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Evolutionary accessibility of mutational pathways.

ABSTRACT: Functional effects of different mutations are known to combine to the total effect in highly nontrivial ways. For the trait under evolutionary selection ('fitness'), measured values over all possible combinations of a set of mutations yield a fitness landscape that determines which mutational states can be reached from a given initial genotype. Understanding the accessibility properties of fitness landscapes is conceptually important in answering questions about the predictability and repeatability of evolutionary adaptation. Here we theoretically investigate accessibility of the globally optimal state on a wide variety of model landscapes, including landscapes with tunable ruggedness as well as neutral 'holey' landscapes. We define a mutational pathway to be accessible if it contains the minimal number of mutations required to reach the target genotype, and if fitness increases in each mutational step. Under this definition accessibility is high, in the sense that at least one accessible pathway exists with a substantial probability that approaches unity as the dimensionality of the fitness landscape (set by the number of mutational loci) becomes large. At the same time the number of alternative accessible pathways grows without bounds. We test the model predictions against an empirical 8-locus fitness landscape obtained for the filamentous fungus Aspergillus niger. By analyzing subgraphs of the full landscape containing different subsets of mutations, we are able to probe the mutational distance scale in the empirical data. The predicted effect of high accessibility is supported by the empirical data and is very robust, which we argue reflects the generic topology of sequence spaces. Together with the restrictive assumptions that lie in our definition of accessibility, this implies that the globally optimal configuration should be accessible to genome wide evolution, but the repeatability of evolutionary trajectories is limited owing to the presence of a large number of alternative mutational pathways.

SUBMITTER: Franke J

PROVIDER: S-EPMC3158036 | biostudies-other | 2011 Aug

REPOSITORIES: biostudies-other

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Evolutionary accessibility of mutational pathways.

Franke Jasper J Klözer Alexander A de Visser J Arjan G M JA Krug Joachim J

PLoS computational biology 20110818 8

Functional effects of different mutations are known to combine to the total effect in highly nontrivial ways. For the trait under evolutionary selection ('fitness'), measured values over all possible combinations of a set of mutations yield a fitness landscape that determines which mutational states can be reached from a given initial genotype. Understanding the accessibility properties of fitness landscapes is conceptually important in answering questions about the predictability and repeatabil ...[more]

PMID: 21876664

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Project description:BackgroundGenotype-derived drug resistance profiles are a valuable asset in HIV-1 therapy decisions. Therapy decisions could be further improved, both in terms of predicting length of current therapy success and in preserving followup therapy options, through better knowledge of mutational pathways- here defined as specific locations on the viral genome which, when mutant, alter the risk that additional specific mutations arise. We limit the search to locations in the reverse transcriptase region of the HIV-1 genome which host resistance mutations to nucleoside (NRTI) and non-nucleoside (NNRTI) reverse transcriptase inhibitors (as listed in the 2008 International AIDS Society report), or which were mutant at therapy start in 5% or more of the therapies studied.MethodsA Cox proportional hazards model was fit to each location with the hazard of a mutation at that location during therapy proportional to the presence/absence of mutations at the remaining locations at therapy start. A pathway from preexisting to occurring mutation was indicated if the covariate was both selected as important via smoothly clipped absolute deviation (a form of regularized regression) and had a small p-value. The Cox model also allowed controlling for non-genetic parameters and potential nuisance factors such as viral resistance and number of previous therapies. Results were based on 1981 therapies given to 1495 distinct patients drawn from the EuResist database.ResultsThe strongest influence on the hazard of developing NRTI resistance was having more than four previous therapies, not any one existing resistance mutation. Known NRTI resistance pathways were shown, and previously speculated inhibition between the thymidine analog pathways was evidenced. Evidence was found for a number of specific pathways between NRTI and NNRTI resistance sites. A number of common mutations were shown to increase the hazard of developing both NRTI and NNRTI resistance. Viral resistance to the therapy compounds did not materially effect the hazard of mutation in our model.ConclusionsThe accuracy of therapy outcome prediction tools may be increased by including the number of previous treatments, and by considering locations in the HIV genome which increase the hazard of developing resistance mutations.

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Evolutionary accessibility of mutational pathways.

Publications

Evolutionary accessibility of mutational pathways.

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