Patterns of recombination in HIV-1M are influenced by selection disfavouring the survival of recombinants with disrupted genomic RNA and protein structures.

Michael Golden,Darren P Martin,Brejnev M Muhire,Yves Semegni,Nadia Singh

doi:10.1371/journal.pone.0100400

Michael Golden, Darren P Martin + Show 3 more

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https://doi.org/10.1371/journal.pone.0100400

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Abstract

Genetic recombination is a major contributor to the ongoing diversification of HIV. It is clearly apparent that across the HIV-genome there are defined recombination hot and cold spots which tend to co-localise both with genomic secondary structures and with either inter-gene boundaries or intra-gene domain boundaries. There is also good evidence that most recombination breakpoints that are detectable within the genes of natural HIV recombinants are likely to be minimally disruptive of intra-protein amino acid contacts and that these breakpoints should therefore have little impact on protein folding. Here we further investigate the impact on patterns of genetic recombination in HIV of selection favouring the maintenance of functional RNA and protein structures. We confirm that chimaeric Gag p24, reverse transcriptase, integrase, gp120 and Nef proteins that are expressed by natural HIV-1 recombinants have significantly lower degrees of predicted folding disruption than randomly generated recombinants. Similarly, we use a novel single-stranded RNA folding disruption test to show that there is significant, albeit weak, evidence that natural HIV recombinants tend to have genomic secondary structures that more closely resemble parental structures than do randomly generated recombinants. These results are consistent with the hypothesis that natural selection has acted both in the short term to purge recombinants with disrupted RNA and protein folds, and in the longer term to modify the genome architecture of HIV to ensure that recombination prone sites correspond with those where recombination will be minimally deleterious.

Highlights

Recombination is a process involving the movement of genetic information within or between DNA/RNA molecules
Recombination that occurs between divergent genome fragments having largely independent evolutionary histories can potentially disrupt coevolved intra-genome interactions such as those occurring between amino acids within three-dimensional protein folds
Actual recombinants sampled from nature would be expected to display less disruption of intra-protein interactions than simulated recombinants either if natural selection disfavoured the survival of recombinants expressing misfolded proteins, or recombination breakpoints tended to coincidentally occur most frequently at sites where they would have minimal impact on protein folding

Summary

Introduction

Recombination is a process involving the movement of genetic information within or between DNA/RNA molecules. Homologous recombination, hereafter referred to as recombination, features prominently in the evolution of many viruses. In these organisms recombination does not necessarily involve the breakage and re-ligation of DNA/RNA molecules. In retroviruses such as HIV, for example, it predominantly occurs when RNA copies of the viral genome are being reverse transcribed into DNA by the viral enzyme, reverse transcriptase [3,4,5]. If the two co-packaged HIV genomes are genetically different such template switching could yield a detectably recombinant genome

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