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The distribution of common genetic variants in the human genome (PGP meeting 2008).

Cis-regulatory sequences in the genome are responsible for the sequential activation and deactivation of all the genes during development, therefore clusters of cis-regulatory elements define a large number of logic modules required for orderly growth and pattern formation [1]. Of the estimated 10 million common single nucleotide polymorphisms (SNPs) in human, more than 98% are expected to fall in the non-coding region[2]. While several promoter and transcription factor binding site databases are available, it is difficult to measure the exact number of function cis-regulatory sites present in the human genome. It is even more difficult to know how many of them are affected by SNPs although some estimates are available [3].

While most deleterious genetic disorders are caused by non-synonymous coding-variants, cis-regulatory polymorphisms are thought to be important for normal evolutionary divergence of growth, function and phenotype.[4, 5, 6]. Thus, the majority of normal human traits and their wide (or narrow, depending on your point of view) spectrum may be due to subtle changes in cis-regulatory elements and in gene expression.

Various cis-regulatory SNPs are known to play a role is a small number of common and rare human diseases.[4, 5, 6, 7, 8, 9, 10] Studies and plants and mice have shown that a large measure of gene expression variation is may be due to a surprisingly common cis-regulatory SNPs/genetic variations. Cis-regulatory SNPs are attractive also because it can readily identify the associated signaling and transcription cascade and biological pathways, and become a target for selective pharmacological agents.

So far, vast majority of genetic studies have focused on the coding SNPs mainly due to the limitations in technology. With the arrival of affordable full genome sequencing and capture technologies, this relatively unexplored area in human genetics is about to explode. This page will be dedicated to groups and laboratories interested in developing and applying methods for exploring functional non-coding, cis-regulatory SNPs.





  1. Materna SC and Davidson EH. Logic of gene regulatory networks. Curr Opin Biotechnol. 2007 Aug;18(4):351-4. DOI:10.1016/j.copbio.2007.07.008 | PubMed ID:17689240 | HubMed [davidson2007]
  2. International HapMap Consortium. A haplotype map of the human genome. Nature. 2005 Oct 27;437(7063):1299-320. DOI:10.1038/nature04226 | PubMed ID:16255080 | HubMed [hapmap2005]
  3. Guo Y and Jamison DC. The distribution of SNPs in human gene regulatory regions. BMC Genomics. 2005 Oct 6;6:140. DOI:10.1186/1471-2164-6-140 | PubMed ID:16209714 | HubMed [guo2005]
  4. Pastinen T and Hudson TJ. Cis-acting regulatory variation in the human genome. Science. 2004 Oct 22;306(5696):647-50. DOI:10.1126/science.1101659 | PubMed ID:15499010 | HubMed [pastinen2004]
  5. Odom DT, Dowell RD, Jacobsen ES, Gordon W, Danford TW, MacIsaac KD, Rolfe PA, Conboy CM, Gifford DK, and Fraenkel E. Tissue-specific transcriptional regulation has diverged significantly between human and mouse. Nat Genet. 2007 Jun;39(6):730-2. DOI:10.1038/ng2047 | PubMed ID:17529977 | HubMed [odom2007]
  6. Wittkopp PJ, Haerum BK, and Clark AG. Regulatory changes underlying expression differences within and between Drosophila species. Nat Genet. 2008 Mar;40(3):346-50. DOI:10.1038/ng.77 | PubMed ID:18278046 | HubMed [wittkopp2008]
  7. Mira MT, Alcaïs A, Nguyen VT, Moraes MO, Di Flumeri C, Vu HT, Mai CP, Nguyen TH, Nguyen NB, Pham XK, Sarno EN, Alter A, Montpetit A, Moraes ME, Moraes JR, Doré C, Gallant CJ, Lepage P, Verner A, Van De Vosse E, Hudson TJ, Abel L, and Schurr E. Susceptibility to leprosy is associated with PARK2 and PACRG. Nature. 2004 Feb 12;427(6975):636-40. DOI:10.1038/nature02326 | PubMed ID:14737177 | HubMed [mira2004]
  8. De Gobbi M, Viprakasit V, Hughes JR, Fisher C, Buckle VJ, Ayyub H, Gibbons RJ, Vernimmen D, Yoshinaga Y, de Jong P, Cheng JF, Rubin EM, Wood WG, Bowden D, and Higgs DR. A regulatory SNP causes a human genetic disease by creating a new transcriptional promoter. Science. 2006 May 26;312(5777):1215-7. DOI:10.1126/science.1126431 | PubMed ID:16728641 | HubMed [degobbi2006]
  9. Kristensen VN, Edvardsen H, Tsalenko A, Nordgard SH, Sørlie T, Sharan R, Vailaya A, Ben-Dor A, Lønning PE, Lien S, Omholt S, Syvänen AC, Yakhini Z, and Børresen-Dale AL. Genetic variation in putative regulatory loci controlling gene expression in breast cancer. Proc Natl Acad Sci U S A. 2006 May 16;103(20):7735-40. DOI:10.1073/pnas.0601893103 | PubMed ID:16684880 | HubMed [kristensen2006]
  10. Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes of BioMedical Research, Saxena R, Voight BF, Lyssenko V, Burtt NP, de Bakker PI, Chen H, Roix JJ, Kathiresan S, Hirschhorn JN, Daly MJ, Hughes TE, Groop L, Altshuler D, Almgren P, Florez JC, Meyer J, Ardlie K, Bengtsson Boström K, Isomaa B, Lettre G, Lindblad U, Lyon HN, Melander O, Newton-Cheh C, Nilsson P, Orho-Melander M, Råstam L, Speliotes EK, Taskinen MR, Tuomi T, Guiducci C, Berglund A, Carlson J, Gianniny L, Hackett R, Hall L, Holmkvist J, Laurila E, Sjögren M, Sterner M, Surti A, Svensson M, Svensson M, Tewhey R, Blumenstiel B, Parkin M, Defelice M, Barry R, Brodeur W, Camarata J, Chia N, Fava M, Gibbons J, Handsaker B, Healy C, Nguyen K, Gates C, Sougnez C, Gage D, Nizzari M, Gabriel SB, Chirn GW, Ma Q, Parikh H, Richardson D, Ricke D, and Purcell S. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science. 2007 Jun 1;316(5829):1331-6. DOI:10.1126/science.1142358 | PubMed ID:17463246 | HubMed [saxena2007]
  11. Kim BC, Kim WY, Park D, Chung WH, Shin KS, and Bhak J. SNP@Promoter: a database of human SNPs (single nucleotide polymorphisms) within the putative promoter regions. BMC Bioinformatics. 2008;9 Suppl 1(Suppl 1):S2. DOI:10.1186/1471-2105-9-S1-S2 | PubMed ID:18315851 | HubMed [kim2008]
All Medline abstracts: PubMed | HubMed