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Igor M Rouzine
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doi:10.1534/genetics.104.029926
A more recent version of this article appeared on May 1, 2005.
REGULAR RESEARCH PAPERS |
Evolution of HIV Under Selection and Weak Recombination
Igor M Rouzine 1* and John M Coffin 1
1 Tufts University
* To whom correspondence should be addressed. E-mail: irouzine{at}tufts.edu.
Submitted on April 11, 2004
Revised on October 12, 2004
Accepted on 16 January 2005
To predict the emergence of drug-resistance in patients undergoing antiretroviral therapy, we studied the accumulation of pre-existing beneficial alleles in a haploid population of N genomes. The factors included in the model are selection with the coefficient s and recombination with the small rate per genome r (r << s
k, where k is the average number of less-fit loci per genome). Mutation events are neglected. To describe evolution at a large number of linked loci, we generalize the analytic method we developed recently for an asexual population. We show that the distribution of genomes over the deleterious allele number moves in time as a "solitary wave" that is quasi-deterministic in the middle (on the average) but has stochastic edges. We arrive at a single-locus expression for the average accumulation rate, in which the effects of linkage, recombination and random drift are all accounted for by the effective selection coefficient s ln(Nr)/ln(Ns2k/r). At large N, the effective selection coefficient approaches the single-locus value s. Below the critical size N ~ 1/r, a population eventually becomes a clone, recombination cannot produce new sequences, and virus evolution stops. Taking into account finite mutation rate predicts a small, finite rate of evolution at N < 1/r. We verify the accuracy of the results analytically and by Monte-Carlo simulation. Based on our findings, we predict that partial depletion of HIV population by combined antiretroviral therapy can suppress the emergence of drug-resistant strains.
Key Words: HIV, drug-resistance, multi-locus, recombination, selection
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