Evolution of Human-Specific Alleles Protecting Cognitive Function of Grandmothers.

Bibliographic Collection: 
CARTA-Inspired Publication
Publication Type: Journal Article
Authors: Saha, Sudeshna; Khan, Naazneen; Comi, Troy; Verhagen, Andrea; Sasmal, Aniruddha; Diaz, Sandra; Yu, Hai; Chen, Xi; Akey, Joshua M; Frank, Martin; Gagneux, Pascal; Varki, Ajit
Year of Publication: 2022
Journal: Mol Biol Evol
Volume: 39
Issue: 8
Date Published: 2022 Aug 03
Publication Language: eng
ISSN: 1537-1719
Keywords: Alleles, Amino Acids, Animals, Cognition, Grandparents, Hominidae, Humans

The myelomonocytic receptor CD33 (Siglec-3) inhibits innate immune reactivity by extracellular V-set domain recognition of sialic acid (Sia)-containing "self-associated molecular patterns" (SAMPs). We earlier showed that V-set domain-deficient CD33-variant allele, protective against late-onset Alzheimer's Disease (LOAD), is derived and specific to the hominin lineage. We now report multiple hominin-specific CD33 V-set domain mutations. Due to hominin-specific, fixed loss-of-function mutation in the CMAH gene, humans lack N-glycolylneuraminic acid (Neu5Gc), the preferred Sia-ligand of ancestral CD33. Mutational analysis and molecular dynamics (MD)-simulations indicate that fixed change in amino acid 21 of hominin V-set domain and conformational changes related to His45 corrected for Neu5Gc-loss by switching to N-acetylneuraminic acid (Neu5Ac)-recognition. We show that human-specific pathogens Neisseria gonorrhoeae and Group B Streptococcus selectively bind human CD33 (huCD33) as part of immune-evasive molecular mimicry of host SAMPs and that this binding is significantly impacted by amino acid 21 modification. In addition to LOAD-protective CD33 alleles, humans harbor derived, population-universal, cognition-protective variants at several other loci. Interestingly, 11 of 13 SNPs in these human genes (including CD33) are not shared by genomes of archaic hominins: Neanderthals and Denisovans. We present a plausible evolutionary scenario to compile, correlate, and comprehend existing knowledge about huCD33-evolution and suggest that grandmothering emerged in humans.

DOI: 10.1093/molbev/msac151
Alternate Journal: Mol Biol Evol