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 species1. 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.
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We thank J. Platko, A. Rachupka, R. Prill and D. Richter for cDNA sequencing; E. Winchester and K. Lindblad-Toh for assistance in identification of appropriate SNPs to assay; Y.M. Lim and P. Sklar for help with initial SBE assays; M. Daly for gel analysis software and discussions; J. Rioux and E.J. Kulbokas for aiding genomic DNA sequencing; and D. Reich, G. Acton, K. Hong, A. Gimelbrant and A. Chess for discussions. This work was supported in part by a fellowship of the Damon Runyon Cancer Research Foundation (to C.R.C.) and by grants from the US National Institutes of Health (to E.S.L.). J.N.H. is a recipient of a Howard Hughes Medical Institute Postdoctoral Fellowship for Physicians.
The authors declare no competing financial interests.
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