Epidemic pathogenic selection: an explanation for hereditary hemochromatosis?
Introduction
Single nucleotide substitutions (point mutations) in genomic or mitochondrial DNA cause many different genetic disorders [1], [2]. Point mutations were recently discovered in individuals with hereditary hemochromatosis (HH), an iron metabolism disorder that leads to excessive iron uptake and deposition in organs such as the liver, pancreas, heart, and spleen. These mutations occur in a gene, now named HFE, located on chromosome 6p21.3 near the human leukocyte antigen (HLA) site (1). Two HH mutations initially described are a cysteine-to-tyrosine substitution (C282Y) and a histidine-to-aspartic acid substitution (H63D) (3). Several others also have been described although these are rarer [4], [5]. The C282Y mutation is causally associated with HH, but the role of the other mutations in HH, including H63D, is still controversial (6). The HFE gene product is a major histocompatibility complex (MHC) class I-like protein (6). Initially, being not obviously involved in immune regulatory function, it was termed a non-classical MHC class I-like protein. A major puzzle is why the population frequency of HFE mutations is so high when the condition of HH is known to be associated with reduced life expectancy. We have carefully considered the possible origins of HH, and propose that certain alterations in HFE help the body to defend itself against pathogens.
Section snippets
Cellular biological consequences of HFE mutations
HFE protein is a transmembrane protein expressed in almost all tissues of the body [7], [8]. The HFE protein protrudes through the cellular plasma membrane, allowing for extracellular interactions. It physically associates with β2-microglobulin and the transferrin receptor (9). Transferrin is a high-affinity iron-binding protein, and the transferrin receptor acts as the major iron transporter into cells. HFE binding to the transferrin receptor increases the dissociation constant of transferrin
Population distributions of HFE mutations
HH is the most common inherited single gene disorder in people of Northern and Western European descent (16). The C282Y mutation is not present in similar frequency among other ethnic groups. Because C282Y is so frequent in the British Isles, its origin has been suggested to be Celtic or Viking [6], [17], [18], [19]. Because C282Y causes increased iron uptake, it has been postulated to be a beneficial mutation that would prevent anemia over long sea voyages (18). Yet, if this were the case then
The Black Death or bubonic plagues
Yersinia pestis, the organism that caused the European plague epidemics, beginning in the 6th century to the 8th century AD (Justinian Plagues) and then continuing from the 14th until the 19th century (Black Death), may have evolved from or into the much less virulent, but genetically related, enteric disease causing Yersinia pseudotuberculosis and Yersinia enterocolitica (21). It is important to realize that the pathogenicity and lethality of all three organisms are significantly enhanced by
HFE mutations and the plague
Researchers have estimated, using linkage disequilibrium, that the C282Y mutation originated 60–70 generations ago (25). Assuming a generation time of 15–20 years, this event dates to 600–1100 AD Given this time frame, we examined catastrophic events in the last 1500 years that might result in selection and amplification of C282Y and/or H63D. The one event, beginning possibly as early 6th century, that had a striking effect on the population of Europe, was the Black Death—also known as the
Other pathogenic agents
Besides Yersinia spp., there are other possible pathogens from which HFE mutations may provide some degree of protection. These include the intracellular pathogen S. typhi the organism responsible for human typhoid fever (enteric fever), a severe systemic infection of the reticuloendothelial system (30). S. typhi usually gains entry into the human host from the intestinal lumen and becomes increasingly more virulent as the availability of iron increases (30). It is important to note that
Epidemic pathogenic selection
The concept that resistance to infectious disease might alter the frequency of a specific genetic marker in a particular population is not new [35], [36]. People with the genetic hematological disorders, thalassemia and sickle cell anemia, are resistant to malaria and have a survival advantage in areas in which malaria is endemic [35], [36]. During disease epidemics, some forms of class I and class II MHC molecules are known to stimulate T cell responses that favor better survival, but which
Acknowledgements
This work was supported, in part, by grants to Sharon Moalem from the Alzheimer Society of Canada and Margaret and Howard Gamble Research Grants. Maire E. Percy was supported by grants from the Alzheimer Society of Canada and the Queen Elizabeth Hospital Research Institute. The authors are grateful to Surrey Place Centre for infrastructure support and to Dr. John Percy for helpful discussions and comments.
References (37)
- et al.
HFE mutations analysis in 711 hemochromatosis probands: evidence for S65C implication in mild form of hemochromatosis
Blood
(1999) Two novel missense mutations of the HFE gene (I105T and G93R) and identification of the S65C mutation in Alabama hemochromatosis probands
Blood Cells Mol. Dis.
(1999)Inappropriately high iron regulatory protein activity in monocytes of patients with genetic hemochromatosis
Blood
(1997)Wild-type HFE protein normalizes transferrin iron accumulation in macrophages from subjects with hereditary hemochromatosis
Blood
(2000)The hemochromatosis founder mutation in HLA-H disrupts beta2- microglobulin interaction and cell surface expression
J. Biol. Chem.
(1997)Multicentric origin of hemochromatosis gene (HFE) mutations
Am. J. Hum. Genet.
(1999)Haplotype analysis of hemochromatosis: evaluation of different linkage-disequilibrium approaches and evolution of disease chromosomes
Am. J. Hum. Genet.
(1997)Celtic origin of the C282Y mutation of hemochromatosis
Blood Cells Mol. Dis.
(1998)Tay–Sachs disease carrier screening: a model for prevention of genetic disease
Genet. Test
(1998)Human mitochondrial diseases: answering questions and questioning answers
Int. Rev. Cytol.
(1999)
A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis
Nat. Genet.
Hemochromatosis: a genetic defect in iron metabolism
Bioessays
Association of HFE protein with transferrin receptor in crypt enterocytes of human duodenum
Proc. Natl. Acad. Sci. USA
Transferrin receptor is negatively modulated by the hemochromatosis protein HFE: implications for cellular iron homeostasis
Proc. Natl. Acad. Sci. USA
Current concepts in mucosal immunity. II. One size fits all: nonclassical MHC molecules fulfill multiple roles in epithelial cell function
Am. J. Physiol.
Association of the transferrin receptor in human placenta with HFE, the protein defective in hereditary hemochromatosis
Proc. Natl. Acad. Sci. USA
Nramp1: a link between intracellular iron transport and innate resistance to intracellular pathogens
J. Leukoc. Biol.
The Nramp1 protein and its role in resistance to infection and macrophage function
Proc. Assoc. Am. Physic.
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