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

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• dc.contributor.author Khan, Naazneen
• dc.contributor.author de Manuel, Marc
• dc.contributor.author Peyregne, Stephane
• dc.contributor.author Do, Raymond
• dc.contributor.author Prufer, Kay
• dc.contributor.author Marquès i Bonet, Tomàs, 1975-
• dc.contributor.author Varki, Nissi
• dc.contributor.author Gagneux, Pascal
• dc.contributor.author Varki, Ajit
• dc.date.accessioned 2020-07-29T06:41:39Z
• dc.date.available 2020-07-29T06:41:39Z
• dc.date.issued 2020
• dc.description.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.
• dc.description.sponsorship This research was supported by NIH grant R01GM32373 to A.V.. T.M.-B. is supported by BFU2017-86471-P (MINECO/FEDER, UE), U01 MH106874 grant, Howard Hughes International Early Career, Obra Social “La Caixa” and Secretaria d’Universitats i Recerca, and CERCA Programme del Departament d’Economia i Coneixement de la Generalitat de Catalunya (GRC 2017 SGR 880).
• dc.format.mimetype application/pdf
• dc.identifier.citation Khan N, de Manuel M, Peyregne S, Do R, Prufer K, Marques-Bonet T, Varki N, Gagneux P, Varki A. Multiple genomic events altering hominin SIGLEC biology and innate immunity predated the common ancestor of humans and archaic hominins. Genome Biol Evol. 2020; 12(7):1040-50. DOI: 10.1093/gbe/evaa125
• dc.identifier.doi http://dx.doi.org/10.1093/gbe/evaa125
• dc.identifier.issn 1759-6653
• dc.identifier.uri http://hdl.handle.net/10230/45211
• dc.language.iso eng
• dc.publisher Oxford University Press
• dc.relation.ispartof Genome Biol Evol. 2020; 12(7):1040-50
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/BFU2017-86471-P
• dc.rights © The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by-nc/4.0/
• dc.subject.keyword CD33rSiglecs
• dc.subject.keyword Neanderthal/Denisovan
• dc.subject.keyword Archaic hominin
• dc.subject.keyword Common ancestor
• dc.subject.keyword Evolution
• dc.subject.keyword Great apes
• dc.subject.keyword Hominin
• dc.subject.keyword Sialic acid
• dc.title Multiple genomic events altering hominin SIGLEC biology and innate immunity predated the common ancestor of humans and archaic hominins
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion