Journal
MOLECULAR BIOLOGY AND EVOLUTION
Volume 27, Issue 4, Pages 819-832Publisher
OXFORD UNIV PRESS
DOI: 10.1093/molbev/msp289
Keywords
coevolution; epistasis; HIV-1; next-generation sequencing; ancestral reconstruction; sequencing error
Funding
- National Institutes of Health [AI69432, AI043638, MH62512, MH083552, AI077304, AI36214, AI047745, AI57167, AI74621, AI27757, RN07-SD-702]
- University of California San Diego Centers for AIDS Research/National Institute of Allergy and Infectious Disease [AI36214]
- Canadian Institutes of Health [200802HFE]
- Royal Society Wolfson Research Merit Award
- National Science Foundation [0714991]
- Division Of Mathematical Sciences
- Direct For Mathematical & Physical Scien [0714991] Funding Source: National Science Foundation
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Rapidly evolving viruses such as HIV-1 display extensive sequence variation in response to host-specific selection, while simultaneously maintaining functions that are critical to replication and infectivity. This apparent conflict between diversifying and purifying selection may be resolved by an abundance of epistatic interactions such that the same functional requirements can be met by highly divergent sequences. We investigate this hypothesis by conducting an extensive characterization of sequence variation in the HIV-1 nef gene that encodes a highly variable multifunctional protein. Population-based sequences were obtained from 686 patients enrolled in the HOMER cohort in British Columbia, Canada, from which the distribution of nonsynonymous substitutions in the phylogeny was reconstructed by maximum likelihood. We used a phylogenetic comparative method on these data to identify putative epistatic interactions between residues. Two interactions (Y120/Q125 and N157/S169) were chosen to further investigate within-host evolution using HIV-1 RNA extractions from plasma samples from eight patients. Clonal sequencing confirmed strong linkage between polymorphisms at these sites in every case. We used massively parallel pyrosequencing (MPP) to reconstruct within-host evolution in these patients. Experimental error associated with MPP was quantified by performing replicates at two different stages of the protocol, which were pooled prior to analysis to reduce this source of variation. Phylogenetic reconstruction from these data revealed correlated substitutions at Y120/Q125 or N157/S169 repeated across multiple lineages in every host, indicating convergent within-host evolution shaped by epistatic interactions.
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