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Related Experiment Video

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In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila

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Published on: August 20, 2019

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

R Cagliani¹, M Fumagalli, M Biasin

¹Scientific Institute IRCCS E. Medea, Via don L. Monza 20, 23842, Bosisio Parini, LC, Italy.

|September 3, 2010

Summary

The TRIM5 gene, a retroviral restriction factor, shows deep evolutionary history in primates due to balancing selection. Variants in its intron may influence TRIM5 activity and HIV-1 susceptibility.

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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.