Clinical and Phenotypic Relevance of cis‐Acting Regulatory Polymorphisms


Genetic variants that regulate the expression level of a transcript are known as expression quantitative trait loci (eQTLs) or regulatory single nucleotide polymorphisms. Cis‐variants are those that only act on a target gene (or genes) on the same chromosomal homologue. They cause additive differences in gene expression that are tightly associated with the three genotypes of the regulatory eQTL, and cause allelic expression imbalance in heterozygous samples. Unlike trans‐variants, which can act on many genes located at a distance, cis‐acting variants are less likely to have all‐or‐none effects if inactivated, and these may be tissue specific and thus less severe. Such cis‐variants are found occasionally in Mendelian disease and now increasingly implicated in polygenic disorders. The interactions of these regulatory variations with other genetic and also environmental factors are likely to account for some of the complexity of multifactorial diseases.

Key Concepts:

  • Regulatory polymorphisms, otherwise known as eQTLs (expression quantitative trait loci), are DNA sequence variations that alter the level of expression of particular transcripts.

  • Cis‐eQTLs are cis‐acting polymorphisms that cause variation in the expression of a nearby gene or genes on the same chromosomal homologue.

  • In heterozygous individuals there is a difference in the level of expression from each of the pair of genes transcribed from the two chromosomal homologues.

  • This difference in expression in heterozygous individuals can be observed as allelic expression imbalance (AEI) if there are also allelic sequence differences in the transcript.

  • Such AEI is distinguishable from imprinting in that unlike the case of imprinting the higher expressing transcript can come from either the mother or the father.

  • Cis‐acting polymorphisms can affect expression in a tissue‐specific and developmentally specific manner.

  • They are strong candidates for positive selection and evolutionary adaptation but such variants might be maladaptive in different environments.

  • Cis‐acting regulatory sequence changes have been identified as a class of rare mutations in Mendelian disorders, and more common variants are increasingly implicated as causal polymorphisms involved in multifactorial diseases.

Keywords: cis‐acting polymorphism; allelic expression imbalance; AEI; eQTL; gene expression; regulation; allelic expression

Figure 1.

eQTL variation and AEI. (a) A mutation in a TFBS (C>A in diagram) may prevent binding of a TF (shown as circular blobs), altering expression of the transcript. The graph shows a typical scatter of expression levels in individuals carrying the three possible genotypes for the cis‐eQTL SNP. Heterozygotes show intermediate levels of expression but it is not possible to distinguish the transcripts expressed by each homologue. (b) SNPs in the exons (G/C) are used to determine transcript ratios. The mutation in cis affects the two alleles differentially as indicated (AEI). (c) A heterozygous mutation in trans (affecting the transcription factor function or level) affects both alleles equally and no AEI will be seen.



de Alarcon A, Steinke JW, Caughey R et al. (2006) Expression of leukotriene C4 synthase and plasminogen activator inhibitor 1 gene promoter polymorphisms in sinusitis. American Journal of Rhinology 20(5): 545–549.

Arnold M, Ellwanger DC, Hartsperger ML, Pfeufer A and Stumpflen V (2012) Cis‐acting polymorphisms affect complex traits through modifications of microRNA regulation pathways. PLoS One 7(5): e36694.

Benko S, Fantes JA, Amiel J et al. (2009) Highly conserved non‐coding elements on either side of SOX9 associated with Pierre Robin sequence. Nature Genetics 41(3): 359–364.

Bosma PJ, Chowdhury JR, Bakker C et al. (1995) The genetic basis of the reduced expression of bilirubin UDP‐glucuronosyltransferase 1 in Gilbert's syndrome. New England Journal of Medicine 333(18): 1171–1175.

Buonocore F, Hill MJ, Campbell CD et al. (2010) Effects of cis‐regulatory variation differ across regions of the adult human brain. Human Molecular Genetics 19(22): 4490–4496.

Cheung VG, Nayak RR, Wang IX et al. (2010) Polymorphic cis‐ and trans‐regulation of human gene expression. PLoS Biology 8(9).

Cheung VG, Spielman RS, Ewens KG et al. (2005) Mapping determinants of human gene expression by regional and genome‐wide association. Nature 437(7063): 1365–1369.

Crossley M and Brownlee GG (1990) Disruption of a C/EBP binding site in the factor IX promoter is associated with haemophilia B. Nature 345(6274): 444–446.

Doniger SW and Fay JC (2007) Frequent gain and loss of functional transcription factor binding sites. PLoS Computational Biology 3(5): e99.

Eiberg H, Troelsen J, Nielsen M et al. (2008) Blue eye color in humans may be caused by a perfectly associated founder mutation in a regulatory element located within the HERC2 gene inhibiting OCA2 expression. Human Genetics 123(2): 177–187.

Elding H, Lau W, Swallow DM and Maniatis N (2013) Refinement in localization and identification of gene regions associated with Crohn disease. American Journal of Human Genetics 92(1): 107–113.

Farooq M, Troelsen JT, Boyd M et al. (2010) Preaxial polydactyly/triphalangeal thumb is associated with changed transcription factor‐binding affinity in a family with a novel point mutation in the long‐range cis‐regulatory element ZRS. European Journal of Human Genetics 18(6): 733–736.

Ferrari SL, Ahn‐Luong L, Garnero P, Humphries SE and Greenspan SL (2003) Two promoter polymorphisms regulating interleukin‐6 gene expression are associated with circulating levels of C‐reactive protein and markers of bone resorption in postmenopausal women. Journal of Clinical Endocrinology and Metabolism 88(1): 255–259.

Genuardi M, Klutz M, Devriendt K et al. (2001) Multiple lipomas linked to an RB1 gene mutation in a large pedigree with low penetrance retinoblastoma. European Journal of Human Genetics 9(9): 690–694.

Girirajan S, Campbell CD and Eichler EE (2011) Human copy number variation and complex genetic disease. Annual Review of Genetics 45: 203–226.

De Gobbi M, Viprakasit V, Hughes JR et al. (2006) A regulatory SNP causes a human genetic disease by creating a new transcriptional promoter. Science 312(5777): 1215–1217.

Goode DL, Cooper GM, Schmutz J et al. (2010) Evolutionary constraint facilitates interpretation of genetic variation in resequenced human genomes. Genome Research 20(3): 301–310.

Jensen TG, Liebert A, Lewinsky R et al. (2011) The ‐14010*C variant associated with lactase persistence is located between an Oct‐1 and HNF1alpha binding site and increases lactase promoter activity. Human Genetics 130(4): 483–493.

Jeong Y, Leskow FC, El‐Jaick K et al. (2008) Regulation of a remote Shh forebrain enhancer by the Six3 homeoprotein. Nature Genetics 40(11): 1348–1353.

Jin H, van't Hof RJ, Albagha OM and Ralston SH (2009) Promoter and intron 1 polymorphisms of COL1A1 interact to regulate transcription and susceptibility to osteoporosis. Human Molecular Genetics 18(15): 2729–2738.

Jones BL, Raga TO, Liebert A et al. (2013) Diversity of lactase persistence alleles in Ethiopia: signature of a soft selective sweep. American Journal of Human Genetics 93(3): 538–544.

Knight JC, Keating BJ, Rockett KA and Kwiatkowski DP (2003) In vivo characterization of regulatory polymorphisms by allele‐specific quantification of RNA polymerase loading. Nature Genetics 33(4): 469–475.

Lapidot M, Mizrahi‐Man O and Pilpel Y (2008) Functional characterization of variations on regulatory motifs. PLoS Genetics 4(3): e1000018.

Lomelin D, Jorgenson E and Risch N (2010) Human genetic variation recognizes functional elements in noncoding sequence. Genome Research 20(3): 311–319.

Ludlow LB, Schick BP, Budarf ML et al. (1996) Identification of a mutation in a GATA binding site of the platelet glycoprotein Ibbeta promoter resulting in the Bernard‐Soulier syndrome. Journal of Biological Chemistry 271(36): 22076–22080.

Natividad A, Holland MJ, Rockett KA et al. (2008) Susceptibility to sequelae of human ocular chlamydial infection associated with allelic variation in IL10 cis‐regulation. Human Molecular Genetics 17(2): 323–329.

Ng W, Loh AX, Teixeira AS, Pereira SP and Swallow DM (2008) Genetic regulation of MUC1 alternative splicing in human tissues. British Journal of Cancer 99(6): 978–985.

Nicolae DL, Gamazon E, Zhang W et al. (2010) Trait‐associated SNPs are more likely to be eQTLs: annotation to enhance discovery from GWAS. PLoS Genetics 6(4): e1000888.

Pastinen T and Hudson TJ (2004) Cis‐acting regulatory variation in the human genome. Science 306(5696): 647–650.

Pollard KS, Serre D, Wang X et al. (2008) A genome‐wide approach to identifying novel‐imprinted genes. Human Genetics 122(6): 625–634.

van der Pouw Kraan TC, van Veen A, Boeije LC et al. (1999) An IL‐13 promoter polymorphism associated with increased risk of allergic asthma. Genes and Immunity 1(1): 61–65.

Rahimov F, Marazita ML, Visel A et al. (2008) Disruption of an AP‐2alpha binding site in an IRF6 enhancer is associated with cleft lip. Nature Genetics 40(11): 1341–1347.

Richardson K, Lai CQ, Parnell LD, Lee YC and Ordovas JM (2011) A genome‐wide survey for SNPs altering microRNA seed sites identifies functional candidates in GWAS. BMC Genomics 12: 504.

Sankaran VG, Xu J and Orkin SH (2010) Advances in the understanding of haemoglobin switching. British Journal of Haematology 149(2): 181–194.

Smith RM, Webb A, Papp AC et al. (2013) Whole transcriptome RNA‐Seq allelic expression in human brain. BMC Genomics 14: 571.

Stranger BE, Forrest MS, Clark AG et al. (2005) Genome‐wide associations of gene expression variation in humans. PLoS Genetics 1(6): e78.

Stranger BE, Nica AC, Forrest MS et al. (2007) Population genomics of human gene expression. Nature Genetics 39(10): 1217–1224.

Stranger BE and Raj T (2013) Genetics of human gene expression. Current Opinion in Genetics and Development 23(6): 627–634.

Sun C, Southard C, Olopade OI and Di Rienzo A (2011) Differential allelic expression of c.1568C>A at UGT2B15 is due to variation in a novel cis‐regulatory element in the 3′UTR. Gene 481(1): 24–28.

Terry CF, Loukaci V and Green FR (2000) Cooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulation. Journal of Biological Chemistry 275(24): 18138–18144.

Tournamille C, Colin Y, Cartron JP and Le Van Kim (1995) Disruption of a GATA motif in the Duffy gene promoter abolishes erythroid gene expression in Duffy‐negative individuals. Nature Genetics 10(2): 224–228.

Verlaan DJ, Ge B, Grundberg E et al. (2009) Targeted screening of cis‐regulatory variation in human haplotypes. Genome Research 19(1): 118–127.

Wang GS and Cooper TA (2007) Splicing in disease: disruption of the splicing code and the decoding machinery. Nature Reviews Genetics 8(10): 749–761.

Wang HY, Fu Y, McPeek MS et al. (2008) Complex genetic interactions underlying expression differences between Drosophila races: analysis of chromosome substitutions. Proceedings of the National Academy of Sciences 105(17): 6362–6367.

Wang Z, Gerstein M and Snyder M (2009) RNA‐Seq: a revolutionary tool for transcriptomics. Nature Reviews Genetics 10(1): 57–63.

van Wijk R, van Solinge WW, Nerlov C et al. (2003) Disruption of a novel regulatory element in the erythroid‐specific promoter of the human PKLR gene causes severe pyruvate kinase deficiency. Blood 101(4): 1596–1602.

Wu Y, Xiao Y, Ding X et al. (2011) A miR‐200b/200c/429‐binding site polymorphism in the 3′ untranslated region of the AP‐2alpha gene is associated with cisplatin resistance. PLoS One 6(12): e29043.

Yu X, Lin J, Zack DJ and Qian J (2007) Identification of tissue‐specific cis‐regulatory modules based on interactions between transcription factors. BMC Bioinformatics 8: 437.

Zhang S, Xu L, Wang F et al. (2013) Genetic control of primary microRNA insight into cis‐ and trans‐regulatory variations by RNA‐seq. Gene 517(2): 224–229.

Zinzen RP, Girardot C, Gagneur J, Braun M and Furlong EE (2009) Combinatorial binding predicts spatio‐temporal cis‐regulatory activity. Nature 462(7269): 65–70.

Further Reading

Cheung VG and Spielman RS (2009) Genetics of human gene expression: mapping DNA variants that influence gene expression. Nature Reviews Genetics 10(9): 595–604.

Doglio L, Goode DK, Pelleri MC et al. (2013) Parallel evolution of chordate cis‐regulatory code for development. PLoS Genetics 9(11): e1003904.

Epstein DJ (2009) Cis‐regulatory mutations in human disease. Briefings in Functional Genomics and Proteomics 8(4): 310–316.

Fay JC and Wittkopp PJ (2008) Evaluating the role of natural selection in the evolution of gene regulation. Heredity 100(2): 191–199.

Ingram CJ, Mulcare CA, Itan Y, Thomas MG and Swallow DM (2009) Lactose digestion and the evolutionary genetics of lactase persistence. Human Genetics 124(6): 579–591.

Jones BL and Swallow DM (2011) The impact of cis‐acting polymorphisms on the human phenotype. Hugo Journal 5(1–4): 13–23.

Nica AC and Dermitzakis ET (2013) Expression quantitative trait loci: present and future. Philosophical Transactions of the Royal Society B: Biological Sciences 368(1620): 20120362.

de Vooght KM, van Wijk R and van Solinge WW (2009) Management of gene promoter mutations in molecular diagnostics. Clinical Chemistry 55(4): 698–708.

Wray GA (2007) The evolutionary significance of cis‐regulatory mutations. Nature Reviews Genetics 8(3): 206–216.

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Liebert, Anke, Jones, Bryony L, and Swallow, Dallas M(May 2014) Clinical and Phenotypic Relevance of cis‐Acting Regulatory Polymorphisms. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0025329]