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Specific inactivation of two immunomodulatory SIGLEC genes during human evolution.

Abstract：

:Sialic acid-recognizing Ig-like lectins (Siglecs) are signaling receptors that modulate immune responses, and are targeted for interactions by certain pathogens. We describe two primate Siglecs that were rendered nonfunctional by single genetic events during hominin evolution after our common ancestor with the chimpanzee. SIGLEC13 was deleted by an Alu-mediated recombination event, and a single base pair deletion disrupted the ORF of SIGLEC17. Siglec-13 is expressed on chimpanzee monocytes, innate immune cells that react to bacteria. The human SIGLEC17P pseudogene mRNA is still expressed at high levels in human natural killer cells, which bridge innate and adaptive immune responses. As both resulting pseudogenes are homozygous in all human populations, we resurrected the originally encoded proteins and examined their functions. Chimpanzee Siglec-13 and the resurrected human Siglec-17 recruit a signaling adapter and bind sialic acids. Expression of either Siglec in innate immune cells alters inflammatory cytokine secretion in response to Toll-like receptor-4 stimulation. Both Siglecs can also be engaged by two potentially lethal sialylated bacterial pathogens of newborns and infants, agents with a potential impact on reproductive fitness. Neanderthal and Denisovan genomes show human-like sequences at both loci, corroborating estimates that the initial pseudogenization events occurred in the common ancestral population of these hominins. Both loci also show limited polymorphic diversity, suggesting selection forces predating the origin of modern humans. Taken together, these data suggest that genetic elimination of Siglec-13 and/or Siglec-17 represents signatures of infectious and/or other inflammatory selective processes contributing to population restrictions during hominin origins.

journal_name

Proc Natl Acad Sci U S A

journal_title

Proceedings of the National Academy of Sciences of the United States of America

authors

Wang X,Mitra N,Secundino I,Banda K,Cruz P,Padler-Karavani V,Verhagen A,Reid C,Lari M,Rizzi E,Balsamo C,Corti G,De Bellis G,Longo L,NISC Comparative Sequencing Program.,Beggs W,Caramelli D,Tishkoff SA,Hayakawa T,Gree

doi

10.1073/pnas.1119459109

subject

Has Abstract

pub_date

2012-06-19 00:00:00

pages

9935-40

issue

eissn

0027-8424

issn

1091-6490

pii

1119459109

journal_volume

109

pub_type

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Specific inactivation of two immunomodulatory SIGLEC genes during human evolution.