Multiple genomic events altering Hominin SIGLEC biology and innate immunity predated the common ancestor of humans and archaic Hominins
Khan, Naazneen (University of California. Glycobiology Research and Training Center. Department of Medicine (USA))
de Manuel, Marc (Institut de Biologia Evolutiva (UPF-CSIC) (Barcelona))
Peyregne, Stephane (Max Planck Institute for Evolutionary Anthropology. Department of Evolutionary Genetics)
Do, Raymond (University of California. Glycobiology Research and Training Center. Department of Medicine (USA))
Prufer, Kay (Max Planck Institute for Evolutionary Anthropology. Department of Evolutionary Genetics)
Marquès i Bonet, Tomàs 1975- (Institut Català de Paleontologia Miquel Crusafont)
Varki, Nissi (University of California. Glycobiology Research and Training Center. Department of Medicine (USA))
Gagneux, Pascal (University of California. Glycobiology Research and Training Center. Department of Medicine (USA))
Varki, Ajit (University of California. Glycobiology Research and Training Center. Department of Medicine (USA))

Date:	2020
Abstract:	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 ∼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 ∼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.
Grants:	Agencia Estatal de Investigación BFU2017-86471-P Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-880
Note:	Altres ajuts: CERCA Programme/Generalitat de Catalunya
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Sialic acid ; Hominin ; Evolution ; CD33rSiglecs ; Common ancestor ; Neanderthal/Denisovan ; Great apes ; Archaic hominin
Published in:	Genome biology and evolution, Vol. 12, Issue 7 (July 2020) , p. 1040-1050, ISSN 1759-6653

DOI: 10.1093/gbe/evaa125
PMID: 32556248

11 p, 571.9 KB

The record appears in these collections:
Research literature > UAB research groups literature > Research Centres and Groups (research output) > Experimental sciences > Institut Català de Paleontologia Miquel Crusafont (ICP)
Articles > Research articles
Articles > Published articles