Send to

Choose Destination
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

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


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.

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center