Specific inactivation of two immunomodulatory SIGLEC genes during human evolution
Por:
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., Mullikin J.C., Nizet V., Bui J., Varki A.
Publicada:
1 ene 2012
Categoría:
Multidisciplinary
Resumen:
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.
Filiaciones:
Wang X.:
Departments of Medicine, Cellular and Molecular Medicine, Pathology, and Pediatrics, University of California at San Diego, San Diego, CA 92093, United States
Glycobiology Research and Training Center, University of California at San Diego, San Diego, CA 92093, United States
Mitra N.:
Departments of Medicine, Cellular and Molecular Medicine, Pathology, and Pediatrics, University of California at San Diego, San Diego, CA 92093, United States
Glycobiology Research and Training Center, University of California at San Diego, San Diego, CA 92093, United States
Secundino I.:
Departments of Medicine, Cellular and Molecular Medicine, Pathology, and Pediatrics, University of California at San Diego, San Diego, CA 92093, United States
Glycobiology Research and Training Center, University of California at San Diego, San Diego, CA 92093, United States
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, San Diego, CA 92093, United States
Banda K.:
Departments of Medicine, Cellular and Molecular Medicine, Pathology, and Pediatrics, University of California at San Diego, San Diego, CA 92093, United States
Glycobiology Research and Training Center, University of California at San Diego, San Diego, CA 92093, United States
Cruz P.:
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, United States
Padler-Karavani V.:
Departments of Medicine, Cellular and Molecular Medicine, Pathology, and Pediatrics, University of California at San Diego, San Diego, CA 92093, United States
Glycobiology Research and Training Center, University of California at San Diego, San Diego, CA 92093, United States
Verhagen A.:
Departments of Medicine, Cellular and Molecular Medicine, Pathology, and Pediatrics, University of California at San Diego, San Diego, CA 92093, United States
Glycobiology Research and Training Center, University of California at San Diego, San Diego, CA 92093, United States
Reid C.:
Departments of Medicine, Cellular and Molecular Medicine, Pathology, and Pediatrics, University of California at San Diego, San Diego, CA 92093, United States
Glycobiology Research and Training Center, University of California at San Diego, San Diego, CA 92093, United States
Lari M.:
Department of Evolutionary Biology, University of Florence, 50122 Florence, Italy
Rizzi E.:
Institute for Biomedical Technologies (ITB), National Research Council (CNR), 20090 Milan, Italy
Balsamo C.:
Department of Evolutionary Biology, University of Florence, 50122 Florence, Italy
Corti G.:
Institute for Biomedical Technologies (ITB), National Research Council (CNR), 20090 Milan, Italy
De Bellis G.:
Institute for Biomedical Technologies (ITB), National Research Council (CNR), 20090 Milan, Italy
Longo L.:
Department of Environmental Science, University of Siena, 53100 Siena, Italy
Beggs W.:
Departments of Genetics and Biology, University of Pennsylvania, Philadelphia, PA 19104, United States
Caramelli D.:
Department of Evolutionary Biology, University of Florence, 50122 Florence, Italy
Tishkoff S.A.:
Departments of Genetics and Biology, University of Pennsylvania, Philadelphia, PA 19104, United States
Hayakawa T.:
Primate Research Institute, Kyoto University, Inuyama 484-8506, Japan
Green E.D.:
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, United States
Mullikin J.C.:
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, United States
Nizet V.:
Departments of Medicine, Cellular and Molecular Medicine, Pathology, and Pediatrics, University of California at San Diego, San Diego, CA 92093, United States
Glycobiology Research and Training Center, University of California at San Diego, San Diego, CA 92093, United States
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, San Diego, CA 92093, United States
Bui J.:
Departments of Medicine, Cellular and Molecular Medicine, Pathology, and Pediatrics, University of California at San Diego, San Diego, CA 92093, United States
Varki A.:
Departments of Medicine, Cellular and Molecular Medicine, Pathology, and Pediatrics, University of California at San Diego, San Diego, CA 92093, United States
Glycobiology Research and Training Center, University of California at San Diego, San Diego, CA 92093, United States
All Open Access, Bronze
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