Epistasis and Pleiotropy Affect the Modularity of the Genotype-Phenotype Map of Cross-Resistance in HIV-1.
The genotype-phenotype (GP) map is a central concept in evolutionary biology as it describes the mapping of molecular genetic variation onto phenotypic trait variation. Our understanding of that mapping remains partial, especially when trying to link functional clustering of pleiotropic gene effects with patterns of phenotypic trait co-variation. Only on rare occasions have studies been able to fully explore that link and tend to show poor correspondence between modular structures within the GP map and among phenotypes. By dissecting the structure of the GP map of the replicative capacity of HIV-1 in 15 drug environments, we provide a detailed view of that mapping from mutational pleiotropic variation to phenotypic co-variation, including epistatic effects of a set of amino-acid substitutions in the reverse transcriptase and protease genes. We show that epistasis increases the pleiotropic degree of single mutations and provides modularity to the GP map of drug resistance in HIV-1. Moreover, modules of epistatic pleiotropic effects within the GP map match the phenotypic modules of correlated replicative capacity among drug classes. Epistasis thus increases the evolvability of cross-resistance in HIV by providing more drug- and class-specific pleiotropic profiles to the main effects of the mutations. We discuss the implications for the evolution of cross-resistance in HIV.
ETH Zürich, Institute of Integrative Biology, Universitätsstr. 16, Zürich, Switzerland.
Robert
R
Polster
Monogram Biosciences, South San Francisco, CA.
Christos J
CJ
Petropoulos
ETH Zürich, Institute of Integrative Biology, Universitätsstr. 16, Zürich, Switzerland.
Sebastian
S
Bonhoeffer
ETH Zürich, Institute of Integrative Biology, Universitätsstr. 16, Zürich, Switzerland frederic.guillaume@ieu.uzh.ch.|Department of Evolutionary Biology and Environmental Studies, University of Zürich, Zürich, Switzerland.
Frédéric
F
Guillaume
D019380:Anti-HIV Agents / Q000494:pharmacology; D005075:Biological Evolution; D024921:Drug Resistance, Multiple, Viral; D004843:Epistasis, Genetic; D019143:Evolution, Molecular; D056726:Genetic Association Studies; D058685:Genetic Pleiotropy; D014644:Genetic Variation; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008957:Models, Genetic; D009154:Mutation; D040641:Quantitative Trait Loci
D019380:Anti-HIV Agents
G-matrix.; M-matrix; genetic integration; mutation
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