title: Adaptation in protein fitness landscapes is facilitated by indirect paths.
abstract: 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 (20(L)) 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 20(4) = 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.
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, United States.|Molecular Biology Institute, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Nicholas C
authors.identifier: 0000-0002-9078-6697
authors.initials: NC
authors.lastname: Wu
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, United States.|Department of Ecology and Evolutionary Biology, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Lei
authors.initials: L
authors.lastname: Dai
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, United States.
authors.forename: C Anders
authors.initials: CA
authors.lastname: Olson
authors.affiliation: Department of Ecology and Evolutionary Biology, University of California, Los Angeles, Los Angeles, United States.
authors.forename: James O
authors.identifier: 0000-0001-7941-502X
authors.initials: JO
authors.lastname: Lloyd-Smith
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, United States.|Molecular Biology Institute, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Ren
authors.initials: R
authors.lastname: Sun
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism*; D019143:Evolution, Molecular; D009154:Mutation
chemical_list: D001426:Bacterial Proteins; C034284:IgG Fc-binding protein, Streptococcus
keywords: adaptive evolution; deep sequencing; epistasis; evolutionary biology; fitness landscape; genomics; none; saturation mutagenesis