Modifier effects between regulatory and protein-coding variation.
Modifier effects between regulatory and protein-coding variation.
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DOI：
10.1371/journal.pgen.1000244
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发表时间：
2008-10
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：
Dimas AS;Stranger BE;Beazley C;Finn RD;Ingle CE;Forrest MS;Ritchie ME;Deloukas P;Tavaré S;Dermitzakis ET
全基因组关联在解剖具有单一变异的人类复杂性状的遗传学方面显示出了很大的希望，但很大一部分遗传效应仍然无法解释。分析变异之间的遗传相互作用（上位性）是潜在的前进方向之一。我们研究了一种特定类型的上位性的丰度和功能影响，即调节和蛋白质编码变体之间的相互作用。使用基因型和基因表达数据，从210个无关的个人原来的四个HapMap人口，我们已经探讨了监管和蛋白质编码单核苷酸多态性（SNP）的综合影响。我们预测，约18%（8，233个nsSNP中的1，502个）的蛋白质编码变体在个体之间差异表达，并证明调节变体可以修改顺式编码变体的功能效应。此外，我们表明，这种顺式相互作用可以影响含有蛋白质编码SNP的基因的下游靶点的表达。以这种方式，调节和蛋白质编码变体之间的顺式相互作用对基因表达具有反式影响。鉴于这两种类型的变异在人群中的丰度，我们建议，共同考虑的监管和蛋白质编码的变异可能会揭示额外的遗传效应的复杂性状和疾病，并可能揭示已知的疾病变异的差异性的原因。全基因组关联研究（GWAS）的最终目标是解释可归因于遗传因素的表型性状变异的比例。在过去的两年里，这一领域取得了大量的成功，然而，对于大多数性状来说，很大一部分变异仍然无法解释。上位性，或遗传变异之间的相互作用，是一个在很大程度上未被探索的因素，这可能会在这一领域带来一些启示。我们使用HapMap群体来研究调控和蛋白质编码变体之间的相互作用及其对基因表达的影响。我们表明，如果一个特定的蛋白质编码变体具有功能的影响，这可以通过共分离的调节变体（顺式相互作用）进行修改。此外，作者证明，在一个基因座上的变体之间的这种修饰效应可能以反式方式影响细胞中其他基因的表达。这篇文章的目的是提出一个框架，虽然可以考虑在GWAS的上下文中的变化。在某些情况下，从这个未被充分认识的角度观察变异可能会解释复杂疾病性状的差异性，也可能解释这种相互作用可能导致的GWAS结果的非复制性。
Genome-wide associations have shown a lot of promise in dissecting the genetics of complex traits in humans with single variants, yet a large fraction of the genetic effects is still unaccounted for. Analyzing genetic interactions between variants (epistasis) is one of the potential ways forward. We investigated the abundance and functional impact of a specific type of epistasis, namely the interaction between regulatory and protein-coding variants. Using genotype and gene expression data from the 210 unrelated individuals of the original four HapMap populations, we have explored the combined effects of regulatory and protein-coding single nucleotide polymorphisms (SNPs). We predict that about 18% (1,502 out of 8,233 nsSNPs) of protein-coding variants are differentially expressed among individuals and demonstrate that regulatory variants can modify the functional effect of a coding variant in cis. Furthermore, we show that such interactions in cis can affect the expression of downstream targets of the gene containing the protein-coding SNP. In this way, a cis interaction between regulatory and protein-coding variants has a trans impact on gene expression. Given the abundance of both types of variants in human populations, we propose that joint consideration of regulatory and protein-coding variants may reveal additional genetic effects underlying complex traits and disease and may shed light on causes of differential penetrance of known disease variants. The ultimate goal of genome-wide association studies (GWAS) is to explain the proportion of variation in a phenotypic trait that can be attributed to genetic factors. The past two years have seen a plethora of successes in this field, yet, for most traits, a large fraction of variation remains unexplained. Epistasis, or interaction between genetic variants, is a largely under-explored factor, which may shed some light in this area. We use the HapMap populations to investigate interactions between regulatory and protein-coding variants and their impact on gene expression. We show that if a specific protein-coding variant has a functional impact, this can be modified by a co-segregating regulatory variant (cis interaction). Furthermore, the authors demonstrate that such modification effects between variants at one locus may affect the expression of other genes in the cell in a trans manner. The aim of this article is to present a framework though which variation can be considered in the context of GWAS. Viewing variation from this underappreciated angle may, in some cases, provide an explanation for differential penetrance of complex disease traits, but also for non-replication of GWAS results that may arise as a consequence of such interactions.
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影响因子：
4.5
作者：
Evans, David M.;Marchini, Jonathan;Morris, Andrew P.;Cardon, Lon R.
通讯作者：
Cardon, Lon R.
影响因子：
7
作者：
Kuhn, K;Baker, SC;Chee, MS
通讯作者：
Chee, MS
影响因子：
64.8
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通讯作者：
Skol, Andrew
影响因子：
4.5
作者：
McVean G;Spencer CC;Chaix R
通讯作者：
Chaix R
影响因子：
30.8
作者：
Goering, Harald H. H.;Curran, Joanne E.;Blangero, John
通讯作者：
Blangero, John