations. We observe an increasing proximity of eQTLs toward the transcription start site as sharing of eQTLs among populations increases, highlighting that variants close to TSS have stronger effects and therefore are more likely to be detected across a wider panel of populations. Together these results offer a unique picture and resource of the degree of differentiation among human populations in functional regulatory variation and provide an estimate for the transferability of complex trait variants across populations. Variation among individuals in the degree to which genes are expressed (i.e. turned on or off) is a characteristic exhibited by all species, and studies have identified regions of the genome harboring genetic variation affecting gene expression levels. To assess the degree of human inter-population variability in regulatory variation, we describe mapping of regions of the genome that have functional effects on gene expression levels. We analyzed genome-wide gene expression in human cell lines derived from 726 unrelated individuals representing 8 global populations that have been genetically well-characterized by the International HapMap Project. We describe the influence of ancestry on gene expression levels within and between these diverse human populations and uncover a non-negligible impact on global patterns of gene expression. We identify ∼5,700 genes whose expression levels are associated with genetic variation located physically close to the gene, and we observe significant sharing of associations that is partially dependent on population genetic relatedness, among Asians, European-admixed, and African subpopulations. We identify biological functions affected by regulatory variation and describe common and unique characteristics of population-specific and population-shared associations. These results offer a unique picture and resource of the degree of differentiation among human populations in functional regulatory variation.
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64.8
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Gilad, Yoav
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