An experimental assay of the interactions of amino acids from orthologous sequences shaping a complex fitness landscape
By Victoria O. Pokusaeva, D. R. Usmanova, E. Putintseva, L. Espinar, K. Sarkisyan, A. Mishin, N. S. Bogatyreva, Dmitry N. Ivankov, A. Akopyan, Sergey Ya. Avvakumov and 4 more. 2019
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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.
Subfields: Ecology, Evolution, Behavior and Systematics, Genetics, Sociology and Political Science
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Citations in the corpus
- Guided Generative Protein Design using Regularized Transformers (2022, background): “…themselves are likely insufficient: past work has shown that protein function is governed by higher-order interactions between residues Russ et al. [2020] (i.e., epistasis) such that the collective effects of mutations can be non-additivand as a result, difficult to predict Pokusaeva et al. [2019].”
- Epistasis and Adaptation on Fitness Landscapes (2022, background): “Pokusaeva et al. (2019) measured competitive fitness resulting in 12 fitness landscapes in S. cerevisiae spanning a total of >4 million genotypes, including the majority of extant amino-acid substitutions of the his3 protein across 21 yeast species.”