Evolutionary and functional evidence for positive selection at the human CD5 immune receptor gene

CD5 is a lymphocyte surface coreceptor of still incompletely understood function. Currently available information indicates that CD5 participates not only in cell-to-cell immune interactions through still poorly defined endogenous ligands expressed on hemopoietic and nonhemopoietic cells but also in recognition of exogenous and highly conserved microbial structures such as fungal β-glucans. Preceding single nucleotide polymorphism (SNP) data analysis provided evidence for a recent selective sweep in East Asia and suggested a nonsynonymous substitution at position 471 (A471V; rs2229177) of the cytoplasmatic region of the CD5 receptor as the most plausible target of selection. The present report further investigates the role of natural selection in the CD5 gene by a resequencing approach in 60 individuals representing populations from 3 different continents (20 Africans, 20 Europeans and 20 East Asians) and by functionally assaying the relevance of the A471V replacement on CD5 signaling. The high differentiation pattern found at the nonsynonymous A471V site together with the low diversity, most of the performed neutrality tests (Tajima's D, Fu and Li's F* and D*, and Fu's Fs) and the predominance of a major haplotype in East Asians strongly argue in favor of positive selection for the A471V site. Importantly, anti-CD5 monoclonal antibody cross-linking unveiled significant differences among A471V variants regarding the mitogen-activated protein kinase (MAPK) cascade activation on COS7 and on human peripheral blood mononuclear cells. Similar differences on MAPK activation and IL-8 cytokine release were also observed upon exposure of HEK293 cell transfectants expressing the A471V variants to Zymosan, a β-glucan-rich fungal particle. Taken together, the results provide evidence for the hypothesis of an adaptive role of the A471V substitution to environmental challenges, most likely infectious pathogens, in East Asian populations. © The Author 2011. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved.This research was supported by grants from the Spanish Ministerio de Ciencia e Innovación (BFU2008-01046/BMC to E.B. and SAF2007-62197 and SAF2010-19717 to F.L.); Generalitat de Catalunya (2009SGR1101); Spanish National Institute for Bioinformatics ( www.inb.org ); Fundación de Investigación y Pre- vención del SIDA en España (FIPSE 36-0773-09 to F.L.); Instituto de Salud Carlos III (Red Española de Investigación en Patología Infecciosa, RD06/0008/1013 to F.L.); Volkswagenstiftung Scholarship (I/85 198 to J.E.).Peer Reviewe