Cowles Christopher R, Hirschhorn Joel N, Altshuler David, Lander Eric S
Whitehead Institute and MIT Center for Genome Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA.
Nat Genet. 2002 Nov;32(3):432-7. doi: 10.1038/ng992. Epub 2002 Oct 15.
Functional polymorphism in genes can be classified as coding variation, altering the amino-acid sequence of the encoded protein, or regulatory variation, affecting the level or pattern of expression of the gene. Coding variation can be recognized directly from DNA sequence, and consequently its frequency and characteristics have been extensively described. By contrast, virtually nothing is known about the extent to which gene regulation varies in populations. Yet it is likely that regulatory variants are important in modulating gene function: alterations in gene regulation have been proposed to influence disease susceptibility and to have been the primary substrate for the evolution of species. Here, we report a systematic study to assess the extent of cis-acting regulatory variation in 69 genes across four inbred mouse strains. We find that at least four of these genes show allelic differences in expression level of 1.5-fold or greater, and that some of these differences are tissue specific. The results show that the impact of regulatory variants can be detected at a significant frequency in a genomic survey and suggest that such variation may have important consequences for organismal phenotype and evolution. The results indicate that larger-scale surveys in both mouse and human could identify a substantial number of genes with common regulatory variation.
基因中的功能多态性可分为编码变异（改变编码蛋白的氨基酸序列）或调控变异（影响基因表达水平或模式）。编码变异可直接从DNA序列中识别出来，因此其频率和特征已得到广泛描述。相比之下，对于群体中基因调控的变异程度几乎一无所知。然而，调控变异很可能在调节基因功能方面很重要：有人提出基因调控的改变会影响疾病易感性，并且是物种进化的主要底物。在此，我们报告一项系统研究，以评估四个近交系小鼠品系中69个基因的顺式作用调控变异程度。我们发现这些基因中至少有四个在表达水平上显示出1.5倍或更大的等位基因差异，并且其中一些差异是组织特异性的。结果表明，在基因组调查中可以以显著频率检测到调控变异的影响，并表明这种变异可能对生物体表型和进化具有重要影响。结果表明，在小鼠和人类中进行更大规模的调查可能会识别出大量具有常见调控变异的基因。
