Long-term balancing selection maintains trans-specific polymorphisms in the human TRIM5 gene
- 323 Downloads
The human TRIM5 genes encodes a retroviral restriction factor (TRIM5α). Evolutionary analyses of this gene in mammals have revealed a complex and multifaceted scenario, suggesting that TRIM5 has been the target of exceptionally strong selective pressures, possibly exerted by recurrent waves of retroviral infections. TRIM5 displays inter-individual expression variability in humans and high levels of TRIM5 mRNA have been associated with a reduced risk of HIV-1 infection. We resequenced TRIM5 in chimpanzees and identified two polymorphisms in intron 1 that are shared with humans. Analysis of the gene region encompassing the two trans-specific variants in human populations identified exceptional nucleotide diversity levels and an excess of polymorphism compared to fixed divergence. Most tests rejected the null hypothesis of neutral evolution for this region and haplotype analysis revealed the presence of two deeply separated clades. Calculation of the time to the most recent common ancestor (TMRCA) for TRIM5 haplotypes yielded estimates ranging between 4 and 7 million years. Overall, these data indicate that long-term balancing selection, an extremely rare process outside MHC genes, has maintained trans-specific polymorphisms in the first intron of TRIM5. Bioinformatic analyses indicated that variants in intron 1 may affect transcription factor-binding sites and, therefore, TRIM5 transcriptional activity. Data herein confirm an extremely complex evolutionary history of TRIM5 genes in primates and open the possibility that regulatory variants in the gene modulate the susceptibility to HIV-1.
KeywordsBalance Selection Coalescent Simulation Sooty Mangabey TRIM5 Expression TRIM5 Gene
MC is supported by grants from Istituto Superiore di Sanita’ “Programma Nazionale di Ricerca sull’ AIDS”, the EMPRO and AVIP EC WP6 Projects, the nGIN EC WP7 Project, the Japan Health Science Foundation, 2008 Ricerca Finalizzata [Italian Ministry of Health], 2008 Ricerca Corrente [Italian Ministry of Health], Progetto FIRB RETI: Rete Italiana Chimica Farmaceutica CHEM-PROFARMA-NET [RBPR05NWWC], and Fondazione CARIPLO. MS is a member of the Doctorate School in Molecular Medicine, University of Milan.
- Bamshad MJ, Mummidi S, Gonzalez E, Ahuja SS, Dunn DM, Watkins WS, Wooding S, Stone AC, Jorde LB, Weiss RB, Ahuja SK (2002) A strong signature of balancing selection in the 5′ cis-regulatory region of CCR5. Proc Natl Acad Sci USA 99:10539–10544. doi: 10.1073/pnas.162046399 CrossRefPubMedGoogle Scholar
- Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, Altschuler D (2002) The structure of haplotype blocks in the human genome. Science 296:2225–2229CrossRefPubMedGoogle Scholar
- Javanbakht H, An P, Gold B, Petersen DC, O’Huigin C, Nelson GW, O’Brien SJ, Kirk GD, Detels R, Buchbinder S, Donfield S, Shulenin S, Song B, Perron MJ, Stremlau M, Sodroski J, Dean M, Winkler C (2006) Effects of human TRIM5α polymorphisms on antiretroviral function and susceptibility to human immunodeficiency virus infection. Virology 354:15–27. doi: 10.1016/j.virol.2006.06.031 CrossRefPubMedGoogle Scholar
- Liu X, Fu Y, Liu Z, Lin B, Xie Y, Liu Y, Xu Y, Lin J, Fan X, Dong M, Zeng K, Wu CI, Xu A (2006) An ancient balanced polymorphism in a regulatory region of human major histocompatibility complex is retained in Chinese minorities but lost worldwide. Am J Hum Genet 78:393–400. doi: 10.1086/500593 CrossRefPubMedGoogle Scholar
- Newman RM, Hall L, Connole M, Chen GL, Sato S, Yuste E, Diehl W, Hunter E, Kaur A, Miller GM, Johnson WE (2006) Balancing selection and the evolution of functional polymorphism in Old World monkey TRIM5α. Proc Natl Acad Sci USA 103:19134–19139. doi: 10.1073/pnas.0605838103 CrossRefPubMedGoogle Scholar
- R Development Core Team (2008) R: a language and environment for statistical computing, Vienna, AustriaGoogle Scholar
- Song B, Gold B, O’Huigin C, Javanbakht H, Li X, Stremlau M, Winkler C, Dean M, Sodroski J (2005) The B30.2(SPRY) domain of the retroviral restriction factor TRIM5alpha exhibits lineage-specific length and sequence variation in primates. J Virol 79:6111–6121. doi: 10.1128/JVI.79.10.6111-6121.2005 CrossRefPubMedGoogle Scholar
- Stremlau M, Perron M, Lee M, Li Y, Song B, Javanbakht H, Diaz-Griffero F, Anderson DJ, Sundquist WI, Sodroski J (2006) Specific recognition and accelerated uncoating of retroviral capsids by the TRIM5α restriction factor. Proc Natl Acad Sci USA 103:5514–5519. doi: 10.1073/pnas.0509996103 CrossRefPubMedGoogle Scholar
- Zogopoulos G, Ha KC, Naqib F, Moore S, Kim H, Montpetit A, Robidoux F, Laflamme P, Cotterchio M, Greenwood C, Scherer SW, Zanke B, Hudson TJ, Bader GD, Gallinger S (2007) Germ-line DNA copy number variation frequencies in a large North American population. Hum Genet 122:345–353. doi: 10.1007/s00439-007-0404-5 CrossRefPubMedGoogle Scholar