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Current Computational Methods for Prioritizing Candidate Regulatory Polymorphisms

  • Stephen Montgomery
Protocol
Part of the Methods in Molecular Biology™ book series (MIMB, volume 569)

Summary

Discovery of DNA sequence variants responsible for human phenotypic variation is key to advances in molecular diagnostics and medicines. Historically, variants that alter the protein-coding sequence of genes have been targeted when attempting to identify a trait’s etiology; this is done because the rules governing these regions are generally well-understood and candidate variants can be easily selected. However, the effects of variants on gene regulation are increasingly regarded as being as important as protein-coding variation in uncovering the nature of phenotypic variation. I discuss resources and methodology that have recently been developed to computationally prioritize variants that may alter gene expression.

Key words

Regulatory polymorphisms SNPs Gene regulation Transcription factor binding sites Natural selection Databases Annotation 

Notes

Acknowledgment

S.B.M. would like to thank Monica C. Sleumer, Daniel C. Jeffares, and Emmanouil T. Dermitzakis for critical review and support in development of this work. S.B.M. is funded by the European Molecular Biology Organization and the Natural Sciences and Engineering Research Council of Canada.

References

  1. 1.
    Pastinen T, Hudson TJ (2004) Cis-acting regulatory variation in the human genome. Science 306: 647–650.PubMedCrossRefGoogle Scholar
  2. 2.
    Knight JC (2005) Regulatory polymorphisms underlying complex disease traits. J Mol Med 83: 97–109.PubMedCrossRefGoogle Scholar
  3. 3.
    Rockman MV, Wray GA (2002) Abundant raw material for cis-regulatory evolution in humans. Mol Biol Evol 19: 1991–2004.PubMedCrossRefGoogle Scholar
  4. 4.
    Wittkopp PJ (2005) Genomic sources of regulatory variation in cis and in trans. Cell Mol Life Sci 62: 1779–1783.PubMedCrossRefGoogle Scholar
  5. 5.
    Whitehead A, Crawford DL (2006) Variation within and among species in gene expression: raw material for evolution. Mol Ecol 15: 1197–1211.PubMedCrossRefGoogle Scholar
  6. 6.
    Miao X, Yu C, Tan W, Xiong P, Liang G, et al. (2003) A functional polymorphism in the matrix metalloproteinase-2 gene promoter (-1306C/T) is associated with risk of development but not metastasis of gastric cardia adenocarcinoma. Cancer Res 63: 3987–3990.PubMedGoogle Scholar
  7. 7.
    Bond GL, Hu W, Bond EE, Robins H, Lutzker SG, et al. (2004) A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 119: 591–602.PubMedCrossRefGoogle Scholar
  8. 8.
    Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, et al. (2003) Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301: 386–389.PubMedCrossRefGoogle Scholar
  9. 9.
    Prokunina L, Castillejo-Lopez C, Oberg F, Gunnarsson I, Berg L, et al. (2002) A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet 32: 666–669.PubMedCrossRefGoogle Scholar
  10. 10.
    Kostrikis LG, Neumann AU, Thomson B, Korber BT, McHardy P, et al. (1999) A polymorphism in the regulatory region of the CC-chemokine receptor 5 gene influences perinatal transmission of human immunodeficiency virus type 1 to African-American infants. J Virol 73: 10264–10271.PubMedGoogle Scholar
  11. 11.
    Saito H, Tada S, Ebinuma H, Wakabayashi K, Takagi T, et al. (2001) Interferon regulatory factor 1 promoter polymorphism and response to type 1 interferon. J Cell Biochem Suppl 36: 191–200.PubMedCrossRefGoogle Scholar
  12. 12.
    Stranger BE, Nica AC, Forrest MS, Dimas A, Bird CP, et al. (2007) Population genomics of human gene expression. Nat Genet 39: 1217–1224.PubMedCrossRefGoogle Scholar
  13. 13.
    Pastinen T, Sladek R, Gurd S, Sammak A, Ge B, et al. (2004) A survey of genetic and epigenetic variation affecting human gene expression. Physiol Genomics 16: 184–193.PubMedGoogle Scholar
  14. 14.
    Frazer KA, Ballinger DG, Cox DR, Hinds DA, Stuve LL, et al. (2007) A second generation human haplotype map of over 3.1 million SNPs. Nature 449: 851–861.PubMedCrossRefGoogle Scholar
  15. 15.
    Nielsen R, Hellmann I, Hubisz M, Bustamante C, Clark AG (2007) Recent and ongoing selection in the human genome. Nat Rev Genet 8: 857–868.PubMedCrossRefGoogle Scholar
  16. 16.
    Sabeti PC, Reich DE, Higgins JM, Levine HZ, Richter DJ, et al. (2002) Detecting recent positive selection in the human genome from haplotype structure. Nature 419: 832–837.PubMedCrossRefGoogle Scholar
  17. 17.
    Voight BF, Kudaravalli S, Wen X, Pritchard JK (2006) A map of recent positive selection in the human genome. PLoS Biol 4: e72.PubMedCrossRefGoogle Scholar
  18. 18.
    Sabeti PC, Varilly P, Fry B, Lohmueller J, Hostetter E, et al. (2007) Genome-wide detection and characterization of positive selection in human populations. Nature 449: 913–918.PubMedCrossRefGoogle Scholar
  19. 19.
    King MC, Wilson AC (1975) Evolution at two levels in humans and chimpanzees. Science 188: 107–116.PubMedCrossRefGoogle Scholar
  20. 20.
    Kornblihtt AR (2005) Promoter usage and alternative splicing. Curr Opin Cell Biol 17: 262–268.PubMedCrossRefGoogle Scholar
  21. 21.
    Davidson EH (2001) Genomic Regulatory Systems: Development and Evolution. San Diego: Academic. xii, 261 pp.Google Scholar
  22. 22.
    Hoogendoorn B, Coleman SL, Guy CA, Smith K, Bowen T, et al. (2003) Functional analysis of human promoter polymorphisms. Hum Mol Genet 12: 2249–2254.PubMedCrossRefGoogle Scholar
  23. 23.
    Hewett D, Lynch J, Child A, Firth H, Sykes B (1994) Differential allelic expression of a fibrillin gene (FBN1) in patients with Marfan syndrome. Am J Hum Genet 55: 447–452.PubMedGoogle Scholar
  24. 24.
    Morley M, Molony CM, Weber TM, Devlin JL, Ewens KG, et al. (2004) Genetic analysis of genome-wide variation in human gene expression. Nature 430: 743–747.PubMedCrossRefGoogle Scholar
  25. 25.
    Monks SA, Leonardson A, Zhu H, Cundiff P, Pietrusiak P, et al. (2004) Genetic inheritance of gene expression in human cell lines. Am J Hum Genet 75: 1094–1105.PubMedCrossRefGoogle Scholar
  26. 26.
    Cheung VG, Spielman RS, Ewens KG, Weber TM, Morley M, et al. (2005) Mapping determinants of human gene expression by regional and genome-wide association. Nature 437: 1365–1369.PubMedCrossRefGoogle Scholar
  27. 27.
    Pastinen T, Ge B, Hudson TJ (2006) Influence of human genome polymorphism on gene expression. Hum Mol Genet 15 Spec No 1: R9–R16.Google Scholar
  28. 28.
    Conde L, Vaquerizas JM, Dopazo H, Arbiza L, Reumers J, et al. (2006) PupaSuite: finding functional single nucleotide polymorphisms for large-scale genotyping purposes. Nucleic Acids Res 34: W621–W625.PubMedCrossRefGoogle Scholar
  29. 29.
    Freimuth RR, Stormo GD, McLeod HL (2005) PolyMAPr: programs for polymorphism database mining, annotation, and functional analysis. Hum Mutat 25: 110–117.PubMedCrossRefGoogle Scholar
  30. 30.
    Matys V, Kel-Margoulis OV, Fricke E, Liebich I, Land S, et al. (2006) TRANSFAC and its module TRANSCompel: transcriptional gene regulation in eukaryotes. Nucleic Acids Res 34: D108–D110.PubMedCrossRefGoogle Scholar
  31. 31.
    Bryne JC, Valen E, Tang MH, Marstrand T, Winther O, et al. (2008) JASPAR, the open access database of transcription factor-binding profiles: new content and tools in the 2008 update. Nucleic Acids Res 36: D102–D106.PubMedCrossRefGoogle Scholar
  32. 32.
    Tomso DJ, Inga A, Menendez D, Pittman GS, Campbell MR, et al. (2005) Functionally distinct polymorphic sequences in the human genome that are targets for p53 transactivation. Proc Natl Acad Sci USA 102: 6431–6436.PubMedCrossRefGoogle Scholar
  33. 33.
    Mottagui-Tabar S, Faghihi MA, Mizuno Y, Engstrom PG, Lenhard B, et al. (2005) Identification of functional SNPs in the 5-prime flanking sequences of human genes. BMC Genomics 6: 18.PubMedCrossRefGoogle Scholar
  34. 34.
    Khan IA, Mort M, Buckland PR, O’Donovan MC, Cooper DN, et al. (2005) In silico discrimination of single nucleotide polymorphisms and pathological mutations in human gene promoter regions by means of local DNA sequence context and regularity. In Silico Biol 6: 0003.Google Scholar
  35. 35.
    Mooney SD, Altman RB (2003) MutDB: annotating human variation with functionally relevant data. Bioinformatics 19: 1858–1860.PubMedCrossRefGoogle Scholar
  36. 36.
    Montgomery SB, Astakhova T, Bilenky M, Birney E, Fu T, et al. (2004) Sockeye: a 3D environment for comparative genomics. Genome Res 14: 956–962.PubMedCrossRefGoogle Scholar
  37. 37.
    Hinrichs AS, Karolchik D, Baertsch R, Barber GP, Bejerano G, et al. (2006) The UCSC Genome Browser Database: update 2006. Nucleic Acids Res 34: D590–D598.PubMedCrossRefGoogle Scholar
  38. 38.
    Ponomarenko JV, Merkulova TI, Orlova GV, Fokin ON, Gorshkova EV, et al. (2003) rSNP_Guide, a database system for analysis of transcription factor binding to DNA with variations: application to genome annotation. Nucleic Acids Res 31: 118–121.PubMedCrossRefGoogle Scholar
  39. 39.
    Stenson PD, Ball EV, Mort M, Phillips AD, Shiel JA, et al. (2003) Human Gene Mutation Database (HGMD): 2003 update. Hum Mutat 21: 577–581.PubMedCrossRefGoogle Scholar
  40. 40.
    Griffith OL, Montgomery SB, Bernier B, Chu B, Kasaian K, et al. (2008) ORegAnno: an open-access community-driven resource for regulatory annotation. Nucleic Acids Res 36: D107–D113.Google Scholar
  41. 41.
    Portales-Casamar E, Kirov S, Lim J, Lithwick S, Swanson MI, et al. (2007) PAZAR: a framework for collection and dissemination of cis-regulatory sequence annotation. Genome Biol 8: R207.PubMedCrossRefGoogle Scholar
  42. 42.
    Montgomery SB, Griffith OL, Schuetz JM, Brooks-Wilson A, Jones SJ (2007) A survey of genomic properties for the detection of regulatory polymorphisms. PLoS Comput Biol 3: e106.PubMedCrossRefGoogle Scholar
  43. 43.
    Drake JA, Bird C, Nemesh J, Thomas DJ, Newton-Cheh C, et al. (2006) Conserved noncoding sequences are selectively constrained and not mutation cold spots. Nat Genet 38: 223–227.PubMedCrossRefGoogle Scholar
  44. 44.
    Khaitovich P, Paabo S, Weiss G (2005) Toward a neutral evolutionary model of gene expression. Genetics 170: 929–939.PubMedCrossRefGoogle Scholar
  45. 45.
    Balhoff JP, Wray GA (2005) Evolutionary analysis of the well characterized endo16 promoter reveals substantial variation within functional sites. Proc Natl Acad Sci USA 102: 8591–8596.PubMedCrossRefGoogle Scholar
  46. 46.
    Romano LA, Wray GA (2003) Conservation of Endo16 expression in sea urchins despite evolutionary divergence in both cis and trans-acting components of transcriptional regulation. Development 130: 4187–4199.PubMedCrossRefGoogle Scholar
  47. 47.
    Klug SJ, Famulok M (1994) All you wanted to know about SELEX. Mol Biol Rep 20: 97–107.PubMedCrossRefGoogle Scholar
  48. 48.
    Stormo GD, Schneider TD, Gold L, Ehrenfeucht A (1982) Use of the ‘Perceptron’ algorithm to distinguish translational initiation sites in E. coli. Nucleic Acids Res 10: 2997–3011.PubMedCrossRefGoogle Scholar
  49. 49.
    Lenhard B, Wasserman WW (2002) TFBS: computational framework for transcription factor binding site analysis. Bioinformatics 18: 1135–1136.PubMedCrossRefGoogle Scholar
  50. 50.
    Crooks GE, Hon G, Chandonia JM, Brenner SE (2004) WebLogo: a sequence logo generator. Genome Res 14: 1188–1190.PubMedCrossRefGoogle Scholar
  51. 51.
  52. 52.
    Clifford R, Edmonson M, Hu Y, Nguyen C, Scherpbier T, et al. (2000) Expression-based genetic/physical maps of single-nucleotide polymorphisms identified by the cancer genome anatomy project. Genome Res 10: 1259–1265.PubMedCrossRefGoogle Scholar
  53. 53.
  54. 54.
    Wu CH, Apweiler R, Bairoch A, Natale DA, Barker WC, et al. (2006) The Universal Protein Resource (UniProt): an expanding universe of protein information. Nucleic Acids Res 34: D187–D191.PubMedCrossRefGoogle Scholar
  55. 55.
    Fay JC, Wu CI (2000) Hitchhiking under positive Darwinian selection. Genetics 155: 1405–1413.PubMedGoogle Scholar
  56. 56.
    Cargill M, Altshuler D, Ireland J, Sklar P, Ardlie K, et al. (1999) Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nat Genet 22: 231–238.PubMedCrossRefGoogle Scholar
  57. 57.
    Walsh EC, Sabeti P, Hutcheson HB, Fry B, Schaffner SF, et al. (2006) Searching for signals of evolutionary selection in 168 genes related to immune function. Hum Genet 119: 92–102.PubMedCrossRefGoogle Scholar
  58. 58.
    Ramensky V, Bork P, Sunyaev S (2002) Human non-synonymous SNPs: server and survey. Nucleic Acids Res 30: 3894–3900.PubMedCrossRefGoogle Scholar
  59. 59.
    Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, et al. (2001) dbSNP: the NCBI database of genetic variation. Nucleic Acids Res 29: 308–311.PubMedCrossRefGoogle Scholar
  60. 60.
    Spencer CC, Deloukas P, Hunt S, Mullikin J, Myers S, et al. (2006) The influence of recombination on human genetic diversity. PLoS Genet 2: e148.PubMedCrossRefGoogle Scholar
  61. 61.
    Schwartz S, Kent WJ, Smit A, Zhang Z, Baertsch R, et al. (2003) Human-mouse alignments with BLASTZ. Genome Res 13: 103–107.PubMedCrossRefGoogle Scholar
  62. 62.
    Palaniswamy SK, James S, Sun H, Lamb RS, Davuluri RV, et al. (2006) AGRIS and AtRegNet. a platform to link cis-regulatory elements and transcription factors into regulatory networks. Plant Physiol 140: 818–829.PubMedCrossRefGoogle Scholar
  63. 63.
  64. 64.
  65. 65.
    Kummerfeld SK, Teichmann SA (2006) DBD: a transcription factor prediction database. Nucleic Acids Res 34: D74–D81.PubMedCrossRefGoogle Scholar
  66. 66.
    Barrasa MI, Vaglio P, Cavasino F, Jacotot L, Walhout AJ (2007) EDGEdb: a transcription factor-DNA interaction database for the analysis of C. elegans differential gene expression. BMC Genomics 8: 21.PubMedCrossRefGoogle Scholar
  67. 67.
    Schmid CD, Perier R, Praz V, Bucher P (2006) EPD in its twentieth year: towards complete promoter coverage of selected model organisms. Nucleic Acids Res 34: D82–D85.PubMedCrossRefGoogle Scholar
  68. 68.
    Adryan B, Teichmann SA (2006) FlyTF: a systematic review of site-specific transcription factors in the fruit fly Drosophila melanogaster. Bioinformatics 22: 1532–1533.PubMedCrossRefGoogle Scholar
  69. 69.
    Pohar TT, Sun H, Davuluri RV (2004) HemoPDB: Hematopoiesis Promoter Database, an information resource of transcriptional regulation in blood cell development. Nucleic Acids Res 32: D86–D90.PubMedCrossRefGoogle Scholar
  70. 70.
  71. 71.
    Palaniswamy SK, Jin VX, Sun H, Davuluri RV (2005) OMGProm: a database of orthologous mammalian gene promoters. Bioinformatics 21: 835–836.PubMedCrossRefGoogle Scholar
  72. 72.
    Grienberg I, Benayahu D (2005) Osteo-Promoter Database (OPD) – promoter analysis in skeletal cells. BMC Genomics 6: 46.PubMedCrossRefGoogle Scholar
  73. 73.
    Higo K, Ugawa Y, Iwamoto M, Korenaga T (1999) Plant cis-acting regulatory DNA elements (PLACE) database: 1999. Nucleic Acids Res 27: 297–300.PubMedCrossRefGoogle Scholar
  74. 74.
    Lescot M, Dehais P, Thijs G, Marchal K, Moreau Y, et al. (2002) PlantCARE, a database of plant cis-acting regulatory elements and a portal to tools for in silico analysis of promoter sequences. Nucleic Acids Res 30: 325–327.PubMedCrossRefGoogle Scholar
  75. 75.
    Shahmuradov IA, Gammerman AJ, Hancock JM, Bramley PM, Solovyev VV (2003) PlantProm: a database of plant promoter sequences. Nucleic Acids Res 31: 114–117.PubMedCrossRefGoogle Scholar
  76. 76.
    Zhu J, Zhang MQ (1999) SCPD: a promoter database of the yeast Saccharomyces cerevisiae. Bioinformatics 15: 607–611.PubMedCrossRefGoogle Scholar
  77. 77.
    Kanamori M, Konno H, Osato N, Kawai J, Hayashizaki Y, et al. (2004) A genome-wide and nonredundant mouse transcription factor database. Biochem Biophys Res Commun 322: 787–793.PubMedCrossRefGoogle Scholar
  78. 78.
    Kolchanov NA, Ignatieva EV, Ananko EA, Podkolodnaya OA, Stepanenko IL, et al. (2002) Transcription Regulatory Regions Database (TRRD): its status in 2002. Nucleic Acids Res 30: 312–317.PubMedCrossRefGoogle Scholar
  79. 79.
    The HapMap Consortium (2005) A haplotype map of the human genome. Nature 437: 1299–1320.Google Scholar
  80. 80.
    Fredman D, Munns G, Rios D, Sjoholm F, Siegfried M, et al. (2004) HGVbase: a curated resource describing human DNA variation and phenotype relationships. Nucleic Acids Res 32: D516–D519.PubMedCrossRefGoogle Scholar
  81. 81.
    Rajeevan H, Osier MV, Cheung KH, Deng H, Druskin L, et al. (2003) ALFRED: the ALelle FREquency Database. Update. Nucleic Acids Res 31: 270–271.PubMedCrossRefGoogle Scholar
  82. 82.
    OMIM (2006) Online Mendelian Inheritance in Man, OMIM (TM). McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD), June 2006. World Wide Web URL: http://www.ncbi.nlm.nih.gov/omim/.
  83. 83.
    Riva A, Kohane IS (2002) SNPper: retrieval and analysis of human SNPs. Bioinformatics 18: 1681–1685.PubMedCrossRefGoogle Scholar
  84. 84.
    Hirakawa M, Tanaka T, Hashimoto Y, Kuroda M, Takagi T, et al. (2002) JSNP: a database of common gene variations in the Japanese population. Nucleic Acids Res 30: 158–162.PubMedCrossRefGoogle Scholar
  85. 85.
    Tahira T, Baba S, Higasa K, Kukita Y, Suzuki Y, et al. (2005) dbQSNP: a database of SNPs in human promoter regions with allele frequency information determined by single-strand conformation polymorphism-based methods. Hum Mutat 26: 69–77.PubMedCrossRefGoogle Scholar
  86. 86.
    Guryev V, Berezikov E, Cuppen E (2005) CASCAD: a database of annotated candidate single nucleotide polymorphisms associated with expressed sequences. BMC Genomics 6: 10.PubMedCrossRefGoogle Scholar
  87. 87.
    Stitziel NO, Binkowski TA, Tseng YY, Kasif S, Liang J (2004) topoSNP: a topographic database of non-synonymous single nucleotide polymorphisms with and without known disease association. Nucleic Acids Res 32: D520–D522.PubMedCrossRefGoogle Scholar
  88. 88.
    SeattleSNPs (2006) NHLBI Program for Genomic Applications, SeattleSNPs, Seattle, WA (URL: http://pga.gs.washington.edu) [Accessed 30 Jul 2006].
  89. 89.
    GeneSNPs (2006) NIEHS SNPs. NIEHS Environmental Genome Project, University of Washington, Seattle, WA (URL: http://egp.gs.washington.edu) [Accessed 30 Jul 2006].
  90. 90.
  91. 91.
    Iafrate AJ, Feuk L, Rivera MN, Listewnik ML, Donahoe PK, et al. (2004) Detection of large-scale variation in the human genome. Nat Genet 36: 949–951.PubMedCrossRefGoogle Scholar
  92. 92.
    Barber JC (2005) Directly transmitted unbalanced chromosome abnormalities and euchromatic variants. J Med Genet 42: 609–629.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press, a part of Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Stephen Montgomery
    • 1
  1. 1.Wellcome Trust Sanger InstituteHinxtonUK

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