An experimental assay of the interactions of amino acids from orthologous sequences shaping a complex fitness landscape

Pokusaeva, Victoria O.; Usmanova, Dinara R.; Putintseva, Ekaterina V.; Espinar, Lorena; Sarkisyan, Karen S.; Mishin, Alexander S.; Bogatyreva, Natalya S.; Ivankov, Dmitry N.; Akopyan, Arseniy V.; Avvakumov, Sergey Ya; Povolotskaya, Inna, 1986-; Filion, Guillaume; Carey, Lucas, 1980-; Kondrashov, Fyodor A., 1979-

doi:http://dx.doi.org/10.1371/journal.pgen.1008079

An experimental assay of the interactions of amino acids from orthologous sequences shaping a complex fitness landscape

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Pokusaeva VO, Usmanova DR, Putintseva EV, Espinar L, Sarkisyan KS, Mishin AS et al. An experimental assay of the interactions of amino acids from orthologous sequences shaping a complex fitness landscape. PLoS Genet. 2019;15(4):e1008079. DOI: 10.1371/journal.pgen.1008079

Abstract

Characterizing the fitness landscape, a representation of fitness for a large set of genotypes, is key to understanding how genetic information is interpreted to create functional organisms. Here we determined the evolutionarily-relevant segment of the fitness landscape of His3, a gene coding for an enzyme in the histidine synthesis pathway, focusing on combinations of amino acid states found at orthologous sites of extant species. Just 15% of amino acids found in yeast His3 orthologues were always neutral while the impact on fitness of the remaining 85% depended on the genetic background. Furthermore, at 67% of sites, amino acid replacements were under sign epistasis, having both strongly positive and negative effect in different genetic backgrounds. 46% of sites were under reciprocal sign epistasis. The fitness impact of amino acid replacements was influenced by only a few genetic backgrounds but involved interaction of multiple sites, shaping a rugged fitness landscape in which many of the shortest paths between highly fit genotypes are inaccessible.