1. Epistasis in RNA Viruses MI615 Andrew J. Pierce Microbiology, Immunology and Molecular Genetics Graduate Center for Toxicology Markey Cancer Center University of Kentucky

2. 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 …say what? metaSTAtic epiSTAtic meTAstasis ePIstasis

3. 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 single- locus 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.

4. Positive Epistasis Genotypic extremes are OVER- represented in a population Why? i)Two beneficial alleles, when combined, are “extra good” (synergism) ii)Two deleterious alleles, when combined, are “not so bad” (antagonism) Negative Epistasis Genotypic extremes are UNDER- represented in a population Why? i)Two beneficial alleles, when combined, are “less good” (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. More fit than expectedLess fit than expected

5. 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.

6. new mutations to be predominantly deleterious epistasis to be negative Most mathematical models trying to explain the evolutionary pressure that selects FOR sexual reproduction require: 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

7. 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. HIV-1 strain fitness vs mutational distance (9466 sequences) (Linear = no epistasis)

8. Epistasis between defined loci in HIV-1 All amino acid pairs Randomized Data pairing Result from (A) Epistasis of the loci with greatest fitness impact 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.

9. Copyright ©2004 by the National Academy of Sciences Sanjuan, Rafael et al. (2004) Proc. Natl. Acad. Sci. USA 101, 15376-15379 Fig. 1. Relationship between observed and expected (multiplicative) fitnesses for 65 VSV genotypes carrying pairs of nucleotide substitutions (Vesicular Stomatits Virus) beneficial deleterious

10. Copyright ©2004 by the National Academy of Sciences Sanjuan, Rafael et al. (2004) Proc. Natl. Acad. Sci. USA 101, 15376-15379 Fig. 2. Distribution of the observed minus expected fitness values (  ij ) (deleterious) excluding synthetic lethals (including decompensatory alleles)