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-offunction 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-offunction 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.glycan antigen | sialic acid | xeno-antigens

Detection of the dietary xenoglycan N-glycolylneuraminic acid (Neu5Gc) and anti-Neu5Gc antibodies within reproductive tracts of male and female infertility subjects

“…With respect to fertility, it has been suggested that antibodies within the uterine environment may impair fertility by two potential mechanisms including sperm inactivation and embryo rejection or failed implantation secondary to incompatibility between the blastocyst and receptive uterus [22]. Our results reveal a lower CPR in the presence of anti-Neu5Gc antibodies within the uterine environment.…”

“…endometriosis, auto-immune diseases, tubal infertility) [20,21]. It has recently been suggested, that the loss of Neu5Gc may have caused reproductive incompatibility in ancestral hominin populations due to sexual selection by female immunity against the xenoglycan Neu5Gc on sperm or implanting blastocysts [22]. In a murine model, Cmah null females with antibodies against Neu5Gc have reduced fertility when mated with Neu5Gc positive wild-type males implicating that female immunity can result in reproductive incompatibility [22].…”

Türkiye, İzmir Sokak Kedilerinde Neonatal İzoeritrolizisle İlişkili Sitidin Monofosfat-N-Asetilnöraminik Asit Hidroksilaz (CMAH) Geninin Analizi

“…CMAH enzyme produces N-glycolylneuraminic acid (Neu5Gc) derived from N-acetylneuraminic acid (Neu5Ac) through enzymatic hydroxylation [1] . Neu5Gc and Neu5Ac are two of the most abundant sialic acids and both of them are expressed in echinoderm to mammalians [1][2][3][4] . These sialic acids have significant biologic roles in cellular recognition, signaling, neuronal development, and host-pathogen interaction in vertebrates, including humans [5][6][7][8][9] .…”

A Mouse Model for Dietary Xenosialitis

“…Female mice genetically engineered with a human-like Cmah Ϫ/Ϫ mutation and immunized to express ␣-Neu5Gc antibodies show reduced fertility when mated with Neu5Gc-positive wild type males (13,24). Furthermore, human ␣-Neu5Gc antibodies are also capable of targeting paternally derived antigens and can mediate cytotoxicity against Neu5Gc-bearing chimpanzee sperm in vitro (13), (37). Here, we investigate the possible consequences of the presence of Neu5Gc and ␣-Neu5Gc antibodies in the reproductive system in a mouse model humanized for its sialic acid and ␣-xenoglycan immune response.…”

“…It has been proposed that circulating anti-sialic acid antibodies target incorporated non-human sialic acid and contribute to chronic inflammation in various tissues (10 -12). Our objective is to determine whether xenoglycan-antibody interactions also affect human infertility (13) given tentative evidence from a clinical study (14). Sialic acids (Sias) are nine-carbon backbone, acidic, amino sugars that decorate the surfaces of all vertebrate cells in high abundance (tens to hundreds of millions of molecules per cell).…”