The structure of fitness landscapes is critical for understanding adaptive protein evolution (e.g. antimicrobial resistance, affinity maturation, etc.). Due to limited throughput in fitness measurements, 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, however, the dimensionality of protein sequence space is higher (20L, L being the length of the relevant sequence) and there may be higher-order interactions among more than two sites. To study how these features impact the course of protein evolution, we experimentally characterized the fitness landscape of four sites in the IgG-binding domain of protein G, containing 204 = 160,000 variants. We found that the fitness landscape was rugged and direct paths of adaptation were often constrained by pairwise epistasis. However, while direct paths were blocked by reciprocal sign epistasis, we found systematic evidence that such evolutionary traps could be circumvented by "extra-dimensional bypass". Extra dimensions in sequence space - with a different amino acid at the site of interest or an additional interacting site - open up indirect paths of adaptation via gain and subsequent loss of mutations. These indirect paths alleviate the constraint on reaching high fitness genotypes via selectively accessible trajectories, suggesting that the heretofore neglected dimensions of sequence space may completely change our views on how proteins evolve.
- Downloaded 578 times
- Download rankings, all-time:
- Site-wide: 38,512
- In evolutionary biology: 2,091
- Year to date:
- Site-wide: 45,690
- Since beginning of last month:
- Site-wide: 49,396
Downloads over time
Distribution of downloads per paper, site-wide
- 27 Nov 2020: The website and API now include results pulled from medRxiv as well as bioRxiv.
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!