Journal
GENOME BIOLOGY AND EVOLUTION
Volume 12, Issue 7, Pages 1040-1050Publisher
OXFORD UNIV PRESS
DOI: 10.1093/gbe/evaa125
Keywords
sialic acid; hominin; evolution; CD33rSiglecs; common ancestor; Neanderthal; Denisovan; great apes; archaic hominin
Categories
Funding
- NIH [R01GM32373]
- MINECO/FEDER, UE [BFU2017-86471-P]
- Howard Hughes International Early Career
- Secretaria d'Universitats i Recerca
- CERCA Programme del Departament d'Economia i Coneixement de la Generalitat de Catalunya [GRC 2017 SGR 880]
- Obra Social La Caixa
- [U01 MH106874]
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Human-specific pseudogenization of the CMAH gene eliminated the mammalian sialic acid (Sia) Neu5Gc (generating an excess of its precursor Neu5Ac), thus changing ubiquitous cell surface self-associated molecular patterns that modulate innate immunity via engagement of CD33-related-Siglec receptors. The Alu-fusion-mediated loss-of-function of CMAH fixed similar to 2-3 Ma, possibly contributing to the origins of the genus Homo. The mutation likely altered human self-associated molecular patterns, triggering multiple events, including emergence of human-adapted pathogens with strong preference for Neu5Ac recognition and/or presenting Neu5Ac-containing molecular mimics of human glycans, which can suppress immune responses via CD33-related-Siglec engagement. Human-specific alterations reported in some gene-encoding Sia-sensing proteins suggested a hotspot in hominin evolution. The availability of more hominid genomes including those of two extinct hominins now allows full reanalysis and evolutionary timing. Functional changes occur in 8/13 members of the human genomic cluster encoding CD33-related Siglecs, all predating the human common ancestor. Comparisons with great ape genomes indicate that these changes are unique to hominins. We found no evidence for strong selection after the Human-Neanderthal/Denisovan common ancestor, and these extinct hominin genomes include almost all major changes found in humans, indicating that these changes in hominin sialobiology predate the Neanderthal-human divergence similar to 0.6 Ma. Multiple changes in this genomic cluster may also explain human-specific expression of CD33rSiglecs in unexpected locations such as amnion, placental trophoblast, pancreatic islets, ovarian fibroblasts, microglia, Natural Killer(NK) cells, and epithelia. Taken together, our data suggest that innate immune interactions with pathogens markedly altered hominin Siglec biology between 0.6 and 2 Ma, potentially affecting human evolution.
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