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Evidence for Positive Epistasis in HIV-1 Sebastian Bonhoeffer, Colombe Chappe, Neil T. Parkin, Jeanette M. Whitcomb, Christos J. Petropoulos Evolutionary basis for sexual reproduction and recombination • Population theories based on effects of fitness interactions between alternate allelles at different loci to control a single phenotype (epistasis) • In a two-locus, two-allele model, it is defined as: E = wab + wAB – waB – wAb where a/A and b/B are the alternative alleles at the two loci and w** is the log fitness of the corresponding genotype • Measures deviations from multiplicativity of the fitness effect caused by individual mutations Positive and negative epistasis Synergistic beneficial mutations; antagonistic deleterious mutations Antagonistic beneficial mutations; synergistic deleterious mutations Michalakis and Roze, Science 306: 1492-1493, 2004 Evolutionary basis for sexual reproduction and recombination •In negative epistasis, beneficial mutations interact antagonistically (increase fitness less than multiplicatively) and detrimental mutations act synergistically (decrease fitness more than multiplicatively) • Increases efficiency in selection •Appeal of negative epistasis is that recombination can efficiently eliminate deleterious mutations, thus providing a strong selective advantage • No clear evidence for an overall predominance of positive or negative epistasis due to inherent difficulties Why use HIV-1 as a model organism to study epistasis • Reproductive cycle is a primitive form of sexual reproduction • Retroviruses pack two full-length copies of the RNA genome • After infection, RT engages one copy and converts it to DNA • RT carrying nascent DNA may disengage from the first template and switch over to the next • If the RNA genomes are heterozygous, this may lead to a recombinant proviral DNA • Common occurrence when host cells are infected by distinct proviruses • RT switches RNA templates approximately 10 times per replication (about 1 recombination event for 1000 NBP) HIV-1 as a model organism to study epistasis • 9466 virus samples from HIV-1 patients • Only PR and most of RT inserted into a HIV-1 clone that can undergo only one round of replication • Fitness assay quantifies the total production of infectious progeny virus, and measured in absence of drug, relative to ability of the clone HIV-1 as a model organism to study epistasis • Plot log fitness as a function of the number of mutations • Less than linear decrease suggests positive epistasis • Could be due to bias in data set against sequences with low fitness HIV-1 as a model organism to study epistasis • Measure fitness interactions between pairs of alternative amino acids (“alleles”) at different positions (“loci”) where all four possible combinations are observed (103,826 pairs) •Average log fitness values used to calculate E • Mean of distribution is 0.052; different from random; mean for those that significantly affect fitness is 0.109 What’s going on here • Most isolates are lower in fitness than the clone, suggesting antagonism between deleterious mutations (positive epistasis) • Not consistent with current genetic theories of sexual reproduction and recombination • May not be extrapolatable to higher eukaryotes • Might be a mechanism to repair single stranded breaks in the RNA genome that is susceptible to degradation What’s going on here – a structural perspective • Analysis done on two enzymes; positive epistasis makes sense for isolates that have high fitness from a protein structure stability perspective • Complementary beneficial mutations that increase stability more than multiplicatively, like two near oppositely charged residues on the surface replacing polar ones • Strong evidence for positive epistasis of beneficial mutations: What’s going on here – a structural perspective • Positive epistasis makes less sense for isolates that have a low fitness from a protein structure stability perspective, but still possible • Deleterious mutations that decrease stability due to environment compensate each other •Strong evidence for positive epistasis of deleterious mutations: