Fifteen to Twenty Percent of HIV substitution mutations are associated with recombination
Schlub, T.E., Grimm, A.J., Smyth, R.P., Cromer, D., Chopra, A., Mallal, S., Venturi, V., Waugh, C., Mak, J. and Davenport, M.P. (2014) Fifteen to Twenty Percent of HIV substitution mutations are associated with recombination. Journal of Virology, 88 (7). pp. 3837-3849.
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HIV undergoes a high rate of mutation and recombination during reverse transcription, but it is not known whether these events occur independently or are linked mechanistically. Here we use a system of silent marker mutations in HIV and a single round of infection in primary T-lymphocytes, combined with a high-throughput sequencing and mathematical modelling approach to directly estimate the viral 38 recombination and mutation rates. From >7 million nt of sequences from HIV infection, we observe 4801 recombination events and 859 substitution mutations (≈1.51 and 0.12 events per 1000 nt respectively). We use experimental controls to account for PCR-induced and transfection-induced recombination and sequencing error. We find the single cycle virus-induced mutation rate is 4.6 x 10-5 mutations per nt after correction. By sorting our data into recombined and non-recombined sequences, we find a significantly higher mutation rate in recombined regions (p=0.003, Fisher’s exact). We use a permutation approach to eliminate a number of potential confounding factors and confirm that mutation occurs around the site of recombination, and is not simply co-located in the genome. By comparing mutation rates in recombined and non-recombined regions we find that recombination associated mutations account for 15-20% of all mutations occurring during reverse transcription.
|Publication Type:||Journal Article|
|Publisher:||American Society for Microbiology|
|Copyright:||© 2014 American Society for Microbiology|
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