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PLoS Genet. 2019 Apr 10;15(4):e1008079. doi: 10.1371/journal.pgen.1008079. eCollection 2019 Apr.

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

Author information

1
Institute of Science and Technology Austria, Am Campus 1, Klosterneuburg, Austria.
2
Department of Systems Biology, Columbia University, New York, NY, United States of America.
3
Bioinformatics and Genomics Programme, Centre for Genomic Regulation (CRG), 88 Dr. Aiguader, Barcelona, Spain.
4
Universitat Pompeu Fabra (UPF), Barcelona, Spain.
5
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia.
6
Medical Research Council London Institute of Medical Sciences, Imperial College London, London, United Kingdom.
7
Laboratory of Protein Physics, Institute of Protein Research of the Russian Academy of Sciences, Pushchino, Moscow region, Russia.
8
Veltischev Research and Clinical Institute for Pediatrics of the Pirogov Russian National Research Medical University, Moscow, Russia.
9
Center for Quantitative Biology and Peking-Tsinghua Joint Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.

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.

PMID:
30969963
PMCID:
PMC6476524
DOI:
10.1371/journal.pgen.1008079
[Indexed for MEDLINE]
Free PMC Article

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