Adaptation in protein fitness landscapes is facilitated by indirect paths

Nicholas C. Wu, Lei Dai, C. Anders Olson, James O. Lloyd-Smith, Ren Sun

Research output: Contribution to journalArticlepeer-review


The structure of fitness landscapes is critical for understanding adaptive protein evolution. Previous empirical studies on fitness landscapes were confined to either the neighborhood around the wild type sequence, involving mostly single and double mutants, or a combinatorially complete subgraph involving only two amino acids at each site. In reality, the dimensionality of protein sequence space is higher (20L) and there may be higher-order interactions among more than two sites. Here we experimentally characterized the fitness landscape of four sites in protein GB1, containing 204 = 160,000 variants. We found that while reciprocal sign epistasis blocked many direct paths of adaptation, such evolutionary traps could be circumvented by indirect paths through genotype space involving gain and subsequent loss of mutations. These indirect paths alleviate the constraint on adaptive protein evolution, suggesting that the heretofore neglected dimensions of sequence space may change our views on how proteins evolve.

Original languageEnglish (US)
Article numbere16965
Issue numberJULY
StatePublished - Jul 8 2016
Externally publishedYes

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)


Dive into the research topics of 'Adaptation in protein fitness landscapes is facilitated by indirect paths'. Together they form a unique fingerprint.

Cite this