Abstract
The ability of pathogens to escape the host's immune response is crucial for the establishment of persistent infections and can influence virulence. Recombination has been observed to contribute to this process by generating novel genetic variants. Although distinctive recombination patterns have been described in many viral pathogens, little is known about the influence of biases in the recombination process itself relative to selective forces acting on newly formed recombinants. Understanding these influences is important for determining how recombination contributes to pathogen genome and proteome evolution. Most previous research on recombination-driven protein evolution has focused on relatively simple proteins, usually in the context of directed evolution experiments. Here, we study recombination in the envelope gene of HIV-1 between primary isolates belonging to subtypes that recombine naturally in the HIV/AIDS pandemic. By characterizing the early steps in the generation of recombinants, we provide novel insights into the evolutionary forces that shape recombination patterns within viral populations. Specifically, we show that the combined effects of mechanistic processes that determine the locations of recombination breakpoints across the HIV-1 envelope gene, and purifying selection acting against dysfunctional recombinants, can explain almost the entire distribution of breakpoints found within this gene in nature. These constraints account for the surprising paucity of recombination breakpoints found in infected individuals within this highly variable gene. Thus, the apparent randomness of HIV evolution via recombination may in fact be relatively more predictable than anticipated. In addition, the dominance of purifying selection in localized areas of the HIV genome defines regions where functional constraints on recombinants appear particularly strong, pointing to vulnerable aspects of HIV biology.
Highlights
Pathogens, and viruses in particular, are subject to strong selective pressures during infection and often have characteristically high degrees of genetic variation [1]
human immunodeficiency virus (HIV)-1 isolates belonging to either different group M subtypes or group O to determine the distribution of breakpoints occurring within the HIV env gene in the absence of selection
In order to quantify variations in recombination rates across env we used a previously described experimental system where human T cells are transduced with HIV-1 replication-defective vectors pseudotyped with the Vesicular Stomatitis Virus (VSV) envelope [29]
Summary
Viruses in particular, are subject to strong selective pressures during infection and often have characteristically high degrees of genetic variation [1]. Recombination is an important evolutionary mechanism that contributes to this genetic diversification. Since recombination generally involves genes that already encode functional products, the probability of producing viable progeny is higher compared to the insertion of an equivalent number of random point mutations [2]. Genes and genomes generally evolve through the slow accumulation of point mutations, which often requires the progressive insertion of compensatory mutations at ‘‘linked’’ sites. This coevolution permits the preservation of epistatic interactions. By simultaneously introducing several substitutions, recombination has the potential to substantially perturb such coevolved intra-genome interaction networks [2,3], impairing the functionality of the genes involved. The balance between the advantages of taking evolutionary shortcuts and the risk of chimeras being dysfunctional [2] determines the role played by recombination in the evolution of a given gene or organism
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