Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

Cryptic genetic variation shapes the adaptive evolutionary potential of enzymes

Baier, Florian ; Hong, Nansook ; Yang, Gloria ; Pabis, Anna ; Miton, Charlotte M ; Barrozo, Alexandre ; Carr, Paul D ; Kamerlin, Shina Cl LU orcid ; Jackson, Colin J and Tokuriki, Nobuhiko (2019) In eLife 8.
Abstract

Genetic variation among orthologous proteins can cause cryptic phenotypic properties that only manifest in changing environments. Such variation may impact the evolvability of proteins, but the underlying molecular basis remains unclear. Here, we performed comparative directed evolution of four orthologous metallo-β-lactamases toward a new function and found that different starting genotypes evolved to distinct evolutionary outcomes. Despite a low initial fitness, one ortholog reached a significantly higher fitness plateau than its counterparts, via increasing catalytic activity. By contrast, the ortholog with the highest initial activity evolved to a less-optimal and phenotypically distinct outcome through changes in expression,... (More)

Genetic variation among orthologous proteins can cause cryptic phenotypic properties that only manifest in changing environments. Such variation may impact the evolvability of proteins, but the underlying molecular basis remains unclear. Here, we performed comparative directed evolution of four orthologous metallo-β-lactamases toward a new function and found that different starting genotypes evolved to distinct evolutionary outcomes. Despite a low initial fitness, one ortholog reached a significantly higher fitness plateau than its counterparts, via increasing catalytic activity. By contrast, the ortholog with the highest initial activity evolved to a less-optimal and phenotypically distinct outcome through changes in expression, oligomerization and activity. We show how cryptic molecular properties and conformational variation of active site residues in the initial genotypes cause epistasis, that could lead to distinct evolutionary outcomes. Our work highlights the importance of understanding the molecular details that connect genetic variation to protein function to improve the prediction of protein evolution.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
keywords
Adaptation, Biological, Directed Molecular Evolution, Evolution, Molecular, Gene Expression, Genetic Variation, Hydrolysis, Protein Conformation, Protein Multimerization, beta-Lactamases/chemistry
in
eLife
volume
8
publisher
eLife Sciences Publications
external identifiers
  • scopus:85061383947
  • pmid:30719972
ISSN
2050-084X
DOI
10.7554/eLife.40789
language
English
LU publication?
no
additional info
© 2019, Baier et al.
id
6b5baca1-43c6-453b-ae01-6039a525c1eb
date added to LUP
2025-01-11 20:28:27
date last changed
2025-06-01 15:08:21
@article{6b5baca1-43c6-453b-ae01-6039a525c1eb,
  abstract     = {{<p>Genetic variation among orthologous proteins can cause cryptic phenotypic properties that only manifest in changing environments. Such variation may impact the evolvability of proteins, but the underlying molecular basis remains unclear. Here, we performed comparative directed evolution of four orthologous metallo-β-lactamases toward a new function and found that different starting genotypes evolved to distinct evolutionary outcomes. Despite a low initial fitness, one ortholog reached a significantly higher fitness plateau than its counterparts, via increasing catalytic activity. By contrast, the ortholog with the highest initial activity evolved to a less-optimal and phenotypically distinct outcome through changes in expression, oligomerization and activity. We show how cryptic molecular properties and conformational variation of active site residues in the initial genotypes cause epistasis, that could lead to distinct evolutionary outcomes. Our work highlights the importance of understanding the molecular details that connect genetic variation to protein function to improve the prediction of protein evolution.</p>}},
  author       = {{Baier, Florian and Hong, Nansook and Yang, Gloria and Pabis, Anna and Miton, Charlotte M and Barrozo, Alexandre and Carr, Paul D and Kamerlin, Shina Cl and Jackson, Colin J and Tokuriki, Nobuhiko}},
  issn         = {{2050-084X}},
  keywords     = {{Adaptation, Biological; Directed Molecular Evolution; Evolution, Molecular; Gene Expression; Genetic Variation; Hydrolysis; Protein Conformation; Protein Multimerization; beta-Lactamases/chemistry}},
  language     = {{eng}},
  month        = {{02}},
  publisher    = {{eLife Sciences Publications}},
  series       = {{eLife}},
  title        = {{Cryptic genetic variation shapes the adaptive evolutionary potential of enzymes}},
  url          = {{http://dx.doi.org/10.7554/eLife.40789}},
  doi          = {{10.7554/eLife.40789}},
  volume       = {{8}},
  year         = {{2019}},
}