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A population genetics study of the Familial Mediterranean Fever gene: evidence of balancing selection under an overdominance regime

Genes & Immunity volume 10, pages 678–686 (2009)Cite this article

Abstract

Familial Mediterranean Fever (FMF) is a recessively inherited systemic autoinflammatory disease caused by mutations in the MEFV gene. The frequency of different disease alleles is extremely high in multiple populations from the Mediterranean region, suggesting heterozygote advantage. Here, we characterize the sequence variation and haplotype structure of the MEFV 3′ gene region (from exon 5 to the 3′ UTR) in seven human populations. In non-African populations, we observed high levels of nucleotide variation, an excess of intermediate-frequency alleles, reduced population differentiation and a genealogy with two common haplotypes separated by deep branches. These features are suggestive of balancing selection having acted on this region to maintain one or more selected alleles. In line with this finding, an excess of heterozygotes was observed in Europeans and Asians, suggesting an overdominance regime. Our data, together with the earlier demonstration that the MEFV exon 10 has been subjected to episodic positive selection over primate evolution, provide evidence for an adaptive role of nucleotide variation in this gene region. Our data suggest that further studies aimed at clarifying the role of MEFV variants might benefit from the integration of molecular evolutionary and functional analyses.

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References

  1. Sohar E, Gafni J, Pras M, Heller H . Familial Mediterranean fever. A survey of 470 cases and review of the literature. Am J Med 1967; 2: 227–253.

    Article  Google Scholar 

  2. The International FMF Consortium. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell 1997; 4: 797–807.

    Article  Google Scholar 

  3. French FMF Consortium. A candidate gene for familial Mediterranean fever. Nat Genet 1997; 1: 25–31.

    Article  Google Scholar 

  4. Centola M, Wood G, Frucht DM, Galon J, Aringer M, Farrell C et al. The gene for familial Mediterranean fever, MEFV, is expressed in early leukocyte development and is regulated in response to inflammatory mediators. Blood 2000; 10: 3223–3231.

    Article  Google Scholar 

  5. Schaner PE, Gumucio DL . Familial Mediterranean fever in the post-genomic era: how an ancient disease is providing new insights into inflammatory pathways. Curr Drug Targets Inflamm Allergy 2005; 1: 67–76.

    Article  Google Scholar 

  6. Richards N, Schaner P, Diaz A, Stuckey J, Shelden E, Wadhwa A et al. Interaction between pyrin and the apoptotic speck protein (ASC) modulates ASC-induced apoptosis. J Biol Chem 2001; 42: 39320–39329.

    Article  Google Scholar 

  7. Chae JJ, Komarow HD, Cheng J, Wood G, Raben N, Liu PP et al. Targeted disruption of pyrin, the FMF protein, causes heightened sensitivity to endotoxin and a defect in macrophage apoptosis. Mol Cell 2003; 3: 591–604.

    Article  Google Scholar 

  8. Chae JJ, Wood G, Masters SL, Richard K, Park G, Smith BJ et al. The B30.2 domain of pyrin, the familial Mediterranean fever protein, interacts directly with caspase-1 to modulate IL-1beta production. Proc Natl Acad Sci USA 2006; 26: 9982–9987.

    Article  CAS  Google Scholar 

  9. Touitou I . The spectrum of Familial Mediterranean Fever (FMF) mutations. Eur J Hum Genet 2001; 7: 473–483.

    Article  CAS  Google Scholar 

  10. Schaner P, Richards N, Wadhwa A, Aksentijevich I, Kastner D, Tucker P et al. Episodic evolution of pyrin in primates: human mutations recapitulate ancestral amino acid states. Nat Genet 2001; 3: 318–321.

    Article  CAS  Google Scholar 

  11. Fisher BA, Lachmann HJ, Rowczenio D, Goodman HJ, Bhalara S, Hawkins PN . Colchicine responsive periodic fever syndrome associated with pyrin I591T. Ann Rheum Dis 2005; 9: 1384–1385.

    Article  Google Scholar 

  12. Watterson GA . On the number of segregating sites in genetical models without recombination. Theor Popul Biol 1975; 2: 256–276.

    Article  Google Scholar 

  13. Nei M, Li WH . Mathematical model for studying genetic variation in terms of restriction endonucleases. Proc Natl Acad Sci USA 1979; 10: 5269–5273.

    Article  Google Scholar 

  14. Tajima F . Statistical method for testing the neutral mutation hypothesis by DNA polymorphism. Genetics 1989; 3: 585–595.

    Article  Google Scholar 

  15. Fu YX, Li WH . Statistical tests of neutrality of mutations. Genetics 1993; 3: 693–709.

    Article  Google Scholar 

  16. Wooding S, Rogers A . The matrix coalescent and an application to human single-nucleotide polymorphisms. Genetics 2002; 4: 1641–1650.

    Article  Google Scholar 

  17. Schaffner SF, Foo C, Gabriel S, Reich D, Daly MJ, Altshuler D . Calibrating a coalescent simulation of human genome sequence variation. Genome Res 2005; 11: 1576–1583.

    Article  CAS  Google Scholar 

  18. Marth GT, Czabarka E, Murvai J, Sherry ST . The allele frequency spectrum in genome-wide human variation data reveals signals of differential demographic history in three large world populations. Genetics 2004; 1: 351–372.

    Article  Google Scholar 

  19. Voight BF, Adams AM, Frisse LA, Qian Y, Hudson RR, Di Rienzo A . Interrogating multiple aspects of variation in a full resequencing data set to infer human population size changes. Proc Natl Acad Sci USA 2005; 51: 18508–18513.

    Article  CAS  Google Scholar 

  20. Kimura M . The Neutral Theory of Molecular Evolution. Cambridge University Press: Cambridge, 1983.

    Book  Google Scholar 

  21. Hudson RR, Kreitman M, Aguade M . A test of neutral molecular evolution based on nucleotide data. Genetics 1987; 1: 153–159.

    Article  Google Scholar 

  22. Wright SI, Charlesworth B . The HKA test revisited: a maximum-likelihood-ratio test of the standard neutral model. Genetics 2004; 2: 1071–1076.

    Article  Google Scholar 

  23. Fumagalli M, Cagliani R, Pozzoli U, Riva S, Comi GP, Menozzi G et al. Widespread balancing selection and pathogen-driven selection at blood group antigen genes. Genome Res 2009; 2: 199–212.

    Article  CAS  Google Scholar 

  24. Zhai W, Nielsen R, Slatkin M . An investigation of the statistical power of neutrality tests based on comparative and population genetic data. Mol Biol Evol 2009; 2: 273–283.

    Article  CAS  Google Scholar 

  25. Wright S . Genetical structure of populations. Nature 1950; 4215: 247–249.

    Article  Google Scholar 

  26. Bowcock AM, Kidd JR, Mountain JL, Hebert JM, Carotenuto L, Kidd KK et al. Drift, admixture, and selection in human evolution: a study with DNA polymorphisms. Proc Natl Acad Sci USA 1991; 3: 839–843.

    Article  Google Scholar 

  27. Akey JM, Zhang G, Zhang K, Jin L, Shriver MD . Interrogating a high-density SNP map for signatures of natural selection. Genome Res 2002; 12: 1805–1814.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bandelt HJ, Forster P, Rohl A . Median-joining networks for inferring intraspecific phylogenies. Mol Biol Evol 1999; 1: 37–48.

    Article  Google Scholar 

  29. Griffiths RC, Tavare S . Sampling theory for neutral alleles in a varying environment. Philos Trans R Soc Lond B Biol Sci 1994; 1310: 403–410.

    Google Scholar 

  30. Griffiths RC, Tavare S . Unrooted genealogical tree probabilities in the infinitely-many-sites model. Math Biosci 1995; 1: 77–98.

    Article  Google Scholar 

  31. Garrigan D, Hammer MF . Reconstructing human origins in the genomic era. Nat Rev Genet 2006; 9: 669–680.

    Article  CAS  Google Scholar 

  32. Takahata N . A simple genealogical structure of strongly balanced allelic lines and trans-species evolution of polymorphism. Proc Natl Acad Sci USA 1990; 7: 2419–2423.

    Article  Google Scholar 

  33. Wall JD . Detecting ancient admixture in humans using sequence polymorphism data. Genetics 2000; 3: 1271–1279.

    Article  Google Scholar 

  34. Barreiro LB, Patin E, Neyrolles O, Cann HM, Gicquel B, Quintana-Murci L . The heritage of pathogen pressures and ancient demography in the human innate-immunity CD209/CD209 L region. Am J Hum Genet 2005; 5: 869–886.

    Article  Google Scholar 

  35. Garrigan D, Mobasher Z, Kingan SB, Wilder JA, Hammer MF . Deep haplotype divergence and long-range linkage disequilibrium at xp21.1 provide evidence that humans descend from a structured ancestral population. Genetics 2005; 4: 1849–1856.

    Article  CAS  Google Scholar 

  36. Alonso S, Lopez S, Izagirre N, de la Rua C . Overdominance in the human genome and olfactory receptor activity. Mol Biol Evol 2008; 5: 997–1001.

    Article  CAS  Google Scholar 

  37. Harding RM, McVean G . A structured ancestral population for the evolution of modern humans. Curr Opin Genet Dev 2004; 6: 667–674.

    Article  CAS  Google Scholar 

  38. Harris EE, Hey J . X chromosome evidence for ancient human histories. Proc Natl Acad Sci USA 1999; 6: 3320–3324.

    Article  Google Scholar 

  39. Labuda D, Zietkiewicz E, Yotova V . Archaic lineages in the history of modern humans. Genetics 2000; 2: 799–808.

    Article  Google Scholar 

  40. Goldstein DB, Chikhi L . Human migrations and population structure: what we know and why it matters. Annu Rev Genomics Hum Genet 2002; 3: 129–152.

    Article  CAS  PubMed  Google Scholar 

  41. Satta Y, Takahata N . The distribution of the ancestral haplotype in finite stepping-stone models with population expansion. Mol Ecol 2004; 4: 877–886.

    Article  Google Scholar 

  42. Tishkoff SA, Verrelli BC . Patterns of human genetic diversity: implications for human evolutionary history and disease. Annu Rev Genomics Hum Genet 2003; 4: 293–340.

    Article  CAS  PubMed  Google Scholar 

  43. Asthana S, Schmidt S, Sunyaev S . A limited role for balancing selection. Trends Genet 2005; 1: 30–32.

    Article  CAS  Google Scholar 

  44. Bubb KL, Bovee D, Buckley D, Haugen E, Kibukawa M, Paddock M et al. Scan of human genome reveals no new Loci under ancient balancing selection. Genetics 2006; 4: 2165–2177.

    Article  CAS  Google Scholar 

  45. Hurst LD . Fundamental concepts in genetics: genetics and the understanding of selection. Nat Rev Genet 2009; 2: 83–93.

    Article  CAS  Google Scholar 

  46. Takahata N, Satta Y . Footprints of intragenic recombination at HLA loci. Immunogenetics 1998; 6: 430–441.

    Article  Google Scholar 

  47. Bamshad MJ, Mummidi S, Gonzalez E, Ahuja SS, Dunn DM, Watkins WS et al. A strong signature of balancing selection in the 5′ cis-regulatory region of CCR5. Proc Natl Acad Sci USA 2002; 16: 10539–10544.

    Article  CAS  Google Scholar 

  48. Fumagalli M, Pozzoli U, Cagliani R, Comi GP, Riva S, Clerici M et al. Parasites represent a major selective force for interleukin genes and shape the genetic predisposition to autoimmune conditions. J Exp Med 2009; 6: 1395–1408.

    Article  CAS  Google Scholar 

  49. Wu X, Di Rienzo A, Ober C . A population genetics study of single nucleotide polymorphisms in the interleukin 4 receptor alpha (IL4RA) gene. Genes Immun 2001; 3: 128–134.

    Article  CAS  Google Scholar 

  50. Hollox EJ, Armour JA, Barber JC . Extensive normal copy number variation of a beta-defensin antimicrobial-gene cluster. Am J Hum Genet 2003; 3: 591–600.

    Article  Google Scholar 

  51. Cagliani R, Fumagalli M, Riva S, Pozzoli U, Comi GP, Menozzi G et al. The signature of long-standing balancing selection at the human defensin beta-1 promoter. Genome Biol 2008; 9: R143.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Prugnolle F, Manica A, Charpentier M, Guegan JF, Guernier V, Balloux F . Pathogen-driven selection and worldwide HLA class I diversity. Curr Biol 2005; 11: 1022–1027.

    Article  CAS  Google Scholar 

  53. Verrelli BC, McDonald JH, Argyropoulos G, Destro-Bisol G, Froment A, Drousiotou A et al. Evidence for balancing selection from nucleotide sequence analyses of human G6PD. Am J Hum Genet 2002; 5: 1112–1128.

    Article  Google Scholar 

  54. Aidoo M, Terlouw DJ, Kolczak MS, McElroy PD, ter Kuile FO, Kariuki S et al. Protective effects of the sickle cell gene against malaria morbidity and mortality. Lancet 2002; 9314: 1311–1312.

    Article  Google Scholar 

  55. Pier GB, Grout M, Zaidi T, Meluleni G, Mueschenborn SS, Banting G et al. Salmonella typhi uses CFTR to enter intestinal epithelial cells. Nature 1998; 6680: 79–82.

    Article  CAS  Google Scholar 

  56. Stiehm ER . Disease versus disease: how one disease may ameliorate another. Pediatrics 2006; 1: 184–191.

    Article  Google Scholar 

  57. Beaty JS, Sukiennicki TL, Nepom GT . Allelic variation in transcription modulates MHC class II expression and function. Microbes Infect 1999; 11: 919–927.

    Article  Google Scholar 

  58. Beaty JS, West KA, Nepom GT . Functional effects of a natural polymorphism in the transcriptional regulatory sequence of HLA-DQB1. Mol Cell Biol 1995; 9: 4771–4782.

    Article  Google Scholar 

  59. La Regina M, Nucera G, Diaco M, Procopio A, Gasbarrini G, Notarnicola C et al. Familial Mediterranean fever is no longer a rare disease in Italy. Eur J Hum Genet 2003; 1: 50–56.

    Article  Google Scholar 

  60. McMichael AJ . Environmental and social influences on emerging infectious diseases: past, present and future. Philos Trans R Soc Lond B Biol Sci 2004; 1447: 1049–1058.

    Article  Google Scholar 

  61. Dobson A . People and disease. In: Jones S, Martin R and Pilbeam D (eds). The Cambridge Encyclopedia of Human Evolution. Cambridge University Press: Cambridge, 1992. pp 411–420.

    Google Scholar 

  62. Kogan A, Shinar Y, Lidar M, Revivo A, Langevitz P, Padeh S et al. Common MEFV mutations among Jewish ethnic groups in Israel: high frequency of carrier and phenotype III states and absence of a perceptible biological advantage for the carrier state. Am J Med Genet 2001; 3: 272–276.

    Article  Google Scholar 

  63. Kalyoncu M, Acar BC, Cakar N, Bakkaloglu A, Ozturk S, Dereli E et al. Are carriers for MEFV mutations ‘healthy’? Clin Exp Rheumatol 2006; 5 (Suppl 42): S120–S122.

    Google Scholar 

  64. Yepiskoposyan L, Harutyunyan A . Population genetics of familial Mediterranean fever: a review. Eur J Hum Genet 2007; 9: 911–916.

    Article  CAS  Google Scholar 

  65. Sackesen C, Bakkaloglu A, Sekerel BE, Ozaltin F, Besbas N, Yilmaz E et al. Decreased prevalence of atopy in paediatric patients with familial Mediterranean fever. Ann Rheum Dis 2004; 2: 187–190.

    Article  Google Scholar 

  66. Brenner-Ullman A, Melzer-Ofir H, Daniels M, Shohat M . Possible protection against asthma in heterozygotes for familial Mediterranean fever. Am J Med Genet 1994; 2: 172–175.

    Article  Google Scholar 

  67. Ross JJ . Goats, germs, and fever: are the pyrin mutations responsible for familial Mediterranean fever protective against Brucellosis? Med Hypotheses 2007; 3: 499–501.

    Article  CAS  Google Scholar 

  68. Cattan D . Familial Mediterranean fever: is low mortality from tuberculosis a specific advantage for MEFV mutations carriers? Mortality from tuberculosis among Muslims, Jewish, French, Italian and Maltese patients in Tunis (Tunisia) in the first half of the 20th century. Clin Exp Rheumatol 2003; 4 (Suppl 30): S53–S54; author reply S54.

    Google Scholar 

  69. Perni SC, Vardhana S, Tuttle SL, Kalish RB, Chasen ST, Witkin SS . Fetal interleukin-1 receptor antagonist gene polymorphism, intra-amniotic interleukin-1beta levels, and history of spontaneous abortion. Am J Obstet Gynecol 2004; 4: 1318–1323.

    Article  CAS  Google Scholar 

  70. Genc MR, Gerber S, Nesin M, Witkin SS . Polymorphism in the interleukin-1 gene complex and spontaneous preterm delivery. Am J Obstet Gynecol 2002; 1: 157–163.

    Article  CAS  Google Scholar 

  71. Wang ZC, Yunis EJ, De los Santos MJ, Xiao L, Anderson DJ, Hill JA . T helper 1–type immunity to trophoblast antigens in women with a history of recurrent pregnancy loss is associated with polymorphism of the IL1B promoter region. Genes Immun 2002; 1: 38–42.

    Article  CAS  Google Scholar 

  72. Hernandez-Guerrero C, Monzon-Bordonaba F, Jimenez-Zamudio L, Ahued-Ahued R, Arechavaleta-Velasco F, Strauss 3rd JF et al. In-vitro secretion of proinflammatory cytokines by human amniochorion carrying hyper-responsive gene polymorphisms of tumour necrosis factor-alpha and interleukin-1beta. Mol Hum Reprod 2003; 10: 625–629.

    Article  Google Scholar 

  73. Yost NP, Cox SM . Infection and preterm labor. Clin Obstet Gynecol 2000; 4: 759–767.

    Article  Google Scholar 

  74. Charlesworth D . Balancing selection and its effects on sequences in nearby genome regions. PLoS Genet 2006; 4: e64.

    Article  CAS  Google Scholar 

  75. Stephens M, Smith NJ, Donnelly P . A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001; 4: 978–989.

    Article  Google Scholar 

  76. Stephens M, Scheet P . Accounting for decay of linkage disequilibrium in haplotype inference and missing-data imputation. Am J Hum Genet 2005; 3: 449–462.

    Article  Google Scholar 

  77. Thornton K . Libsequence: a C++ class library for evolutionary genetic analysis. Bioinformatics 2003; 17: 2325–2327.

    Article  CAS  Google Scholar 

  78. Hudson RR . Generating samples under a Wright-Fisher neutral model of genetic variation. Bioinformatics 2002; 2: 337–338.

    Article  Google Scholar 

  79. Hudson RR . Two-locus sampling distributions and their application. Genetics 2001; 4: 1805–1817.

    Article  Google Scholar 

  80. Hudson RR, Boos DD, Kaplan NL . A statistical test for detecting geographic subdivision. Mol Biol Evol 1992; 1: 138–151.

    Google Scholar 

  81. Hudson RR, Slatkin M, Maddison WP . Estimation of levels of gene flow from DNA sequence data. Genetics 1992; 2: 583–589.

    Article  Google Scholar 

  82. Glazko GV, Nei M . Estimation of divergence times for major lineages of primate species. Mol Biol Evol 2003; 3: 424–434.

    Article  Google Scholar 

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Acknowledgements

We are grateful to Roberto Giorda for helpful discussion about the paper.

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Authors and Affiliations

  1. Scientific Institute IRCCS E. Medea, Bioinformatic Laboratory, Bosisio Parini (LC), Italy

    M Fumagalli, R Cagliani, U Pozzoli, S Riva, G Menozzi, N Bresolin & M Sironi

  2. Department of Bioengineering, Politecnico di Milano, Milan, Italy

    M Fumagalli

  3. Department of Neurological Sciences, Dino Ferrari Centre, University of Milan, IRCCS Ospedale Maggiore Policlinico, Mangiagalli and Regina Elena Foundation, Milan, Italy

    G P Comi & N Bresolin

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Fumagalli, M., Cagliani, R., Pozzoli, U. et al. A population genetics study of the Familial Mediterranean Fever gene: evidence of balancing selection under an overdominance regime. Genes Immun 10, 678–686 (2009). https://doi.org/10.1038/gene.2009.59

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