title: Evolutionary history of copy-number-variable locus for the low-affinity Fcγ receptor: mutation rate, autoimmune disease, and the legacy of helminth infection.
abstract: Both sequence variation and copy-number variation (CNV) of the genes encoding receptors for immunoglobulin G (Fcγ receptors) have been genetically and functionally associated with a number of autoimmune diseases. However, the molecular nature and evolutionary context of this variation is unknown. Here, we describe the structure of the CNV, estimate its mutation rate and diversity, and place it in the context of the known functional alloantigen variation of these genes. Deletion of Fcγ receptor IIIB, associated with systemic lupus erythematosus, is a result of independent nonallelic homologous recombination events with a frequency of approximately 0.1%. We also show that pathogen diversity, in particular helminth diversity, has played a critical role in shaping the functional variation at these genes both between mammalian species and between human populations. Positively selected amino acids are involved in the interaction with IgG and include some amino acids that are known polymorphic alloantigens in humans. This supports a genetic contribution to the hygiene hypothesis, which states that past evolution in the context of helminth diversity has left humans with an array of susceptibility alleles for autoimmune disease in the context of a helminth-free environment. This approach shows the link between pathogens and autoimmune disease at the genetic level and provides a strategy for interrogating the genetic variation underlying autoimmune-disease risk and infectious-disease susceptibility.
authors.affiliation: Department of Genetics, University of Leicester, UK.
authors.forename: Lee R
authors.initials: LR
authors.lastname: Machado
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Hardwick
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bowdrey
authors.forename: Helen
authors.initials: H
authors.lastname: Bogle
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Knowles
authors.forename: Manuela
authors.initials: M
authors.lastname: Sironi
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Hollox
mesh_terms: D000483:Alleles; D001327:Autoimmune Diseases / Q000235:genetics*; D019143:Evolution, Molecular; D017353:Gene Deletion; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation; D006239:Haplotypes; D006373:Helminthiasis / Q000469:parasitology*; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D008957:Models, Genetic; D009154:Mutation; D059645:Mutation Rate; D010802:Phylogeny; D017452:Receptors, IgG / Q000235:genetics*; D011995:Recombination, Genetic
chemical_list: D007074:Immunoglobulin G; D017452:Receptors, IgG