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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Amino Acids / genetics
  • Amino Acids / metabolism
  • Epistasis, Genetic
  • Evolution, Molecular*
  • Fungal Proteins / chemistry
  • Fungal Proteins / genetics*
  • Fungal Proteins / metabolism*
  • Genes, Fungal
  • Genetic Fitness*
  • Genotype
  • Hydro-Lyases / chemistry
  • Hydro-Lyases / genetics
  • Hydro-Lyases / metabolism
  • Models, Genetic
  • Models, Molecular
  • Phylogeny
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / chemistry
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism
  • Yeasts / genetics*
  • Yeasts / metabolism*


  • Amino Acids
  • Fungal Proteins
  • Saccharomyces cerevisiae Proteins
  • Hydro-Lyases
  • HIS3 protein, S cerevisiae