Journal
GENETICS
Volume 170, Issue 1, Pages 7-18Publisher
GENETICS SOC AM
DOI: 10.1534/genetics.104.029926
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Funding
- NCI NIH HHS [CA89441, R01 CA089441, R35CA44385, R37 CA089441] Funding Source: Medline
- NIAID NIH HHS [K25 AI001811, K25AI01811] Funding Source: Medline
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To predict emergence of drug resistance in patients undergoing antiretroviral therapy, we study accumulation of preexisting 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 root k, where (k) over bar 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 In(Nr)/In(NA/r). At large N, the effective selection coefficient approaches the single-locus value s. Below the critical size N-c similar to 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 < N-c. We verify the accuracy of the results analytically and by Monte Carlo simulation. On the basis of our findings, we predict that partial depletion of the HfV population by combined antiretroviral therapy can suppress emergence of drug resistant strains.
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