ArticleNature communications2020
Bridging non-overlapping reads illuminates high-order epistasis between distal protein sites in a GPCR.
Article in Nature communications, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
4 citing papers in PubMed, 12 citations in OpenAlex.
- Article
- Deep mutational scanning: A versatile tool in systematically mapping genotypes to phenotypes.Frontiers in genetics · 2023Review
- Three-dimensional structure-guided evolution of a ribosome with tethered subunits.Nature chemical biology · 2022Article
- UMI-linked consensus sequencing enables phylogenetic analysis of directed evolution.Nature communications · 2020Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Epistasis emerges when the effects of an amino acid depend on the identities of interacting residues. This phenomenon shapes fitness landscapes, which have the power to reveal evolutionary paths and inform evolution of desired functions. However, there is a need for easily implemented, high-throughput methods to capture epistasis particularly at distal sites. Here, we combine deep mutational scanning (DMS) with a straightforward data processing step to bridge reads in distal sites within genes (BRIDGE). We use BRIDGE, which matches non-overlapping reads to their cognate templates, to uncover prevalent epistasis within the binding pocket of a human G protein-coupled receptor (GPCR) yielding variants with 4-fold greater affinity to a target ligand. The greatest functional improvements in our screen result from distal substitutions and substitutions that are deleterious alone. Our results corroborate findings of mutational tolerance in GPCRs, even in conserved motifs, but reveal inherent constraints restricting tolerated substitutions due to epistasis.
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Registered trials
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