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doi:10.1534/genetics.105.052019
A more recent version of this article appeared on November 1, 2006.
REGULAR RESEARCH PAPERS |
Evolution of the HIV-1 Envelope Gene is Dominated by Purifying Selection
Charles Edwards 1*, Edward Holmes 2, Oliver Pybus 3, Daniel Wilson 4, Raphael Viscidi 5, Elaine Abrams 6, Rodney Phillips 1 and Alexei Drummond 7
1 Department of Clinical Medicine, University of Oxford
2 Department of Biology, The Pennsylvania State University
3 Department of Zoology, University of Oxford
4 Department of Statistics, University of Oxford
5 Department of Pediatrics, The Johns Hopkins Hospital
6 Department of Pediatrics, Columbia University College of Physicians and Surgeons and Harlem Hospital
7 Department of Computer Science, University of Auckland
* To whom correspondence should be addressed. E-mail: cedwards{at}maths.uct.ac.za.
Submitted on October 7, 2005
Revised on March 23, 2006
Accepted on 17 August 2006
The evolution of the human immunodeficiency virus (HIV-1) during chronic infection involves the rapid, continuous turnover of genetic diversity. However, the role of natural selection, relative to random genetic drift, in governing this process is unclear. We tested a stochastic model of genetic drift using partial envelope sequences sampled longitudinally in 28 infected children. In each case the Bayesian posterior (empirical) distribution of coalescent genealogies was estimated using Markov Chain Monte Carlo methods. Posterior predictive simulation was then used to generate a null distribution of genealogies assuming neutrality, with the null and empirical distributions compared using four genealogy-based summary statistics sensitive to non-neutral evolution. Because both null and empirical distributions were generated within a coalescent framework, we were able to explicitly account for the confounding influence of demography. From the distribution of corrected p values across patients, we conclude that empirical genealogies are more asymmetric than expected if evolution is driven by mutation and genetic drift only, with an excess of low frequency polymorphisms in the population. This indicates that although drift may still play an important role, natural selection has a strong influence on the evolution of HIV-1 envelope. A negative relationship between effective population size and substitution rate indicates that as the efficacy of selection increases, a smaller proportion of mutations approaches fixation in the population. This suggests the presence of deleterious mutations. We therefore conclude that intra-host HIV-1 evolution in envelope is dominated by purifying selection against low frequency deleterious mutations that do not reach fixation.
Key Words: Coalescent Theory, Evolution, HIV-1, MCMC, Mutational Load
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