Evidence for Positive Epistasis in HIV-1

Bonhoeffer, Sebastian; Chappey, Colombe; Parkin, Neil; Whitcomb, Jeanette M.; Petropoulos, Christos J.

doi:10.1126/science.1101786

Cited by 254 publications

(222 citation statements)

References 25 publications

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“…Here, we made a number of simplifications. (i) Epistasis is known to exist for other RNA viruses (45)(46)(47)(48) and has been reported for HIV (49,50); it may contribute to the average values of LD. We hope that the importance of epistasis for the HIV genome in vivo will become clearer in the future, but we have ignored it here.…”

Section: Discussionmentioning

confidence: 99%

Estimate of effective recombination rate and average selection coefficient for HIV in chronic infection

Batorsky

Kearney

Palmer

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

102

152

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HIV adaptation to a host in chronic infection is simulated by means of a Monte-Carlo algorithm that includes the evolutionary factors of mutation, positive selection with varying strength among sites, random genetic drift, linkage, and recombination. By comparing two sensitive measures of linkage disequilibrium (LD) and the number of diverse sites measured in simulation to patient data from one-time samples of pol gene obtained by single-genome sequencing from representative untreated patients, we estimate the effective recombination rate and the average selection coefficient to be on the order of 1% per genome per generation (10 −5 per base per generation) and 0.5%, respectively. The adaptation rate is twofold higher and fourfold lower than predicted in the absence of recombination and in the limit of very frequent recombination, respectively. The level of LD and the number of diverse sites observed in data also range between the values predicted in simulation for these two limiting cases. These results demonstrate the critical importance of finite population size, linkage, and recombination in HIV evolution.

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Section: Discussionmentioning

confidence: 99%

Estimate of effective recombination rate and average selection coefficient for HIV in chronic infection

Batorsky

Kearney

Palmer

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

102

152

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“…Empirical evidence for epistatic variance: Despite the notorious difficulty of detecting epistatic variance (eg Cheverud and Routman, 1995;Goodnight, 1995;Whitlock, 1995;Frankel and Schork, 1996;Wade and Goodnight, 1998;Cheverud, 2000;Wade, 2001), epistatic variance can and does contribute to fitness-related traits (eg Bryant and Meffert, 1996;Long et al, 1996;Routman and Cheverud, 1997;Cheverud et al, 1999;Meffert, 2000;Kover and Caicedo, 2001;Bonhoeffer et al, 2004;Sanjuán et al, 2004). Recent QTL studies provide additional, more direct evidence that genes important to fitness do interact epistatically (Brockmann et al, 2000;Rü ppell et al, 2004;reviewed in Cheverud, 2000).…”

Section: Conversion Of Variance and Adaptive Evolution M Neiman And Tmentioning

confidence: 99%

The conversion of variance and the evolutionary potential of restricted recombination

Neiman

Linksvayer

2005

Heredity

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Genetic recombination is usually considered to facilitate adaptive evolution. However, recombination prevents the reliable cotransmission of interacting gene combinations and can disrupt complexes of coadapted genes. If interactions between genes have important fitness effects, restricted recombination may lead to evolutionary responses that are different from those predicted from a purely additive model and could even aid adaptation. Theory and data have demonstrated that phenomena that limit the effectiveness of recombination via increasing homozygosity, such as inbreeding and population subdivision and bottlenecks, can temporarily increase the additive genetic variance available to these populations. This effect has been attributed to the conversion of nonadditive to additive genetic variance.Analogously, phenomena such as chromosomal inversions and apomictic parthenogenesis that physically restrict recombination in part or all of the genome may also result in a release of additive variance. Here, we review and synthesize literature concerning the evolutionary potential of populations with effectively or physically restricted recombination. Our goal is to emphasize the common theme of increased short-term access to additive genetic variance in all of these situations and to motivate research directed towards a more complete characterization of the relevance of the conversion of variance to the evolutionary process.

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“…A large number of mutations in tightly organized RNA viral genomes should lead to frequent epistatic interactions between sites. Several experiments have provided strong evidence of extensive epistasis in RNA viruses, confirming that during viral evolution certain substitutions at different sites may occur in a coordinated manner (7)(8)(9)(10)(11)(12). Experimental studies into the adaptation of genetically modified HCV genomes propagated in cell culture also have shown antagonistic epistatic interactions between deleterious mutations exhibited in the form of compensatory mutations (13)(14)(15).…”

mentioning

confidence: 99%

Coordinated evolution of the hepatitis C virus

Campo

Dimitrova

Mitchell

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Hepatitis C virus is a genetically heterogeneous RNA virus that is a major cause of liver disease worldwide. Here, we show that, despite its extensive heterogeneity, the evolution of hepatitis C virus is primarily shaped by negative selection and that numerous coordinated substitutions in the polyprotein can be organized into a scale-free network whose degree of connections between sites follows a power-law distribution. This network shares all major properties with many complex biological and technological networks. The topological structure and hierarchical organization of this network suggest that a small number of amino acid sites exert extensive impact on hepatitis C virus evolution. Nonstructural proteins are enriched for negatively selected sites of high centrality, whereas structural proteins are enriched for positively selected sites located in the periphery of the network. The complex network of coordinated substitutions is an emergent property of genetic systems with implications for evolution, vaccine research, and drug development. In addition to such properties as polymorphism or strength of selection, the epistatic connectivity mapped in the network is important for typing individual sites, proteins, or entire genetic systems. The network topology may help devise molecular intervention strategies for disrupting viral functions or impeding compensatory changes for vaccine escape or drug resistance mutations. Also, it may be used to find new therapeutic targets, as suggested in this study for the NS4A protein, which plays an important role in the network.complex systems ͉ scale-free network ͉ covariation ͉ natural selection ͉ epistasis H epatitis C virus (HCV) is a major cause of liver disease worldwide. The global prevalence of HCV infection is estimated to be 2.2%, representing 130 million people (1). HCV causes chronic infection in 70-85% of infected adults (2). There is no vaccine against HCV and current antiviral therapy is relatively toxic, being effective in 50-60% of patients treated (3). HCV is a single-stranded RNA virus of Ϸ9.4 kb belonging to the Flaviviridae family (4). The positive-sense genome of HCV contains one large ORF that encodes a polyprotein that can undergo proteolytic cleavage into 10 mature proteins (C-E1-E2-P7-NS2-NS3-NS4A-NS4B-NS5A-NS5B). The structural proteins, the core (C) and envelope glycoproteins E1 and E2, are present in the N-terminal part of the polyprotein and presumably self-assemble to form the virion. The nonstructural (NS) proteins have various functions and form the replication complex (5).The HCV genome continually mutates during virus replication. Although a high rate of mutation significantly contributes to the enormous adaptability of RNA viruses, it also limits the size of viral genomes by causing error catastrophe (6). The small size of viral genomes imposes strong evolutionary constraints on their organization, as a result of which each genomic region may encode multiple and often conflicting functions. Such genomic organization requires a tight coor...

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Evidence for Positive Epistasis in HIV-1

Cited by 254 publications

References 25 publications

Estimate of effective recombination rate and average selection coefficient for HIV in chronic infection

Estimate of effective recombination rate and average selection coefficient for HIV in chronic infection

The conversion of variance and the evolutionary potential of restricted recombination

Coordinated evolution of the hepatitis C virus

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