Was the C282Y mutation an Irish Gaelic mutation that the Vikings helped disseminate?*

Olsson, K. Sigvard; Konar, Jan; Dufva, Inge Høgh; Ricksten, Anne; Raha-Chowdhury, Ruma

doi:10.1111/j.1600-0609.2010.01536.x

Cited by 13 publications

(7 citation statements)

References 39 publications

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“…Molecular studies demonstrate that p.C282Y arose ~4000 years ago in the Neolithic Age [145,146] in Europe [147], possibly in Celtic people [148,149]. Although Vikings may have dispersed p.C282Y [146,149–151], especially in the late 8th-11th C, p.C282Y arose much earlier than the Viking era and thus may have also been spread in Europe by earlier seafarers [150]. Today, there are clines of decreasing p.C282Y frequency from Northwestern Europe to more eastern and southern regions of the continent [64,150].…”

Section: Hfe Coding Region Mutationsmentioning

confidence: 99%

HFE gene: Structure, function, mutations, and associated iron abnormalities

Barton

Edwards

Acton

2015

Gene

111

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The hemochromatosis gene HFE was discovered in 1996, more than a century after clinical and pathologic manifestations of hemochromatosis were reported. Linked to the major histocompatibility complex (MHC) on chromosome 6p, HFE encodes the MHC class I-like protein HFE that binds beta-2 microglobulin. HFE influences iron absorption by modulating the expression of hepcidin, the main controller of iron metabolism. Common HFE mutations account for ~90% of hemochromatosis phenotypes in whites of western European descent. We review HFE mapping and cloning, structure, promoters and controllers, and coding region mutations, HFE protein structure, cell and tissue expression and function, mouse Hfe knockouts and knockins, and HFE mutations in other mammals with iron overload. We describe the pertinence of HFE and HFE to mechanisms of iron homeostasis, the origin and fixation of HFE polymorphisms in European and other populations, and the genetic and biochemical basis of HFE hemochromatosis and iron overload.

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Section: Hfe Coding Region Mutationsmentioning

confidence: 99%

HFE gene: Structure, function, mutations, and associated iron abnormalities

Barton

Edwards

Acton

2015

Gene

111

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“…Highest frequencies are found in Ireland (mean 10.1%) and prevalence declines to near 0% in southeast Europe (Fairbanks, 2000; Olsson et al, 2011). Current analyses suggest that the temporal origin of the C282Y mutation, occurred 200 to 250 generations ago or at approximately 6,000 BP (4000 BCE) (Raha‐Chowdhury and Gruen, 2000) in central Europe (Symonette and Adams, 2011).…”

mentioning

confidence: 99%

The evolutionary adaptation of the C282Y mutation to culture and climate during the European Neolithic

Heath

Axton

McCullough

et al. 2016

American J Phys Anthropol

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ObjectivesThe C282Y allele is the major cause of hemochromatosis as a result of excessive iron absorption. The mutation arose in continental Europe no earlier than 6,000 years ago, coinciding with the arrival of the Neolithic agricultural revolution. Here we hypothesize that this new Neolithic diet, which originated in the sunny warm and dry climates of the Middle East, was carried by migrating farmers into the chilly and damp environments of Europe where iron is a critical micronutrient for effective thermoregulation. We argue that the C282Y allele was an adaptation to this novel environment.Materials and MethodsTo address our hypothesis, we compiled C282Y allele frequencies, known Neolithic sites in Europe and climatic data on temperature and rainfall for statistical analysis.ResultsOur findings indicate that the geographic cline for C282Y frequency in Europe increases as average temperatures decrease below 16°C, a critical threshold for thermoregulation, with rainy days intensifying the trend.DiscussionThe results indicate that the deleterious C282Y allele, responsible for most cases of hemochromatosis, may have evolved as a selective advantage to culture and climate during the European Neolithic. Am J Phys Anthropol 160:86–101, 2016. © 2016 The Authors American Journal of Physical Anthropology Published by Wiley Periodicals, Inc.

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“…Although this haplotype is also described as a common HH ancestral haplotype in hemochromatosis populations in many northwestern European countries, particularly in Scandinavia [36], its appearance in Alabama HH patients is unlikely to be attributed predominantly to Norwegian or other Scandinavian founders because ancestry reports from these geographic areas of Europe are rare in Alabama hemochromatosis probands and population control subjects [39]. Nevertheless this haplotype could have a common ancestral Irish origin and be spread in Norway by the close contacts between Ireland and Scandinavia through the Vickings’ movements [35], [36]. In the case of Porto patients, the relative low diversity of HH haplotypes could be attributed to the particular demographic characteristics of the Portuguese population in the north region namely the unipolar mode of migration and the low rate of mobility from other regions [43].…”

Section: Discussionmentioning

confidence: 95%

“…The question of HLA haplotype conservation in HH has been a focus of scientific interest for a long time, and several interpretations about its role in the recent evolutionary history of chromosomes carrying the C282Y mutation have been largely discussed [3]–[7], [14], [17], [35], [36]. Besides the well described A*03–B*07 ancestral haplotype [3]–[7], also the A*01–B*08 haplotype is very long and resistant against recombination, and appears to be derived from a single ancestor [14], [17].…”

Section: Discussionmentioning

confidence: 99%

Effects of Highly Conserved Major Histocompatibility Complex (MHC) Extended Haplotypes on Iron and Low CD8+ T Lymphocyte Phenotypes in HFE C282Y Homozygous Hemochromatosis Patients from Three Geographically Distant Areas

et al. 2013

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Hereditary Hemochromatosis (HH) is a recessively inherited disorder of iron overload occurring commonly in subjects homozygous for the C282Y mutation in HFE gene localized on chromosome 6p21.3 in linkage disequilibrium with the human leukocyte antigen (HLA)-A locus. Although its genetic homogeneity, the phenotypic expression is variable suggesting the presence of modifying factors. One such genetic factor, a SNP microhaplotype named A-A-T, was recently found to be associated with a more severe phenotype and also with low CD8+T-lymphocyte numbers. The present study aimed to test whether the predictive value of the A-A-T microhaplotype remained in other population settings. In this study of 304 HH patients from 3 geographically distant populations (Porto, Portugal 65; Alabama, USA 57; Nord-Trøndelag, Norway 182), the extended haplotypes involving A-A-T were studied in 608 chromosomes and the CD8+ T-lymphocyte numbers were determined in all subjects. Patients from Porto had a more severe phenotype than those from other settings. Patients with A-A-T seemed on average to have greater iron stores (p = 0.021), but significant differences were not confirmed in the 3 separate populations. Low CD8+ T-lymphocytes were associated with HLA-A*03-A-A-T in Porto and Alabama patients but not in the greater series from Nord-Trøndelag. Although A-A-T may signal a more severe iron phenotype, this study was unable to prove such an association in all population settings, precluding its use as a universal predictive marker of iron overload in HH. Interestingly, the association between A-A-T and CD8+ T-lymphocytes, which was confirmed in Porto and Alabama patients, was not observed in Nord-Trøndelag patients, showing that common HLA haplotypes like A*01–B*08 or A*03–B*07 segregating with HFE/C282Y in the three populations may carry different messages. These findings further strengthen the relevance of HH as a good disease model to search for novel candidate loci associated with the genetic transmission of CD8+ T-lymphocyte numbers.

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Was the C282Y mutation an Irish Gaelic mutation that the Vikings helped disseminate?*

Abstract: The C282Y frequency shows a west to east decline from Ireland through the north of Europe. Vikings may have been involved in the spread of C282Y, but the mutation is probably older and may have been spread in Europe by earlier seafarers.

Cited by 13 publications

References 39 publications

HFE gene: Structure, function, mutations, and associated iron abnormalities

HFE gene: Structure, function, mutations, and associated iron abnormalities

The evolutionary adaptation of the C282Y mutation to culture and climate during the European Neolithic

Effects of Highly Conserved Major Histocompatibility Complex (MHC) Extended Haplotypes on Iron and Low CD8+ T Lymphocyte Phenotypes in HFE C282Y Homozygous Hemochromatosis Patients from Three Geographically Distant Areas

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