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Analysis of prevalence of epistasis on the basis of huge phylogenies Galya Klink, Georgii A Bazykin
MSU, Leninskie Gory, Moscow, 119991, Russian Federation, galkaklink@gmail.com

Epistatic interactions between amino acid sites shape the local fit ness landscapes, affect ing the site-specific probabilit ies o f fixat ions of different amino acids. Comparisons o f prevalences of amino acids at individual sites with sit e-specific dn/ds values suggest that the vast majorit y o f amino acid fixat ions that occur at a given instant would be deleterious at another instant (Breen et al. 2012). However, this analysis can be confounded by the differences in fit ness between differe nt fixed variants (McCandlish et al. 2012). Indeed, a slight ly deleterious allele can remain fixed for a while, inflat ing the number of amino acids observed at a site, but not increasing the dn/ds value significant ly. This effect can be particularly pronounced in huge datasets, in which even rare slight ly deleterious mutations are likely to be observed. The data on instantaneous select ion coefficients associated with allele replacements is implicit in phylogenies. Here, we reconstruct the phylogeny of 8,000 cytochrome B proteins fro m 8,000 metazoan species, and use this data to obtain high-reso lution site-specific distribut ions of survival times of all the amino acids observed at a site. An average amino acid site is occupied by ~10 amino acids at different species, consistent with the previous estimates (Breen et al. 2012). However, the sums of branch lengths occupied by individual amino acids differed greatly, with most of the amino acids occurring only at small near-terminal clades. In other words, the mo lecular clock is strongly overdispersed, consistent with select ion disfavoring rare amino acids; and much of the incongruence between site-specific amino acid prevalences and dn/ds values can be explained without invoking epistasis. Still, the data cannot be fully explained under the assumpt ion of invariant fit ness landscape, and thus so me changes between relat ive site -specific fit nessed of different amino acids, probably associated with epistasis, occur.

1. M.S. Breen et al. (2012) Epistasis as the primary factor in mo lecular evo lut ion, Nature, 490:535-538.


2. D.M.McCandlish et al. (2012) Epistasis not needed to explain low dN/dS, Cornell University Library, arXiv:1212.5239