Initial mutations direct alternative pathways of protein evolution.
Whether evolution is erratic due to random historical details, or is repeatedly directed along similar paths by certain constraints, remains unclear. Epistasis (i.e. non-additive interaction between mutations that affect fitness) is a mechanism that can contribute to both scenarios. Epistasis can co...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2011-03-01
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| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC3048372?pdf=render |
| _version_ | 1819028795682717696 |
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| author | Merijn L M Salverda Eynat Dellus Florien A Gorter Alfons J M Debets John van der Oost Rolf F Hoekstra Dan S Tawfik J Arjan G M de Visser |
| author_facet | Merijn L M Salverda Eynat Dellus Florien A Gorter Alfons J M Debets John van der Oost Rolf F Hoekstra Dan S Tawfik J Arjan G M de Visser |
| author_sort | Merijn L M Salverda |
| collection | DOAJ |
| description | Whether evolution is erratic due to random historical details, or is repeatedly directed along similar paths by certain constraints, remains unclear. Epistasis (i.e. non-additive interaction between mutations that affect fitness) is a mechanism that can contribute to both scenarios. Epistasis can constrain the type and order of selected mutations, but it can also make adaptive trajectories contingent upon the first random substitution. This effect is particularly strong under sign epistasis, when the sign of the fitness effects of a mutation depends on its genetic background. In the current study, we examine how epistatic interactions between mutations determine alternative evolutionary pathways, using in vitro evolution of the antibiotic resistance enzyme TEM-1 β-lactamase. First, we describe the diversity of adaptive pathways among replicate lines during evolution for resistance to a novel antibiotic (cefotaxime). Consistent with the prediction of epistatic constraints, most lines increased resistance by acquiring three mutations in a fixed order. However, a few lines deviated from this pattern. Next, to test whether negative interactions between alternative initial substitutions drive this divergence, alleles containing initial substitutions from the deviating lines were evolved under identical conditions. Indeed, these alternative initial substitutions consistently led to lower adaptive peaks, involving more and other substitutions than those observed in the common pathway. We found that a combination of decreased enzymatic activity and lower folding cooperativity underlies negative sign epistasis in the clash between key mutations in the common and deviating lines (Gly238Ser and Arg164Ser, respectively). Our results demonstrate that epistasis contributes to contingency in protein evolution by amplifying the selective consequences of random mutations. |
| first_indexed | 2024-12-21T06:04:03Z |
| format | Article |
| id | doaj.art-e2cd3e44fe91411386f2e17617d67350 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-12-21T06:04:03Z |
| publishDate | 2011-03-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-e2cd3e44fe91411386f2e17617d673502022-12-21T19:13:42ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042011-03-0173e100132110.1371/journal.pgen.1001321Initial mutations direct alternative pathways of protein evolution.Merijn L M SalverdaEynat DellusFlorien A GorterAlfons J M DebetsJohn van der OostRolf F HoekstraDan S TawfikJ Arjan G M de VisserWhether evolution is erratic due to random historical details, or is repeatedly directed along similar paths by certain constraints, remains unclear. Epistasis (i.e. non-additive interaction between mutations that affect fitness) is a mechanism that can contribute to both scenarios. Epistasis can constrain the type and order of selected mutations, but it can also make adaptive trajectories contingent upon the first random substitution. This effect is particularly strong under sign epistasis, when the sign of the fitness effects of a mutation depends on its genetic background. In the current study, we examine how epistatic interactions between mutations determine alternative evolutionary pathways, using in vitro evolution of the antibiotic resistance enzyme TEM-1 β-lactamase. First, we describe the diversity of adaptive pathways among replicate lines during evolution for resistance to a novel antibiotic (cefotaxime). Consistent with the prediction of epistatic constraints, most lines increased resistance by acquiring three mutations in a fixed order. However, a few lines deviated from this pattern. Next, to test whether negative interactions between alternative initial substitutions drive this divergence, alleles containing initial substitutions from the deviating lines were evolved under identical conditions. Indeed, these alternative initial substitutions consistently led to lower adaptive peaks, involving more and other substitutions than those observed in the common pathway. We found that a combination of decreased enzymatic activity and lower folding cooperativity underlies negative sign epistasis in the clash between key mutations in the common and deviating lines (Gly238Ser and Arg164Ser, respectively). Our results demonstrate that epistasis contributes to contingency in protein evolution by amplifying the selective consequences of random mutations.http://europepmc.org/articles/PMC3048372?pdf=render |
| spellingShingle | Merijn L M Salverda Eynat Dellus Florien A Gorter Alfons J M Debets John van der Oost Rolf F Hoekstra Dan S Tawfik J Arjan G M de Visser Initial mutations direct alternative pathways of protein evolution. PLoS Genetics |
| title | Initial mutations direct alternative pathways of protein evolution. |
| title_full | Initial mutations direct alternative pathways of protein evolution. |
| title_fullStr | Initial mutations direct alternative pathways of protein evolution. |
| title_full_unstemmed | Initial mutations direct alternative pathways of protein evolution. |
| title_short | Initial mutations direct alternative pathways of protein evolution. |
| title_sort | initial mutations direct alternative pathways of protein evolution |
| url | http://europepmc.org/articles/PMC3048372?pdf=render |
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