title: Widespread balancing selection and pathogen-driven selection at blood group antigen genes.
abstract: Historically, allelic variations in blood group antigen (BGA) genes have been regarded as possible susceptibility factors for infectious diseases. Since host-pathogen interactions are major determinants in evolution, BGAs can be thought of as selection targets. In order to verify this hypothesis, we obtained an estimate of pathogen richness for geographic locations corresponding to 52 populations distributed worldwide; after correction for multiple tests and for variables different from selective forces, significant correlations with pathogen richness were obtained for multiple variants at 11 BGA loci out of 26. In line with this finding, we demonstrate that three BGA genes, namely CD55, CD151, and SLC14A1, have been subjected to balancing selection, a process, rare outside MHC genes, which maintains variability at a locus. Moreover, we identified a gene region immediately upstream the transcription start site of FUT2 which has undergone non-neutral evolution independently from the coding region. Finally, in the case of BSG, we describe the presence of a highly divergent haplotype clade and the possible reasons for its maintenance, including frequency-dependent balancing selection, are discussed. These data indicate that BGAs have been playing a central role in the host-pathogen arms race during human evolutionary history and no other gene category shows similar levels of widespread selection, with the only exception of loci involved in antigen recognition.
authors.affiliation: Scientific Institute IRCCS E. Medea, Bioinformatic Lab, 23842 Bosisio Parini (LC), Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Fumagalli
authors.forename: Rachele
authors.initials: R
authors.lastname: Cagliani
authors.forename: Uberto
authors.initials: U
authors.lastname: Pozzoli
authors.forename: Stefania
authors.initials: S
authors.lastname: Riva
authors.forename: Giacomo P
authors.initials: GP
authors.lastname: Comi
authors.forename: Giorgia
authors.initials: G
authors.lastname: Menozzi
authors.forename: Nereo
authors.initials: N
authors.lastname: Bresolin
authors.forename: Manuela
authors.initials: M
authors.lastname: Sironi
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D051926:Basigin / Q000235:genetics; D001789:Blood Group Antigens / Q000235:genetics*; D017848:Blood-Borne Pathogens / Q000302:isolation & purification; D018958:CD55 Antigens / Q000235:genetics; D005647:Fucosyltransferases / Q000235:genetics; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005828:Genetics, Population; D054884:Host-Pathogen Interactions / Q000235:genetics*; D006801:Humans; D007239:Infections / Q000235:genetics; D026901:Membrane Transport Proteins / Q000235:genetics; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D012641:Selection, Genetic; D060185:Tetraspanin 24; D000096982:Urea Transporters; D000097631:Galactoside 2-alpha-L-fucosyltransferase
chemical_list: D015703:Antigens, CD; D051926:Basigin; D001789:Blood Group Antigens; D018958:CD55 Antigens; D005647:Fucosyltransferases; D026901:Membrane Transport Proteins; D060185:Tetraspanin 24; D000096982:Urea Transporters; D000097631:Galactoside 2-alpha-L-fucosyltransferase; C497886:BSG protein, human; C554715:CD151 protein, human