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Cited by 408

The DOI matches its Crossref record; 68 of the 68 references it cites were found in a registry or an index.

A Comprehensive Biophysical Description of Pairwise Epistasis throughout an Entire Protein Domain

Olson, C. Anders, Wu, Nicholas C., Sun, Ren·2014·Current Biology
DOI 10.1016/j.cub.2014.09.072
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Abstract

SUMMARY Background Non-additivity in fitness effects from two or more mutations, termed epistasis, can result in compensation of deleterious mutations or negation of beneficial mutations. Recent evidence shows the importance of epistasis in individual evolutionary pathways. However, an unresolved question in molecular evolution is how often and how significantly fitness effects change in alternative genetic backgrounds. Results To answer this question we quantified the effects of all single mutations and double mutations between all positions in the IgG-binding domain of protein G (GB1). By observing the first two steps of all possible evolutionary pathways, this fitness profile enabled the characterization of the extent and magnitude of pairwise epistasis throughout an entire protein molecule. Furthermore, we developed a novel approach to quantitatively determine the effects of single mutations on structural stability (ΔΔGU). This enabled determination of the importance of stability effects in functional epistasis. Conclusions Our results illustrate common biophysical mechanisms for occurrences of positive and negative epistasis. Our results show pervasive positive epistasis within a conformationally dynamic network of residues. The stability analysis shows that significant negative epistasis, which is more common than positive epistasis, mostly occurs between combinations of destabilizing mutations. Furthermore, we show that although significant positive epistasis is rare, many deleterious mutations are beneficial in at least one alternative mutational background. The distribution of conditionally beneficial mutations throughout the domain demonstrates that the functional portion of sequence space can be significantly expanded by epistasis.

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Metadata

Authors
Olson, C. A., Wu, N. C., & Sun, R.
Venue
Current Biology
Publisher
Elsevier BV
Published
2014-11
Volume
24
Issue
22
Pages
2643-2651
ISSN
0960-9822
DOI
10.1016/j.cub.2014.09.072
Cited by
408
References
68
Language
en
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