Abstract
The mutation responsible for most cases of genetic haemochromatosis in Europe (HFE C282Y) appears to have been originated as a unique event on a chromosome carrying HLA-A3 and -B7. It is often described as a “Celtic mutation”—originating in a Celtic population in central Europe and spreading west and north by population movement. It has also been suggested that Viking migrations were largely responsible for the distribution of this mutation. Two, initial estimates of the age of the mutation are compatible with either of these suggestions. Here we examine the evidence about HFE C282Y frequencies, extended haplotypes involving HLA-A and -B alleles, the validity of calculations of mutation age, selective advantage and current views on the relative importance of “demic-diffusion” (population migration) and “adoption-diffusion” (cultural change) in the neolithic transition in Europe and since then. We conclude that the HFE C282Y mutation occurred in mainland Europe before 4,000 BC.
Similar content being viewed by others
References
Adams PC (1994) Prevalence of abnormal iron studies in heterozygotes for hereditary hemochromatosis: an analysis of 255 heterozygotes. Am J Hematol 45:146–149
Ajioka RS, Jorde LB, Gruen JR, Yu P, Dimitrova D, Barrow J, Radisky E, Edwards CQ, Griffen LM, Kushner JP (1997) Haplotype analysis of hemochromatosis: evaluation of different linkage-disequilibrium approaches and evolution of disease chromosomes. Am J Hum Genet 60:1439–1447
Arnaiz-Viellena A, Rodrigues de Cordoba S, Vela F, Pascual JC, Cervero J, Bootello A (1981) HLA antigens in a sample of the Spanish population: common features among Spaniards, Basques and Sardinians. Hum Genet 58:344–348
Arnaiz-Villena A (2001) Historic genomics: an emergent discipline. Hum Immunol 62:869–870
Arnaiz-Villena A, Martinezlaso J, Gomezcasado E, Diazcampos N, Santos P, Martinho A, Bredacoimbra H (1997) Relatedness among Basques, Portuguese, Spaniards, and Algerians studied by HLA allelic frequencies and haplotypes. Immunogenetics 47:37–43
Arnaiz-Villena A, Gomez-Casdo E, Martinez-Laso J (2002) Population genetic relationships between Mediterranean populations determined by HLA allele distribution and a historic perspective. Tissue Antigens 60:111–121
Asberg A, Hveem K, Thorstensen K, Ellekjaer E, Kannelonning K, Fjosne U, Halvorsen TB, Smethurst HBG, Sagen E, Bjerve KS (2001) Screening for hemochromatosis: high prevalence and low morbidity in an unselected population of 65,238 persons. Scand J Gastro 36:1108–1115
Batey C, Clarke H, Page RI, Price NS (1994) Cultural atlas of the Viking world. Andromeda, Oxford
Beutler E, Gelbart T, West C, Lee P, Adams M, Blackstone R, Pockros P, Kosty M, Venditti CP, Phatak PD, Seese NK, Chorney KA, Tenelshof AE, Gerhard GS, Chorney M (1996) Mutation analysis in hereditary hemochromatosis. Blood Cells Mol Dis 22:187–194
Beutler E, Felitti V, Gelbart T, Ho N (2000) The effect of HFE genotypes on measurements of iron overload in patients attending a health appraisal clinic. Ann Int Med 133:329–337
Beutler E, Felitti VJ, Koziol JA, Ho NJ, Gelbart T (2002) Penetrance of 845G>A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet 359:211–218
Beutler E, Felitti V, Gelbart T, Waalen J (2003) Haematological effects of the C282Y HFE mutation in homozygous and heterozygous states among subjects of northern and southern European ancestry. Br J Haematol 120:887–893
Blanco I, Fernandez E, Bustillo EF (2001) Alpha-1-antitrypsin PI phenotypes S and Z in Europe: an analysis of the published surveys. Clin Genet 60:31–41
Bothwell TH, Macphail AP (1998) Hereditary hemochromatosis: etiologic, pathologic, and clinical aspects. Semin Hematol 35:55–71
Bulaj ZJ, Griffen LM, Jorde LB, Edwards CQ, Kushner JP (1996) Clinical and biochemical abnormalities in people heterozygous for hemochromatosis. N Engl J Med 335:1799–1805
Burt MJ, George PM, Upton JD, Collett JA, Frampton CMA, Chapman TM, Walmsley TA, Chapman BA (1998) The significance of haemochromatosis gene mutations in the general population: implications for screening. Gut 43:830–836
Byrnes V, Ryan E, Barrett S, Kenny P, Mayne P, Crowe J (2001) Genetic hemochromatosis, a Celtic disease: is it now time for population screening? Genet Test 5:127–130
Campbell S, George DK, Robb SD, Spooner R, McDonagh TA, Dargie HJ, Mills PR (2003) The prevalence of haemochromatosis gene mutations in the West of Scotland and their relation to ischaemic heart disease. Heart 89:1023–1026
Camaschella C, Roetto A, De Gobbi M (2002) Genetic haemochromatosis: genes and mutations associated with iron loading. Best Pract Res Clin Haematol 15:261–276
Cardoso CS, Alves H, Mascarenhas M, Goncalves R, Oliveira P, Rodrigues P, Cruz E, de Sousa M, Porto G (2002) Co-selection of the H63D mutation and the HLA-A29 allele: a new paradigm of linkage disequilibrium? Immunogenetics 53:1002–1008
Cavalli-Sforza L, Mennozzi P, Piazza A (1994) The history and geography of human genes. Princeton University Press, Princeton
Clayton, Lonjou C (1996) Allele and haplotype frequencies for HLA loci in various ethnic groups. In: Charron D (ed) Genetic diversity of HLA, functional and medical implications. EDK, Paris, pp 650–820
Crawford DHG, Powell LW, Leggett BA, Francis JS, Fletcher LM, Webb SI, Halliday JW, Jazwinska EC (1995) Evidence that the ancestral haplotype in Australian hemochromatosis patients may be associated with a common mutation in the gene. Am J Hum Genet 57:362–367
Cunliffe B (2003) The ancient Celts. Oxford University Press, Oxford
Darke C, Guttridge MG, Thompson J, McNamara S, Street J, Thomas M (1998) HLA class I (A, B) and II (DR, DQ) gene and haplotype frequencies in blood donors from Wales. Immunogenetics 15:69–83
Darke C, Guttridge MG, Mcnamara S (1999) Distribution of HFE alleles and HLA-HFE haplotypes in blood donors resident in Wales. Eur J Immunogenet 25 (Suppl 3):263
Datz C, Haas T, Rinner H, Sandhofer F, Patsch W, Paulweber B (1998) Heterozygosity for the C282Y mutation in the hemochromatosis gene is associated with increased serum iron, transferrin saturation, and hemoglobin in young women: a protective role against iron deficiency? Clin Chem 44:2429–2432
De Braekeleer M (1993) A prevalence and fertility study of haemochromatosis in Saguenay-Lac-Saint-Jean. Ann Hum Biol 20:501–505
De Serres FJ (2002) Worldwide racial and ethnic distributioin of α1-antitrypsin deficiency. Chest 122:1818–1829
Eisensmith RC, Okano Y, Dasovich M, Wang T, Guttler F, Lou H, Guldberg P, Lichterkonecki U, Konecki DS, Svensson E, Hagenfeldt L, Rey F, Munnich A, Lyonnet S, Cockburn F, Connor JM, Pembrey ME, Smith I, Gitzelmann R, Steinmann B, Apold J, Eiken HG, Giovannini M, Riva E, Longhi R, Romano C, Cerone R, Naughten ER, Mullins C, Cahalane S, Ozalp I, Fekete G, Schuler D, Berencsi GY, Nasz I, Brdicka R, Kamaryt J, Pijackova A, Cabalska B, Boszkowa K, Schwartz E, Kalinin VN, Jin L, Chakraborty R, Woo SLC (1992) Multiple origins for phenylketonuria in Europe. Am J Hum Genet 51:1355–1365
Eisensmith RC, Goltsov AA, Oneill C, Tyfield LA, Schwartz EI, Kuzmin AI, Baranovskaya SS, Tsukerman GL, Treacy E, Scriver CR, Guttler F, Guldberg P, Eiken HG, Apold J, Svensson E, Naughten E, Cahalane SF, Croke DT, Cockburn F, Woo SLC (1995) Recurrence of the R408W mutation in the phenylalanine-hydroxylase locus in Europeans. Am J Hum Genet 56:278–286
Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A, Dormishian F, Domingo R, Ellis MC, Fullan A, Hinton LM, Jones NL, Kimmel BE, Kronmal GS, Lauer P, Lee VK, Loeb DB, Mapa FA, Mcclelland E, Meyer NC, Mintier GA, Moeller N, Moore T, Morikang E, Prass CE, Quintana L, Starnes SM, Schatzman RC, Brunke KJ, Drayna DT, Risch NJ, Bacon BR, Wolff RK (1996) A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 13:399–408
Feder JN, Tsuchihashi Z, Irrinki A, Lee VK, Mapa FA, Morikang E, Prass CE, Starnes SM, Wolff RK, Parkkila S, Sly WS, Schatzman RC (1997) The hemochromatosis founder mutation in HLA-H disrupts beta(2)-microglobulin interaction and cell surface expression. J Biol Chem 272:14025–14028
Feder JN, Penny DM, Irrinki A, Lee VK, Lebron JA, Watson N, Tsuchihashi Z, Sigal E, Bjorkman PJ, Schatzman RC (1998) The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding. Proc Natl Acad Sci USA 95:1472–1477
Finch T, Lawlor E, Borton M, Barnes CA, McNamara S, Oriordan J, McCann SR, Darke C (1997) Distribution of HLA-A, B and DR genes and haplotypes in the Irish population. Exp Clin Immunogenet 14:250–263
Ganz T (2003) Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood 102:783–788
Gkiasta M, Russell T, Shennan S, Steele J (2003) Neolithic transition in Europe: the radiocarbon record revisited. Antiquity 77:45–62
Helgason A, Hickey E, Goodacre S, Bosnes V, Stefansson K, Ward R, Sykes B (2001) mtDNA and the islands of the north Atlantic: estimating the proportions of Norse and Gaelic ancestry. Am J Hum Genet 68:723–737
Jackson HA, Carter K, Darke C, Guttridge MG, Ravine D, Hutton RD, Napier JA, Worwood M (2001) HFE mutations, iron deficiency and overload in 10,500 blood donors. Br J Haematol 114:474–484
Kaplan NL, Lewis PO, Weir BS (1994) Age of the delta-F508 cystic-fibrosis mutation. Nat Genet 8:216
Krawczak M, Zschocke J (2003) A role for overdominant selection in phenylketonuria? Evidence from molecular data. Hum Mutat 21:394–397
Lebron JA, Bennett MJ, Vaughn DE, Chirino AJ, Snow PM, Mintier GA, Feder JN, Bjorkman PJ (1998) Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor. Cell 93:111–123
Lucotte G (2001) Frequency analysis and allele map in favor of the Celtic origin of the C282Y mutation of hemochromatosis. Blood Cells Mol Dis 27:549–556
Lucotte G, Dieterlen F (2003) A European allele map of the C282Y mutation of hemochromatosis: Celtic versus Viking origin of the mutation? Blood Cells Mol Dis 31:262–267
Luisetti M, Seersholm N (2004) α1-Antitrypsin deficiency. 1: epidemiology of α1-antitrypsin deficiency. Thorax 59:164–169
Malfroy L, Roth MP, Carrington M, Borot N, Volz A, Ziegler A, Coppin H (1997) Heterogeneity in rates of recombination in the 6-Mb region telomeric to the human major histocompatibility complex. Genomics 43:226–231
McCune CA, Al-Jader LN, May A, Hayes SL, Jackson HA, Worwood M (2002) Hereditary haemochromatosis: only 1% of adult HFE C282Y homozygotes in South Wales have a clinical diagnosis of iron overload. Hum Genet 111:538–543
McEvedy C (2002) The new Penguin atlas of ancient history. Penguin Books, London
Merryweather-Clarke AT, Pointon JJ, Jouanolle AM, Rochette J, Robson KJH (2000) Georgraphy of HFE C282Y and H63D mutations. Genet Test 4:183–198
Milman N, Pedersen P (2003) Evidence that the Cys282Tyr mutation of the HFE gene originated from a population in Southern Scandinavia and spread with the Vikings. Clin Genet 64:36–47
Milman N, Sorensen SA (1983) Idiopathic haemochromatosis. Was the ancestor a Danish Viking? Ugeskr Laeger 145:832–833
Moalem S, Percy ME, Kruck TPA, Gelbart RR (2002) Epidemic pathogenic selection: an explanation for hereditary hemochromatosis? Med Hypotheses 59:325–329
Moirand R, Guyader D, Mendler MH, Jouanolle AM, Le Gall JY, David V, Brissot P, Deugnier Y (2002) HFE based re-evaluation of heterozygous hemochromatosis. Am J Med Genet 111:356–361
Morral N, Bertranpetit J, Estivill X, Nunes V, Casals T, Gimenez J, Reis A, Varonmateeva R, Macek M, Kalaydjieva L, Angelicheva D, Dancheva R, Romeo G, Russo MP, Garnerone S, Restagno G, Ferrari M, Magnani C, Claustres M, Desgeorges M, Schwartz M, Schwarz M, Dallapiccola B, Novelli G, Ferec C, Dearce M, Nemeti M, Kere T, Anvret M, Dahl N, Kadasi L (1994) The origin of the major cystic-fibrosis mutation (delta-F508) in European populations. Nat Genet 7:169–175
Motulsky AG (1979) Genetics of hemochromatosis. N Engl J Med 301:1291
Muller CR, Ehninger G, Goldmann SF (2003) Gene and haplotype frequencies for the loci HLA-A, HLA-B, and HLA-DR based on over 13,000 German blood donors. Hum Immunol 64:137–151
Mura C, Raguenes O, Ferec C (1999) HFE mutations in 711 hemochromatosis probands: evidence for S65C implication in mild form of hemochromatosis. Blood 93:2202–2205
Nicolas G, Bennoun M, Devaux I, Beaumont C, Grandchamp B, Kahn A, Vaulont S (2001) Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (Usf2) knockout mice. Proc Natl Acad Sci USA 98:8780–8785
Niederau C, Fischer R, Purschel A, Stremmel W, Haussinger D, Strohmeyer G (1996) Long-term survival in patients with hereditary hemochromatosis. Gastroenterology 110:1107–1119
Olsson KS, Ritter B (1981) Idiopatisk hemokromatose. Tidsskrift for Den Norske Laegeforen 29:101
Papanikolaou G, Politou M, Terpos E, Fourlemadis S, Sakellaropoulos N, Loukopoulos D (2000) Hereditary hemochromatosis: HFE mutation analysis in Greeks reveals genetic heterogeneity. Blood Cells Mol Dis 26:163–168
Pigeon C, Ilyin G, Courselaud B, Leroyer P, Turlin B, Brissot P, l’Oréal O (2001) A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem 276:7811–7819
Piperno A, Arosio C, Fargion S, Roetto A, Nicoli C, Girelli D, Sbaiz L, Gasparini P, Boari G, Sampietro M, Camaschella C (1996) The ancestral hemochromatosis haplotype is associated with a severe phenotype expression in Italian patients. Hepatology 24:43–46
Piperno A, Sampietro M, Pietrangelo A, Arosio C, Lupica L, Montosi G, Vergani A, Fraquelli M, Girelli D, Pasquero P, Roetto A, Gasparini P, Fargion S, Conte D, Camaschella C (1998) Heterogeneity of hemochromatosis in Italy. Gastroenterology 114:996–1002
Powell LW, Summers KM, Board PG, Axelsen E, Webb S, Halliday JW (1990) Expression of hemochromatosis in homozygous subjects. Implications for early diagnosis and prevention. Gastroenterology 98:1625–1632
Price P, Witt C, Allcock R, Sayer D, Garlepp M, Kok CC, French M, Mallal S, Christiansen F (1999) The genetic basis for the association of the 8.1 ancestral haplotype (A1, B8, DR3) with multiple immuopathological diseases. Immunol Rev 167:257–274
Raha-Chowdhury, Gruen JR (2000) Localization, allelic heterogeneity, and origins of the hemochromatosis gene. In: Barton JC, Edwards CQ (eds) Hemochromatosis: genetics, pathophysiology, diagnosis and treament. Cambridge University Press, Cambridge, pp 75–90
Raha-Chowdhury R, Bowen DJ, Stone C, Pointon JJ, Terwilliger JD, Shearman JD, Robson KJH, Bomford A, Worwood M (1995) New polymorphic microsatellite markers place the haemochromatosis gene telomeric to D6S105. Hum Mol Genet 4:1869–1874
Richards HD (2000) Viking age England. Tempus, Stroud
Risch N (1997) Haemochromatosis, HFE and genetic complexity. Nat Genet 17:375–376
Rochette J, Pointon JJ, Fisher CA, Perera G, Arambepola M, Arichchi DSK, De Silva S, Vandwalle JL, Monti JP, Old JM, Merryweather-Clarke AT, Weatherall DJ, Robson KJH (1999) Multicentric origin of hemochromatosis gene (HFE) mutations. Am J Hum Genet 64:1056–1062
Rossi E, Olynyk JK, Cullen DJ, Papadopoulos G, Bulsara M, Summerville L, Powell LW (2000) Compound heterozygous hemochromatosis genotype predicts increased iron and erythrocyte indices in women. Clin Chem 46:162–166
Sabeti PC, Reich DE, Higgins JM, Levine HZP, Richter DJ, Schaffner SF, Gabriel SB, Platko JV, Patterson NJ, McDonald GJ, Ackerman HC, Campbell SJ, Altshuler DCR, Kwiatkowski D, Ward R, Lander ES (2002) Detecting recent positive selection in the human genome from haplotype structure. Nature 419:832–837
Schipper RF, Damaro J, Bakker JT, Vanrood JJ, Oudshoorn M (1997) HLA gene and haplotype frequencies in bone marrow donors worldwide registries. Hum Immunol 52:54–71
Simon M, Pawlotsky Y, Bourel M, Fauchet R, Genetet B (1975) Hémochromatose idopathique. Maladie associée à l’antigène tissulaire HL-A3? Nouvelle Presse Med 4:1432
Simon M, Alexandre A, Fauchet R, Genetet B, Bourel M (1980) The genetics of hemochromatosis. In: Steinberg AG, Bearn AG, Motulsky AG, Childs B (eds) Progress in medical genetics. Saunders, Philadelphia, pp 135–168
Smith JM, Haigh J (1974) The hitch-hiking effect of a favourable gene. Genet Res 23:23–25
Thomas J (2003) Thoughts on the ‘repacked’ Neolithic revolution. Antiquity 77:67–74
Thomas W, Fullan A, Loeb DB, Mcclelland EE, Bacon BR, Wolff RK (1998) A haplotype and linkage disequilibrium analysis of the hereditary hemochromatosis gene region. Hum Genet 102:517–525
Weale ME, Weiss DA, Jager RF, Bradman N, Thomas MG (2002) Y chromosome evidence for Anglo-Saxon mass migration. Mol Biol and Evol 19:1008–1021
Willis G, Scott DGI, Jennings BA, Smith K, Bukhari M, Wimperis JZ (2002) HFE mutations in an inflammatory arthritis population. Rheumatology 41:176–179
Wilson JF, Weiss DA, Richards M, Thomas MG, Bradman N, Goldstein DB (2001) Genetic evidence for different male and female roles during cultural transitions in the British Isles. Proc Natl Acad Sci USA 98:5078–5083
Yaouanq J (2000) Human leukocyte antigen (HLA) assocoiation and typing in hemochromatosis. In: Barton JC, Edwards CQ (eds) Hemochromatosis: genetics, pathophysiology, diagnosis and treatment. Cambridge University Press, Cambridge, pp 63–74
Zhou XY, Tomatsu S, Fleming RE, Parkkila S, Waheed A, Jiang JX, Fei Y, Brunt EM, Ruddy DA, Prass CE, Schatzman RC, Oneill R, Britton RS, Bacon BR, Sly WS (1998) HFE gene knockout produces mouse model of hereditary hemochromatosis. Proc Natl Acad Sci USA 95:2492–2497
Zschocke J (2003) Phenylketonuria mutations in Europe. Hum Mutat 21:345–356
Zschocke J, Mallory JP, Eiken HG, Nevin NC (1997) Phenylketonuria and the peoples of Northern Ireland. Hum Genet 100:189–194
Acknowledgements
This paper resulted from a meeting on “The Origin and Spread of the Haemochromatosis Mutation” held at the Moller Centre, Cambridge, 31 January–1 February 2003. The participants were: Antonio Arnaiz-Villena, Universidad Complutense, Madrid; Berit Borch-Iohnsen, School of Medicine, University of Oslo; Pierre Brissot, Faculté de Médecine, Rennes; Tim Cox, University of Cambridge; Sonia Distante, Aker University Hospital; James Graham-Campbell, University College London; Carmen Lanzara, Second University of Naples; Gérard Lucotte, Centre de Génétique Moléculaire, Paris; Alison Merryweather-Clarke, Weatherall Institute of Molecular Medicine, Oxford; Nils Milmann, Department of Medicine, Naestved Hospital; Jennifer Pointon, Weatherall Institute of Molecular Medicine, Oxford; Graça Porto, Abel Salazar Institute for the Biomedical Sciences, Porto; Ruma Raha-Chowdhury, University of Cambridge; Kathryn Robson, Weatherall Institute of Molecular Medicine, Oxford; Jacques Rochette, University of Amiens; Marie-Paule Roth, INSERM, Toulouse; Ketil Thorstensen, University Hospital, Trondheim; Ann Walker, Royal Free Hospital, London; Victoria Wimhurst, Weatherall Institute of Molecular Medicine, Oxford; Mark Worwood, University of Wales College of Medicine.
We are grateful to the British Journal of Haematology Research Trust and the late Dr. H. Bell (Hepatology unit, Aker University Hospital, Oslo, Norway) for financial support. Travel costs for some participants were supported by the EC (QLRT-1999-02237).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Distante, S., Robson, K.J.H., Graham-Campbell, J. et al. The origin and spread of the HFE-C282Y haemochromatosis mutation. Hum Genet 115, 269–279 (2004). https://doi.org/10.1007/s00439-004-1152-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00439-004-1152-4