title: Sexual selection by female immunity against paternal antigens can fix loss of function alleles.
abstract: Humans lack the common mammalian cell surface molecule N-glycolylneuraminic acid (Neu5Gc) due to a CMAH gene inactivation, which occurred approximately three million years ago. Modern humans produce antibodies specific for Neu5Gc. We hypothesized that anti-Neu5Gc antibodies could enter the female reproductive tract and target Neu5Gc-positive sperm or fetal tissues, reducing reproductive compatibility. Indeed, female mice with a human-like Cmah(-/-) mutation and immunized to express anti-Neu5Gc antibodies show lower fertility with Neu5Gc-positive males, due to prezygotic incompatibilities. Human anti-Neu5Gc antibodies are also capable of targeting paternally derived antigens and mediate cytotoxicity against Neu5Gc-bearing chimpanzee sperm in vitro. Models of populations polymorphic for such antigens show that reproductive incompatibility by female immunity can drive loss-of-function alleles to fixation from moderate initial frequencies. Initially, the loss of a cell-surface antigen can occur due to drift in isolated populations or when natural selection favors the loss of a receptor exploited by pathogens, subsequently the same loss-of-function allele can come under sexual selection because it avoids being targeted by the female immune system. Thus, we provide evidence of a link between sexual selection and immune function: Antigenicity in females can select against foreign paternal antigens on sperm and rapidly fix loss-of-function alleles. Similar circumstances existed when the CMAH null allele was polymorphic in ancestral hominins, just before the divergence of Homo from australopithecines.
authors: Center for Academic Research and Training in Anthropogeny, Glycobiology Research and Training Center and Departments of Medicine and Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
authors: Darius
authors: D
authors: Ghaderi
authors: Stevan A
authors: SA
authors: Springer
authors: Fang
authors: F
authors: Ma
authors: Miriam
authors: M
authors: Cohen
authors: Patrick
authors: P
authors: Secrest
authors: Rachel E
authors: RE
authors: Taylor
authors: Ajit
authors: A
authors: Varki
authors: Pascal
authors: P
authors: Gagneux
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology*; D000941:Antigens / Q000276:immunology; D005260:Female; D005787:Gene Frequency; D005828:Genetics, Population; D006801:Humans; D008297:Male; D052586:Mating Preference, Animal / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism; D009438:Neuraminic Acids / Q000276:immunology*; D002679:Pan troglodytes / Q000276:immunology* / Q000378:metabolism; D012641:Selection, Genetic; D012794:Sialic Acids / Q000378:metabolism*; D013094:Spermatozoa / Q000276:immunology / Q000378:metabolism
chemical_list: D000906:Antibodies; D000941:Antigens; D009438:Neuraminic Acids; D012794:Sialic Acids; C032592:N-glycolylneuraminic acid; D006899:Mixed Function Oxygenases; C074383:CMPacetylneuraminate monooxygenase