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. 2004 Jun;167(2):867–877. doi: 10.1534/genetics.103.025726

Population genetic and phylogenetic evidence for positive selection on regulatory mutations at the factor VII locus in humans.

Matthew W Hahn 1, Matthew V Rockman 1, Nicole Soranzo 1, David B Goldstein 1, Gregory A Wray 1
PMCID: PMC1470926  PMID: 15238535

Abstract

The abundance of cis-regulatory polymorphisms in humans suggests that many may have been important in human evolution, but evidence for their role is relatively rare. Four common polymorphisms in the 5' promoter region of factor VII (F7), a coagulation factor, have been shown to affect its transcription and protein abundance both in vitro and in vivo. Three of these polymorphisms have low-frequency alleles that decrease expression of F7 and may provide protection against myocardial infarction (heart attacks). The fourth polymorphism has a minor allele that increases the level of transcription. To look for evidence of natural selection on the cis-regulatory variants flanking F7, we genotyped three of the polymorphisms in six Old World populations for which we also have data from a group of putatively neutral SNPs. Our population genetic analysis shows evidence for selection within humans; surprisingly, the strongest evidence is due to a large increase in frequency of the high-expression variant in Singaporean Chinese. Further characterization of a Japanese population shows that at least part of the increase in frequency of the high-expression allele is found in other East Asian populations. In addition, to examine interspecific patterns of selection we sequenced the homologous 5' noncoding region in chimpanzees, bonobos, a gorilla, an orangutan, and a baboon. Analysis of these data reveals an excess of fixed differences within transcription factor binding sites along the human lineage. Our results thus further support the hypothesis that regulatory mutations have been important in human evolution.

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Selected References

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  1. Akey Joshua M., Zhang Ge, Zhang Kun, Jin Li, Shriver Mark D. Interrogating a high-density SNP map for signatures of natural selection. Genome Res. 2002 Dec;12(12):1805–1814. doi: 10.1101/gr.631202. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bamshad Michael J., Mummidi Srinivas, Gonzalez Enrique, Ahuja Seema S., Dunn Diane M., Watkins W. Scott, Wooding Stephen, Stone Anne C., Jorde Lynn B., Weiss Robert B. A strong signature of balancing selection in the 5' cis-regulatory region of CCR5. Proc Natl Acad Sci U S A. 2002 Jul 29;99(16):10539–10544. doi: 10.1073/pnas.162046399. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bernardi F., Arcieri P., Bertina R. M., Chiarotti F., Corral J., Pinotti M., Prydz H., Samama M., Sandset P. M., Strom R. Contribution of factor VII genotype to activated FVII levels. Differences in genotype frequencies between northern and southern European populations. Arterioscler Thromb Vasc Biol. 1997 Nov;17(11):2548–2553. doi: 10.1161/01.atv.17.11.2548. [DOI] [PubMed] [Google Scholar]
  4. Bernardi F., Marchetti G., Pinotti M., Arcieri P., Baroncini C., Papacchini M., Zepponi E., Ursicino N., Chiarotti F., Mariani G. Factor VII gene polymorphisms contribute about one third of the factor VII level variation in plasma. Arterioscler Thromb Vasc Biol. 1996 Jan;16(1):72–76. [PubMed] [Google Scholar]
  5. Carew J. A., Pollak E. S., High K. A., Bauer K. A. Severe factor VII deficiency due to a mutation disrupting an Sp1 binding site in the factor VII promoter. Blood. 1998 Sep 1;92(5):1639–1645. [PubMed] [Google Scholar]
  6. Crawford D. L., Segal J. A., Barnett J. L. Evolutionary analysis of TATA-less proximal promoter function. Mol Biol Evol. 1999 Feb;16(2):194–207. doi: 10.1093/oxfordjournals.molbev.a026102. [DOI] [PubMed] [Google Scholar]
  7. Di Bitondo Rosa, Hall Adrian J., Peake Ian R., Iacoviello Licia, Winship Peter R. Oestrogenic repression of human coagulation factor VII expression mediated through an oestrogen response element sequence motif in the promoter region. Hum Mol Genet. 2002 Apr 1;11(7):723–731. doi: 10.1093/hmg/11.7.723. [DOI] [PubMed] [Google Scholar]
  8. Di Castelnuovo A., D'Orazio A., Amore C., Falanga A., Donati M. B., Iacoviello L. The decanucleotide insertion/deletion polymorphism in the promoter region of the coagulation factor VII gene and the risk of familial myocardial infarction. Thromb Res. 2000 Apr 1;98(1):9–17. doi: 10.1016/s0049-3848(99)00220-0. [DOI] [PubMed] [Google Scholar]
  9. Fullerton Stephanie M., Bartoszewicz Angelika, Ybazeta Gustavo, Horikawa Yukio, Bell Graeme I., Kidd Kenneth K., Cox Nancy J., Hudson Richard R., Di Rienzo Anna. Geographic and haplotype structure of candidate type 2 diabetes susceptibility variants at the calpain-10 locus. Am J Hum Genet. 2002 Mar 12;70(5):1096–1106. doi: 10.1086/339930. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Fuster V., Badimon L., Badimon J. J., Chesebro J. H. The pathogenesis of coronary artery disease and the acute coronary syndromes (1). N Engl J Med. 1992 Jan 23;326(4):242–250. doi: 10.1056/NEJM199201233260406. [DOI] [PubMed] [Google Scholar]
  11. Gabriel Stacey B., Schaffner Stephen F., Nguyen Huy, Moore Jamie M., Roy Jessica, Blumenstiel Brendan, Higgins John, DeFelice Matthew, Lochner Amy, Faggart Maura. The structure of haplotype blocks in the human genome. Science. 2002 May 23;296(5576):2225–2229. doi: 10.1126/science.1069424. [DOI] [PubMed] [Google Scholar]
  12. Girelli D., Russo C., Ferraresi P., Olivieri O., Pinotti M., Friso S., Manzato F., Mazzucco A., Bernardi F., Corrocher R. Polymorphisms in the factor VII gene and the risk of myocardial infarction in patients with coronary artery disease. N Engl J Med. 2000 Sep 14;343(11):774–780. doi: 10.1056/NEJM200009143431104. [DOI] [PubMed] [Google Scholar]
  13. Goldstein David B., Chikhi Lounès. Human migrations and population structure: what we know and why it matters. Annu Rev Genomics Hum Genet. 2002 Apr 15;3:129–152. doi: 10.1146/annurev.genom.3.022502.103200. [DOI] [PubMed] [Google Scholar]
  14. Green F., Kelleher C., Wilkes H., Temple A., Meade T., Humphries S. A common genetic polymorphism associated with lower coagulation factor VII levels in healthy individuals. Arterioscler Thromb. 1991 May-Jun;11(3):540–546. doi: 10.1161/01.atv.11.3.540. [DOI] [PubMed] [Google Scholar]
  15. Hamblin M. T., Di Rienzo A. Detection of the signature of natural selection in humans: evidence from the Duffy blood group locus. Am J Hum Genet. 2000 Apr 12;66(5):1669–1679. doi: 10.1086/302879. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hamblin Martha T., Thompson Emma E., Di Rienzo Anna. Complex signatures of natural selection at the Duffy blood group locus. Am J Hum Genet. 2001 Dec 20;70(2):369–383. doi: 10.1086/338628. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Heinrich J., Balleisen L., Schulte H., Assmann G., van de Loo J. Fibrinogen and factor VII in the prediction of coronary risk. Results from the PROCAM study in healthy men. Arterioscler Thromb. 1994 Jan;14(1):54–59. doi: 10.1161/01.atv.14.1.54. [DOI] [PubMed] [Google Scholar]
  18. Horan Martin, Millar David S., Hedderich Jürgen, Lewis Geraint, Newsway Vicky, Mo Neil, Fryklund Linda, Procter Annie M., Krawczak Michael, Cooper David N. Human growth hormone 1 (GH1) gene expression: complex haplotype-dependent influence of polymorphic variation in the proximal promoter and locus control region. Hum Mutat. 2003 Apr;21(4):408–423. doi: 10.1002/humu.10167. [DOI] [PubMed] [Google Scholar]
  19. Humphries S., Temple A., Lane A., Green F., Cooper J., Miller G. Low plasma levels of factor VIIc and antigen are more strongly associated with the 10 base pair promoter (-323) insertion than the glutamine 353 variant. Thromb Haemost. 1996 Apr;75(4):567–572. [PubMed] [Google Scholar]
  20. Jenkins D. L., Ortori C. A., Brookfield J. F. A test for adaptive change in DNA sequences controlling transcription. Proc Biol Sci. 1995 Aug 22;261(1361):203–207. doi: 10.1098/rspb.1995.0137. [DOI] [PubMed] [Google Scholar]
  21. Jordan I. K., McDonald J. F. Interelement selection in the regulatory region of the copia retrotransposon. J Mol Evol. 1998 Dec;47(6):670–676. doi: 10.1007/pl00006425. [DOI] [PubMed] [Google Scholar]
  22. Kaessmann H., Wiebe V., Päbo S. Extensive nuclear DNA sequence diversity among chimpanzees. Science. 1999 Nov 5;286(5442):1159–1162. doi: 10.1126/science.286.5442.1159. [DOI] [PubMed] [Google Scholar]
  23. Kario K., Narita N., Matsuo T., Kayaba K., Tsutsumi A., Matsuo M., Miyata T., Shimada K. Genetic determinants of plasma factor VII activity in the Japanese. Thromb Haemost. 1995 Apr;73(4):617–622. [PubMed] [Google Scholar]
  24. Karl S. A., Avise J. C. Balancing selection at allozyme loci in oysters: implications from nuclear RFLPs. Science. 1992 Apr 3;256(5053):100–102. doi: 10.1126/science.1348870. [DOI] [PubMed] [Google Scholar]
  25. King M. C., Wilson A. C. Evolution at two levels in humans and chimpanzees. Science. 1975 Apr 11;188(4184):107–116. doi: 10.1126/science.1090005. [DOI] [PubMed] [Google Scholar]
  26. Kudaravalli Rama, Tidd Theresa, Pinotti Mirko, Ratti Antonia, Santacroce Rosa, Margaglione Maurizio, Dallapiccola Bruno, Bernardi Francesco, Fortina Paolo, Devoto Marcella. Polymorphic changes in the 5' flanking region of factor VII have a combined effect on promoter strength. Thromb Haemost. 2002 Nov;88(5):763–767. [PubMed] [Google Scholar]
  27. Lander E. S. The new genomics: global views of biology. Science. 1996 Oct 25;274(5287):536–539. doi: 10.1126/science.274.5287.536. [DOI] [PubMed] [Google Scholar]
  28. Lane A., Cruickshank J. K., Mitchell J., Henderson A., Humphries S., Green F. Genetic and environmental determinants of factor VII coagulant activity in ethnic groups at differing risk of coronary heart disease. Atherosclerosis. 1992 May;94(1):43–50. doi: 10.1016/0021-9150(92)90186-k. [DOI] [PubMed] [Google Scholar]
  29. Lewontin R. C., Krakauer J. Distribution of gene frequency as a test of the theory of the selective neutrality of polymorphisms. Genetics. 1973 May;74(1):175–195. doi: 10.1093/genetics/74.1.175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Ludwig M. Z., Kreitman M. Evolutionary dynamics of the enhancer region of even-skipped in Drosophila. Mol Biol Evol. 1995 Nov;12(6):1002–1011. doi: 10.1093/oxfordjournals.molbev.a040277. [DOI] [PubMed] [Google Scholar]
  31. Marchetti G., Patracchini P., Papacchini M., Ferrati M., Bernardi F. A polymorphism in the 5' region of coagulation factor VII gene (F7) caused by an inserted decanucleotide. Hum Genet. 1993 Jan;90(5):575–576. doi: 10.1007/BF00217463. [DOI] [PubMed] [Google Scholar]
  32. McDonald J. H., Kreitman M. Adaptive protein evolution at the Adh locus in Drosophila. Nature. 1991 Jun 20;351(6328):652–654. doi: 10.1038/351652a0. [DOI] [PubMed] [Google Scholar]
  33. Meade T. W., Mellows S., Brozovic M., Miller G. J., Chakrabarti R. R., North W. R., Haines A. P., Stirling Y., Imeson J. D., Thompson S. G. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study. Lancet. 1986 Sep 6;2(8506):533–537. doi: 10.1016/s0140-6736(86)90111-x. [DOI] [PubMed] [Google Scholar]
  34. NEEL J. V. Diabetes mellitus: a "thrifty" genotype rendered detrimental by "progress"? Am J Hum Genet. 1962 Dec;14:353–362. [PMC free article] [PubMed] [Google Scholar]
  35. Pollak E. S., Hung H. L., Godin W., Overton G. C., High K. A. Functional characterization of the human factor VII 5'-flanking region. J Biol Chem. 1996 Jan 19;271(3):1738–1747. doi: 10.1074/jbc.271.3.1738. [DOI] [PubMed] [Google Scholar]
  36. Pritchard J. K. Are rare variants responsible for susceptibility to complex diseases? Am J Hum Genet. 2001 Jun 12;69(1):124–137. doi: 10.1086/321272. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Redondo M., Watzke H. H., Stucki B., Sulzer I., Biasiutti F. D., Binder B. R., Furlan M., Lämmle B., Wuillemin W. A. Coagulation factors II, V, VII, and X, prothrombin gene 20210G-->A transition, and factor V Leiden in coronary artery disease: high factor V clotting activity is an independent risk factor for myocardial infarction. Arterioscler Thromb Vasc Biol. 1999 Apr;19(4):1020–1025. doi: 10.1161/01.atv.19.4.1020. [DOI] [PubMed] [Google Scholar]
  38. Reich D. E., Lander E. S. On the allelic spectrum of human disease. Trends Genet. 2001 Sep;17(9):502–510. doi: 10.1016/s0168-9525(01)02410-6. [DOI] [PubMed] [Google Scholar]
  39. Rockman Matthew V., Hahn Matthew W., Soranzo Nicole, Goldstein David B., Wray Gregory A. Positive selection on a human-specific transcription factor binding site regulating IL4 expression. Curr Biol. 2003 Dec 2;13(23):2118–2123. doi: 10.1016/j.cub.2003.11.025. [DOI] [PubMed] [Google Scholar]
  40. Rockman Matthew V., Wray Gregory A. Abundant raw material for cis-regulatory evolution in humans. Mol Biol Evol. 2002 Nov;19(11):1991–2004. doi: 10.1093/oxfordjournals.molbev.a004023. [DOI] [PubMed] [Google Scholar]
  41. Sabeti Pardis C., Reich David E., Higgins John M., Levine Haninah Z. P., Richter Daniel J., Schaffner Stephen F., Gabriel Stacey B., Platko Jill V., Patterson Nick J., McDonald Gavin J. Detecting recent positive selection in the human genome from haplotype structure. Nature. 2002 Oct 9;419(6909):832–837. doi: 10.1038/nature01140. [DOI] [PubMed] [Google Scholar]
  42. Taylor M. F., Shen Y., Kreitman M. E. A population genetic test of selection at the molecular level. Science. 1995 Dec 1;270(5241):1497–1499. doi: 10.1126/science.270.5241.1497. [DOI] [PubMed] [Google Scholar]
  43. Thompson J. D., Higgins D. G., Gibson T. J. CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res. 1994 Nov 11;22(22):4673–4680. doi: 10.1093/nar/22.22.4673. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Watkins W. Scott, Rogers Alan R., Ostler Christopher T., Wooding Steve, Bamshad Michael J., Brassington Anna-Marie E., Carroll Marion L., Nguyen Son V., Walker Jerilyn A., Prasad B. V. Ravi. Genetic variation among world populations: inferences from 100 Alu insertion polymorphisms. Genome Res. 2003 Jun 12;13(7):1607–1618. doi: 10.1101/gr.894603. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Wilcox Josiah N., Noguchi Sumiko, Casanova Juan. Extrahepatic synthesis of factor VII in human atherosclerotic vessels. Arterioscler Thromb Vasc Biol. 2003 Jan 1;23(1):136–141. doi: 10.1161/01.atv.0000043418.84185.3c. [DOI] [PubMed] [Google Scholar]
  46. Wray Gregory A., Hahn Matthew W., Abouheif Ehab, Balhoff James P., Pizer Margaret, Rockman Matthew V., Romano Laura A. The evolution of transcriptional regulation in eukaryotes. Mol Biol Evol. 2003 May 30;20(9):1377–1419. doi: 10.1093/molbev/msg140. [DOI] [PubMed] [Google Scholar]
  47. Yang Z, Bielawski JP. Statistical methods for detecting molecular adaptation. Trends Ecol Evol. 2000 Dec 1;15(12):496–503. doi: 10.1016/S0169-5347(00)01994-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Yi Soojin, Ellsworth Darrell L., Li Wen-Hsiung. Slow molecular clocks in Old World monkeys, apes, and humans. Mol Biol Evol. 2002 Dec;19(12):2191–2198. doi: 10.1093/oxfordjournals.molbev.a004043. [DOI] [PubMed] [Google Scholar]
  49. de Maat M. P., Green F., de Knijff P., Jespersen J., Kluft C. Factor VII polymorphisms in populations with different risks of cardiovascular disease. Arterioscler Thromb Vasc Biol. 1997 Oct;17(10):1918–1923. doi: 10.1161/01.atv.17.10.1918. [DOI] [PubMed] [Google Scholar]
  50. van 't Hooft F. M., Silveira A., Tornvall P., Iliadou A., Ehrenborg E., Eriksson P., Hamsten A. Two common functional polymorphisms in the promoter region of the coagulation factor VII gene determining plasma factor VII activity and mass concentration. Blood. 1999 May 15;93(10):3432–3441. [PubMed] [Google Scholar]

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