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

Area of Science:

• Evolutionary genetics
• Immunology
• Primate genomics

Background:

• The TRIM5 gene encodes TRIM5α, a retroviral restriction factor crucial in innate immunity.
• Evolutionary studies suggest TRIM5 has faced strong selective pressures, potentially from retroviral infections.
• Human TRIM5 exhibits expression variability, with higher levels linked to reduced HIV-1 infection risk.

Purpose of the Study:

• To investigate the evolutionary history of the TRIM5 gene in primates.
• To identify genetic variants within TRIM5 that may influence its function and human susceptibility to retroviral infections.
• To explore the role of selection pressures on TRIM5 evolution.

Main Methods:

• Resequencing of the TRIM5 gene in chimpanzees.
• Analysis of nucleotide diversity and polymorphism in human populations for shared variants.
• Haplotype analysis and calculation of the time to the most recent common ancestor (TMRCA).
• Bioinformatic analysis of potential regulatory elements in TRIM5 intron 1.

Main Results:

• Identified two shared polymorphisms in TRIM5 intron 1 between humans and chimpanzees.
• Observed exceptional nucleotide diversity and an excess of polymorphism in this region, rejecting neutral evolution.
• Detected two deeply separated haplotype clades, with TMRCA estimates between 4 and 7 million years.
• Bioinformatic analysis suggests intron 1 variants may affect transcription factor binding sites and TRIM5 activity.

Conclusions:

• Long-term balancing selection has maintained trans-specific polymorphisms in human TRIM5 intron 1, a rare evolutionary process.
• These findings reveal a complex evolutionary trajectory for TRIM5 in primates.
• Regulatory variants in TRIM5 intron 1 may play a role in modulating susceptibility to HIV-1 infection.