NDLI: Specific inactivation of two immunomodulatory SIGLEC genes during human evolution

Content Provider	PubMed Central
Author	Wang, Xiaoxia Mitra, Nivedita Ismael, Secundino Banda, Kalyan Cruz, Pedro Vered, Padler-karavani Verhagen, Andrea Reid, Chris Lari, Martina Rizzi, Ermanno Balsamo, Carlotta Corti, Giorgio Bellis, Gianluca De Longo, Laura Beggs, William Caramelli, David Tishkoff, Sarah A. Hayakawa, Toshiyuki Green, Eric D. Mullikin, James C. Nizet, Victor Bui, Jack Varki, Ajit Benjamin, Betty Blakesley, Robert Bouffard, Gerry Brooks, Shelise Chu, Grace Coleman, Holly Mila, Dekhtyar Gregory, Michael Guan, Xiaobin Gupta, Jyoti Han, Joel Hargrove, April Ho, Shi-ling Johnson, Taccara Legaspi, Richelle Lovett, Sean Maduro, Quino Masiello, Cathy Maskeri, Baishali Mcdowell, Jenny Montemayor, Casandra Novotny, Betsy Park, Morgan Riebow, Nancy Schandler, Karen Schmidt, Brian Sison, Christina Mal, Stantripop Thomas, James Vemulapalli, Meg Young, Alice
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.
Related Links	http://dx.doi.org/10.1073/pnas.1119459109
Ending Page	9940
Page Count	6
Starting Page	9935
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	25
Volume Number	109
Language	English
Publisher	National Academy of Sciences
Publisher Date	2012-06-19
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
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3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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