Detection and replication of epistasis influencing transcription in humans.
Detection and replication of epistasis influencing transcription in humans.
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上位性是一种现象，即一种多态性对性状的影响取决于基因组中存在的其他多态性。上位性在多大程度上影响复杂性状并导致其变异，是进化和人类遗传学中的一个基本问题。虽然在模式生物的人工基因操作研究中经常被证明，并且在其他物种中也有一些例子被报道，但在人类性状的自然多态性中存在上位性的例子很少。它在实证研究中的缺失可能仅仅是由于复杂性状的遗传控制发生率低，但另一种观点是，由于统计和计算问题，它以前在技术上太具有挑战性而无法检测。在这里，我们表明，使用先进的计算和基因表达研究设计，在常见的单核苷酸多态性（snp）之间发现了许多上位性实例。在一组846人的外周血中测量7339个基因表达水平的队列中，我们发现影响238个基因表达的常见snp之间存在501个显著的两两相互作用（p < 2.91 × 10−16）。在两个独立的数据集中复制这些相互作用表明上位效应方向的一致性（p = 5.56 ×10−31）和相互作用p值的丰富性，其中30在p < 0.05/501的保守阈值下具有显著性。44个遗传相互作用位于已知物理染色体相互作用的2Mb区域内（p = 1.8 × 10−10）。三个或更多SNP的上位网络影响129个基因的表达水平，其中一个顺式作用的SNP被几个反式作用的SNP调节。例如，MBNL1受到rs13069559上的加性效应的影响，该效应本身被14个不同染色体上的反式snp所掩盖，每个顺式-反式相互作用具有几乎相同的基因型-表型（GP）图谱。这项研究提供了第一个证据，证明了多种分离的共同多态性相互作用影响人类特征。
Epistasis is the phenomenon whereby one polymorphism’s effect on a trait depends on other polymorphisms present in the genome. The extent to which epistasis influences complex traits and contributes to their variation is a fundamental question in evolution and human genetics. Though often demonstrated in artificial gene manipulation studies in model organisms, and some examples have been reported in other species, few examples exist for epistasis amongst natural polymorphisms in human traits. Its absence from empirical findings may simply be due to low incidence in the genetic control of complex traits, but an alternative view is that it has previously been too technically challenging to detect due to statistical and computational issues. Here we show that, using advanced computation and a gene expression study design, many instances of epistasis are found between common single nucleotide polymorphisms (SNPs). In a cohort of 846 individuals with 7339 gene expression levels measured in peripheral blood, we found 501 significant pairwise interactions between common SNPs influencing the expression of 238 genes (p < 2.91 × 10−16). Replication of these interactions in two independent data sets showed both concordance of direction of epistatic effects (p = 5.56 ×10−31) and enrichment of interaction p-values, with 30 being significant at a conservative threshold of p < 0.05/501. Forty-four of the genetic interactions are located within 2Mb of regions of known physical chromosome interactions (p = 1.8 × 10−10). Epistatic networks of three SNPs or more influence the expression levels of 129 genes, whereby one cis-acting SNP is modulated by several trans-acting SNPs. For example MBNL1 is influenced by an additive effect at rs13069559 which itself is masked by trans-SNPs on 14 different chromosomes, with nearly identical genotype-phenotype (GP) maps for each cis-trans interaction. This study presents the first evidence for multiple instances of segregating common polymorphisms interacting to influence human traits.