Human Genetics

, Volume 128, Issue 6, pp 577–588 | Cite as

Long-term balancing selection maintains trans-specific polymorphisms in the human TRIM5 gene

  • R. Cagliani
  • M. Fumagalli
  • M. Biasin
  • L. Piacentini
  • S. Riva
  • U. Pozzoli
  • M. C. Bonaglia
  • N. Bresolin
  • M. Clerici
  • Manuela SironiEmail author
Original Investigation


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.


Balance Selection Coalescent Simulation Sooty Mangabey TRIM5 Expression TRIM5 Gene 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



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.

Supplementary material

439_2010_884_MOESM1_ESM.doc (365 kb)
Supplementary material 1 (DOC 365 kb)
439_2010_884_MOESM2_ESM.xls (110 kb)
Supplementary material 2 (XLS 110 kb)


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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • R. Cagliani
    • 1
  • M. Fumagalli
    • 1
    • 2
  • M. Biasin
    • 3
  • L. Piacentini
    • 3
  • S. Riva
    • 1
  • U. Pozzoli
    • 1
  • M. C. Bonaglia
    • 1
  • N. Bresolin
    • 1
    • 4
  • M. Clerici
    • 5
    • 6
  • Manuela Sironi
    • 1
    Email author
  1. 1.Scientific Institute IRCCS E. MedeaBosisio Parini (LC)Italy
  2. 2.Bioengineering DepartmentPolitecnico di MilanoMilanItaly
  3. 3.Chair of Immunology, DISP LITA VialbaUniversity of MilanoMilanItaly
  4. 4.Dino Ferrari Centre, Department of Neurological SciencesUniversity of Milan, IRCCS Ospedale Maggiore Policlinico, Mangiagalli and Regina Elena FoundationMilanItaly
  5. 5.Chair of Immunology, Department of Biomedical Sciences and Technologies LITA SegrateUniversity of MilanoMilanItaly
  6. 6.Fondazione Don C. Gnocchi IRCCSMilanItaly

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