Dimas Antigone S, Stranger Barbara E, Beazley Claude, Finn Robert D, Ingle Catherine E, Forrest Matthew S, Ritchie Matthew E, Deloukas Panos, Tavaré Simon, Dermitzakis Emmanouil T
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
PLoS Genet. 2008 Oct;4(10):e1000244. doi: 10.1371/journal.pgen.1000244. Epub 2008 Oct 31.
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.
全基因组关联研究在通过单变异体剖析人类复杂性状的遗传学方面展现出了很大的前景，然而，很大一部分遗传效应仍未得到解释。分析变异体之间的遗传相互作用（上位性）是一条潜在的前进道路。我们研究了一种特定类型的上位性，即调控变异体与蛋白质编码变异体之间的相互作用的丰度和功能影响。利用来自原始四个HapMap群体的210个无关个体的基因型和基因表达数据，我们探索了调控性和蛋白质编码单核苷酸多态性（SNP）的联合效应。我们预测，约18%（8233个非同义SNP中的1502个）的蛋白质编码变异体在个体间存在差异表达，并证明调控变异体可在顺式作用中改变编码变异体的功能效应。此外，我们表明这种顺式相互作用可影响含有蛋白质编码SNP的基因的下游靶标的表达。通过这种方式，调控变异体与蛋白质编码变异体之间的顺式相互作用对基因表达具有反式影响。鉴于人类群体中这两种类型变异体的丰度，我们提出，联合考虑调控变异体和蛋白质编码变异体可能会揭示复杂性状和疾病背后的额外遗传效应，并可能阐明已知疾病变异体不同外显率的原因。
