Specific inactivation of two immunomodulatory SIGLEC genes during human evolution

Xiaoxia Wang, Nivedita Mitra, Ismael Secundino, Kalyan Banda, Pedro Cruz, Vered Padler-Karavani, Andrea Verhagen, Chris Reid, Martina Lari, Ermanno Rizzi, Carlotta Balsamo, Giorgio Corti, Gianluca De Bellis, Laura Longo, William Beggs, David Caramelli, Sarah A. Tishkoff, Toshiyuki Hayakawa, Eric D. Green, James C. MullikinVictor Nizet, Jack Bui, Ajit Varki

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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.

Original languageEnglish
Pages (from-to)9935-9940
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number25
DOIs
Publication statusPublished - Jun 19 2012

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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., Beggs, W., Caramelli, D., Tishkoff, S. A., Hayakawa, T., Green, E. D., ... Varki, A. (2012). Specific inactivation of two immunomodulatory SIGLEC genes during human evolution. Proceedings of the National Academy of Sciences of the United States of America, 109(25), 9935-9940. https://doi.org/10.1073/pnas.1119459109