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题名:High-Frequency Persistence of an Impaired Allele of the Retroviral Defense Gene TRIM5α in Humans
作者:Sara L. Sawyer, Lily I. Wu,...
来源:Current Biology 2006 16: 95-100.
URL :http://www.current-biology.com/content/article/fulltext?uid=PIIS0960982205014545
日期:061215
摘要:Sara L. Sawyer,1 Lily I. Wu,2 Joshua M. Akey,3 Michael Emerman,1,2,4 and Harmit S. Malik1,4,

1 Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109
2 Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109
3 Department of Genome Sciences, University of Washington, Seattle, Washington 98109

Corresponding author
Harmit S. Malik
Ph: (206) 667-5204
Fax: (206) 667-6497
hsmalik@fhcrc.org


Summary

The intracellular TRIM5α protein successfully inhibits HIV-1 infection in rhesus monkeys, but not in humans [1, 2, 3, 4, 5, 6]. A few amino acids in the virus-interacting SPRY domain [7] were found to be responsible for most of this anti-viral specificity [8, 9, 10], raising the possibility that genetic variation among humans could result in TRIM5α proteins with a spectrum of potencies. We found several nonsynonymous SNPs at the human TRIM5 locus, but only one of these (H43Y) was found to have a significant functional consequence. We demonstrate that H43Y impairs TRIM5α restriction of two distantly related retroviruses. H43Y lies in the RING domain of TRIM5α and may negatively affect its putative E3 ubiquitin ligase activity. This detrimental allele dates back to before the African diaspora and is found at a frequency of 43% in indigenous Central and South Americans. We suggest that relaxed constraint due to a recent period of low retroviral challenge has allowed the deleterious H43Y mutation to persist and even to expand after the bottleneck that occurred upon human migration to the New World. The unexpectedly high frequency of an impaired retroviral restriction allele among humans is likely to have a significant impact on our ability to ward off future retroviral challenges.

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