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Epistasis in RNA Viruses Andrew J. Pierce Microbiology, Immunology and Molecular Genetics Graduate Center for Toxicology Markey Cancer Center University of Kentucky MI615 What is “epistasis”? Main Entry: epis·ta·sis Pronunciation: i-'pis-t&-s&s Function: noun Inflected Form(s): plural epis·ta·ses /-"sEz/ Etymology: New Latin, from Greek, act of stopping, from ephistanai to stop, from epi- + histanai to cause to stand -- more at STAND : suppression of the effect of a gene by a nonallelic gene - ep·i·stat·ic /"e-p&-'sta-tik/ adjective Merriam-Webster online: www.m-w.com metaSTAtic epiSTAtic meTAstasis ePIstasis …say what? What is “epistasis”? (take II) “To improve our understanding of the role of epistasis, it is necessary to differentiate between physiological and statistical genetic definitions of the phenomenon. In physiological genetics, epistasis occurs when the phenotypic differences among individuals with various genotypes at one locus depends on their genotypes at other loci. In statistical genetics, the epistatic (or interaction) deviation is the deviation of multilocus genotypic values from the additive combination of the singlelocus components. Statistical epistasis is a population phenomenon depending on allele frequencies present in a specific population …whereas… physiological epistasis is a genotypic phenomenon, independent of allele frequencies at the loci in question.” Cheverud JM, Routman EJ Epistasis and its contribution to genetic variance components. Genetics. 1995 Mar;139(3):1455-61. More fit than expected Less fit than expected Positive Epistasis Negative Epistasis Genotypic extremes are OVERrepresented in a population Genotypic extremes are UNDERrepresented in a population Why? Why? i) Two beneficial alleles, when combined, are “extra good” (synergism) i) Two beneficial alleles, when combined, are “less good” (antagonism) ii) Two deleterious alleles, when combined, are “not so bad” (antagonism) ii) Two deleterious alleles, when combined, are “even worse” (synergism) In all cases, recombination acts against epistasis, by randomizing the distribution of alleles. Michalakis Y, Roze D. Evolution. Epistasis in RNA viruses. Science. 2004 Nov 26;306(5701):1492-3. Froissart R, Wilke CO, Montville R, Remold SK, Chao L, Turner PE. Co-infection weakens selection against epistatic mutations in RNA viruses. Genetics. 2004 Sep;168(1):9-19. Most mathematical models trying to explain the evolutionary pressure that selects FOR sexual reproduction require: • new mutations to be predominantly deleterious • epistasis to be negative Negative epistasis between deleterious alleles means the deleterious phenotypes interact synergistically to give an extra-large decrease in the reproductive fitness of individuals that carry both alleles Individuals with the lowest fitness are preferentially selected out of the population thereby removing deleterious alleles from the population Since recombination opposes epistatic population distributions, recombination will increase the number of individuals with two deleterious alleles, which will subsequently be removed from the gene pool, thereby increasing the rate at which the deleterious alleles are removed from the population HIV-1 strain fitness vs mutational distance (9466 sequences) (Linear = no epistasis) Bonhoeffer S, Chappey C, Parkin NT, Whitcomb JM, Petropoulos CJ. Evidence for positive epistasis in HIV-1. Science. 2004 Nov 26;306(5701):1547-50. Epistasis between defined loci in HIV-1 All amino acid pairs Epistasis of the loci with greatest fitness impact Randomized Data pairing Result from (A) Bonhoeffer S, Chappey C, Parkin NT, Whitcomb JM, Petropoulos CJ. Evidence for positive epistasis in HIV-1. Science. 2004 Nov 26;306(5701):1547-50. Fig. 1. Relationship between observed and expected (multiplicative) fitnesses for 65 VSV genotypes carrying pairs of nucleotide substitutions beneficial deleterious Sanjuan, Rafael et al. (2004) Proc. Natl. Acad. Sci. USA 101, 15376-15379 (Vesicular Stomatits Virus) Copyright ©2004 by the National Academy of Sciences Fig. 2. Distribution of the observed minus expected fitness values ( ij) (deleterious) excluding synthetic lethals (including decompensatory alleles) Sanjuan, Rafael et al. (2004) Proc. Natl. Acad. Sci. USA 101, 15376-15379 Copyright ©2004 by the National Academy of Sciences