Multiple genomic events altering hominin SIGLEC biology and innate immunity predated the common ancestor of humans and archaic hominins

Abstract

Human-specific pseudogenization of theCMAHgene eliminated themammalian 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 ~2-3 Ma, possibly contributing to the origins of the genus Homo. The mutation likely alteredhuman self-associatedmolecular 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 reportedinsomegene-encoding Sia-sensingproteins suggesteda"hotspot" inhominin evolution. The availabilityofmorehominid genomes including those of two extinct homininsnowallows full reanalysis and evolutionary timing. Functional changes occur in 8/13members of the human genomic cluster encoding CD33-related Siglecs, all predating the human commonancestor.Comparisonswithgreat apegenomes indicate that these changesare unique tohominins.Wefoundnoevidence for strong selection after theHuman-Neanderthal/Denisovan commonancestor, 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 0.6Ma.Multiple changes in this genomic clustermay also explainhuman-specific expression ofCD33rSiglecs in unexpected locations suchas amnion,placental trophoblast, pancreatic islets,ovarian fibroblasts, microglia,NaturalKiller(NK) cells, andepithelia. Taken together,our data suggest that innate immuneinteractionswith pathogensmarkedly altered hominin Siglec biologybetween 0.6 and 2 Ma, potentially affecting human evolution.