Sexual selection by female immunity against paternal antigens can fix loss of function alleles
Open accessAbstract
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.
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“During the latter process, there is even evidence that circulating antibodies can enter the uterine fluid and destroy sperm carrying nonspecies-specific glycan antigens (943).”
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- Authors
- Ghaderi, D., Springer, S. A., Ma, F., Cohen, M., Secrest, P., Taylor, R. E., Varki, A., & Gagneux, P.
- Affiliations
- University of California San Diego (US)
- University of Washington (US)
- Corresponding author
- Gagneux, Pascal
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-10-10
- Volume
- 108
- Issue
- 43
- Pages
- 17743-17748
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3203784
- OpenAlex
- W2099208764
- Cited by
- 79
- References
- 38
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 5 · 2023: 9 · 2022: 4 · 2021: 8 · 2020: 4 · 2019: 7 · 2018: 4 · 2017: 8 · 2016: 4 · 2015: 8 · 2014: 5 · 2013: 4 · 2012: 1
- FWCI
- 2.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- University of California, San Diego
- National Institute of General Medical Sciences (R01GM032373, R01GM095882, R01-GM-32373)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Animal Behavior and Reproduction
- Health Sciences › Medicine › Hematology › Blood groups and transfusion
- Keywords
- sexual selection, anti-Neu5Gc antibodies, N-glycolylneuraminic acid, loss-of-function alleles, allele fixation, reproductive compatibility, human evolution, sperm surface antigens
- MeSH terms
- Animals, Antibodies, Antigens, Pan troglodytes, Female, Gene Frequency, Genetics, Population, Humans, Mixed Function Oxygenases, Male, Neuraminic Acids, Selection, Genetic, Sialic Acids, Spermatozoa, Mice, Knockout, Mice, Mating Preference, Animal
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