Hemochromatosis: A Neolithic adaptation to cereal grain diets

https://doi.org/10.1016/j.mehy.2007.06.020Get rights and content

Summary

The Neolithic period in Europe marked the transition from a hunter-gatherer diet rich in red meat to an iron-reduced cereal grain diet. This dietary shift likely resulted in an increased incidence of iron deficiency anemia, especially in women of reproductive age. I propose that hereditary hemochromatosis and in particular the common HFE C282Y mutation may represent an adaptation to decreased dietary iron in cereal grain-based Neolithic diets. Both homozygous and heterozygous carriers of the HFE C282Y mutation have increased iron stores and therefore possessed an adaptive advantage under Neolithic conditions. An allele age estimate places the origin of the HFE C282Y mutation in the early Neolithic period in Northern Europe and is thus consistent with this hypothesis. The lower incidence of this mutation in other agrarian regions (the Mediterranean and Near East) may be due to higher dietary intakes of the iron uptake cofactor vitamin C in those regions. The HFE C282Y mutation likely only became maladaptive in the past several centuries as dietary sources of iron and vitamin C improved in Northern Europe.

Introduction

Evolutionary medicine attempts to apply the principles of natural selection to answer questions about the ultimate causation of human diseases. Such explanations often involve a genetic adaptation to an ancient (e.g. Paleolithic hunter-gatherer) environment, which has become maladaptive in modern environments [1]. The previous adaptive advantage of these alleles explains their high incidence in modern populations despite their associated disease states. For instance, this nature/nurture mismatch has been invoked to explain the modern epidemics of hypertension, obesity and coronary artery diseases [2]. The presence of striking geographic variation in the frequencies of disease-associated alleles can also be seen as suggestive of prior selection pressure [3].

Hereditary hemochromatosis is one such disease that shows strong geographic differences in allele frequencies, with the highest incidence in Northern Europe (up to 10% allele frequency) and in populations originating in Northern Europe [4]. Hereditary hemochromatosis is also of interest in evolutionary medicine as the age of the common HFE C282Y allele mutation in hemochromatosis has been estimated to be 138 generations [5] (about 3450 years), allowing correlation with archeological and environmental factors. In Northern Europe, this places the origin of the HFE C282Y allele mutation in the Neolithic period, approximately 1500 years after the latest start of agriculture in that region [6]. The Neolithic period in Europe marked the transition from a Paleolithic hunter-gatherer diet high in red meat to an agricultural diet high in cereal grains [7]. Indeed, phytochemical, vitamin and mineral intakes all appear to have decreased with the switch from a red meat to a cereal grain diet [8].

Section snippets

Hypothesis

I propose that hereditary hemochromatosis and in particular the common HFE C282Y allele mutation may represent an adaptation to decreased dietary iron in cereal grain-based Neolithic diets.

Evaluation and consequences

Iron deficiency anemia was likely a significant problem for Neolithic peoples [8], especially women of reproductive age, and thus a gene mutation that increased iron stores would have conferred a definite selective advantage. For the HFE C282Y allele mutation, both heterozygotes and homozygotes display increased iron stores [4] with homozygotes showing variable penetrance for the clinical disease of hemochromatosis.

If the HFE C282Y allele mutation presented a selective advantage to Neolithic

References (8)

  • J. Bradbury

    Ancient footsteps in our genes: evolution and human disease

    Lancet

    (2004)
  • E.E. Harris et al.

    Evolutionary explanations in medical and health profession courses: are you answering your students’ “why” questions?

    BMC Med Educ

    (2005)
  • R.M. Nesse et al.

    Why we get sick: the new science of Darwinian medicine

    (1994)
  • P. Adams

    Hemochromatosis and iron-overload screening in a racially diverse population

    New Eng J Med

    (2005)
There are more references available in the full text version of this article.

Cited by (29)

  • A haemochromatosis-causing HFE mutation is associated with SARS-CoV-2 susceptibility in the Czech population

    2023, Clinica Chimica Acta
    Citation Excerpt :

    With its ability to increase iron absorption from food by almost threefold, the Cys282Tyr mutation constituted an adaptive advantage. The rapid spread of the mutation during the Neolithic age has been explained [18,33] as an adaptive response of farmers migrating from the warm climates of the Middle East to the cooler environments of Europe and/or due to a dietary shift from meat-based foods high in iron to cereal-based foods low in iron. Like mutations that cause familial hypercholesterolaemia [34,35], this adaptive advantage later declined as a consequence of cultural and environmental improvements.

  • Food fermentations for improved digestibility of plant foods – an essential ex situ digestion step in agricultural societies?

    2020, Current Opinion in Food Science
    Citation Excerpt :

    In contrast, the diet of agricultural societies relied on only few plant species, particularly cereals, legumes, and oilseeds. Nutritional consequences of this transition include a reduced intake of protein and dietary fiber, a reduced supply of minerals, and increased exposure to anti-nutritive factors in seeds [2,3]. The origin of food fermentations, which are defined as the preparation of foods or beverages by controlled microbial growth and enzymatic conversions [4••], predates the origin of agriculture [5••,6•].

  • C282Y/H63D hemochromatosis mutations and microevolution: Speculations concerning the Basque population

    2017, HOMO- Journal of Comparative Human Biology
    Citation Excerpt :

    There was an increase in iron deficiency prevalence when humans switched from hunting and gathering to agriculture because of the cereal-based diet replacing the regular consumption of meat (Ammerman and Cavalli-Sforza, 1984). According to Naugler (2008), C282Y may be an adaptation to the decreased iron intake associated with the Neolithic diet. Selection of heterozygotes for C282Y could have been related to protection against iron deficiency, especially in women because of menses and pregnancies (Datz et al., 1998).

  • Hemochromatosis and iron overload: From bench to clinic

    2013, American Journal of the Medical Sciences
    Citation Excerpt :

    This infers that heterozygosity for this allele was advantageous centuries ago. The slightly greater serum iron and ferritin measures in C282Y homozygotes observed in recent population screening studies34,35 suggest that C282Y was either an adaptation to a cereal diet or the effects of celiac disease in early Europeans77,78 or provided an evolutionary or natural selection advantage because it increased absorption of iron in women and its subsequent availability to their fetuses.79 Perhaps, the absorption of increased fractions of essential non-iron trace metals was a nutritional advantage of C282Y heterozygotes.

  • The last two millennias echo-catastrophes are the driving forces for the potential genetic advantage mechanisms in celiac disease

    2011, Medical Hypotheses
    Citation Excerpt :

    2) Mitigating effect on the infertility associated with CD. ( 3) An adaptive process to the decreased dietary iron concentration in cereal grain-based Neolithic diets. [31,32]. ( 4) Macrophages in iron-loaded C282Y homozygotes are very low in iron.

View all citing articles on Scopus
View full text