Initial Mutations Direct Alternative Pathways of Protein Evolution
Publication Date
March 03, 2011
Journal
PLOS Genetics
Authors
Merijn L. M. Salverda, Eynat Dellus, Florien A. Gorter, Alfons J. M. Debets, et al
Volume
7
Issue
3
Pages
e1001321
DOI
https://dx.plos.org/10.1371/journal.pgen.1001321
Publisher URL
http://journals.plos.org/plosgenetics/article?id=10.1371%2Fjournal.pgen.1001321
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/21408208
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3048372
Europe PMC
http://europepmc.org/abstract/MED/21408208
Web of Science
000288996600003
Scopus
79953738501
Mendeley
http://www.mendeley.com/research/initial-mutations-direct-alternative-pathways-protein-evolution
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Mendeley | Further Information

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CrossRef

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/397163", "https://ndownloader.figshare.com/files/397218", "https://ndownloader.figshare.com/files/397261", "https://ndownloader.figshare.com/files/397285", "https://ndownloader.figshare.com/files/397352", "https://ndownloader.figshare.com/files/397368", "https://ndownloader.figshare.com/files/397397", "https://ndownloader.figshare.com/files/397413", "https://ndownloader.figshare.com/files/397439"], "description"=>"<div><p>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 <em>in vitro</em> 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.</p></div>", "links"=>[], "tags"=>["mutations", "pathways"], "article_id"=>138453, "categories"=>["Evolutionary Biology", "Genetics"], "users"=>["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"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1001321.s001", "https://dx.doi.org/10.1371/journal.pgen.1001321.s002", "https://dx.doi.org/10.1371/journal.pgen.1001321.s003", "https://dx.doi.org/10.1371/journal.pgen.1001321.s004", "https://dx.doi.org/10.1371/journal.pgen.1001321.s005", "https://dx.doi.org/10.1371/journal.pgen.1001321.s006", "https://dx.doi.org/10.1371/journal.pgen.1001321.s007", "https://dx.doi.org/10.1371/journal.pgen.1001321.s008", "https://dx.doi.org/10.1371/journal.pgen.1001321.s009"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Initial_Mutations_Direct_Alternative_Pathways_of_Protein_Evolution/138453", "title"=>"Initial Mutations Direct Alternative Pathways of Protein Evolution", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2011-03-03 02:20:53"}
  • {"files"=>["https://ndownloader.figshare.com/files/793558"], "description"=>"<p>(A) Adaptation of TEM-1 β-lactamase towards improved hydrolysis of cefotaxime. Lines show changes in the average Minimal Inhibitory Concentration (MIC) of cefotaxime for the twelve lines shown in <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1001321#pgen-1001321-g002\" target=\"_blank\">Figure 2</a> (see <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1001321#pgen.1001321.s006\" target=\"_blank\">Table S3</a> for replicate MIC values). Aberrant lines 3 and 4 are indicated with solid lines and open and closed triangles, respectively. (B) Increase in cefotaxime MIC for TEM-1 (bold line, the average of <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1001321#pgen-1001321-g001\" target=\"_blank\">Figure 1A</a>) and mutants R164S (open diamonds, dashed line), A237T (diamonds, dashed line), R164S/G238S (open squares) and A237T/G238S (squares).</p>", "links"=>[], "tags"=>["mic", "tem"], "article_id"=>463924, "categories"=>["Evolutionary Biology", "Genetics"], "users"=>["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"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1001321.g001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cefotaxime_MIC_of_selected_TEM_alleles_/463924", "title"=>"Cefotaxime MIC of selected TEM alleles.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-03-03 01:05:24"}
  • {"files"=>["https://ndownloader.figshare.com/files/793638"], "description"=>"<p>(A) Substitutions are shown as the TEM-1 amino acid according to the IUPAC single-letter code (left), the position in the protein <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1001321#pgen.1001321-Ambler1\" target=\"_blank\">[39]</a> (middle), and the mutant amino acid (right). Substitutions found after the first round (and hence in all subsequent rounds) have no shade, those found after the second round have a light shade and those found after the third round have a dark shade. The three substitutions indicated with an asterisk appeared in the first round, but disappeared again after round 2 (V33I and M155I in line 10) and round 3 (V10I in line 1). Mutation details (including the official nucleotide numbering as in reference <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1001321#pgen.1001321-Sutcliffe1\" target=\"_blank\">[40]</a>) and silent mutations can be found in <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1001321#pgen.1001321.s004\" target=\"_blank\">Table S1</a>. (B) MIC values of the alleles isolated after the different rounds of evolution, as shown in (A). Values shown are the median value across three replicates (see <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1001321#pgen.1001321.s006\" target=\"_blank\">Table S3</a> for replicate measurements). Shading as above.</p>", "links"=>[], "tags"=>["substitutions", "evolved", "tem-1"], "article_id"=>464003, "categories"=>["Evolutionary Biology", "Genetics"], "users"=>["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"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1001321.g002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Amino_acid_substitutions_in_evolved_TEM_1_alleles_/464003", "title"=>"Amino acid substitutions in evolved TEM-1 alleles.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-03-03 01:06:43"}
  • {"files"=>["https://ndownloader.figshare.com/files/793755"], "description"=>"<p>(A) See legend of <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1001321#pgen-1001321-g002\" target=\"_blank\">Figure 2A</a> for details. The substitutions present in the starting alleles and still present at the end of the experiment have been highlighted by a thick-lined box. Note that line 1 of the A237T alleles acquired substitution R164C after the first round of evolution, and substitution C164Y after the third round. (B) See legend of <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1001321#pgen-1001321-g002\" target=\"_blank\">Figure 2B</a> for details.</p>", "links"=>[], "tags"=>["substitutions", "evolved", "tem-mutants", "r164s"], "article_id"=>464117, "categories"=>["Evolutionary Biology", "Genetics"], "users"=>["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"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1001321.g003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Amino_acid_substitutions_in_evolved_TEM_mutants_R164S_and_A237T_/464117", "title"=>"Amino acid substitutions in evolved TEM-mutants R164S and A237T.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-03-03 01:08:37"}
  • {"files"=>["https://ndownloader.figshare.com/files/793881"], "description"=>"<p>(A) See legend of <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1001321#pgen-1001321-g002\" target=\"_blank\">Figure 2A</a> for details. The substitutions present in the starting alleles and still present at the end of the experiment have been highlighted by a thick-lined box. (B) See legend of <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1001321#pgen-1001321-g002\" target=\"_blank\">Figure 2B</a> for details.</p>", "links"=>[], "tags"=>["substitutions", "evolved", "tem", "double-mutant"], "article_id"=>464248, "categories"=>["Evolutionary Biology", "Genetics"], "users"=>["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"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1001321.g004"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Amino_acid_substitutions_in_evolved_TEM_double_mutant_A184V_G238S_/464248", "title"=>"Amino acid substitutions in evolved TEM double-mutant A184V/G238S.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-03-03 01:10:48"}
  • {"files"=>["https://ndownloader.figshare.com/files/793950"], "description"=>"<p>(A) See legend of <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1001321#pgen-1001321-g002\" target=\"_blank\">Figure 2A</a> for details. The substitutions present in the starting alleles and still present at the end of the experiment have been highlighted by a thick-lined box. Note that all R164S substitutions initially present in the five R164S/G238S lines eventually revert, either after the first (lines 2,3,4 and 5) or the third round of evolution (line 1). Line 1 of the A237T/G238S alleles shows a reversion of A237T after the second round of evolution, while the other four A237T/G238S lines do not show any reversion. (B) See legend of <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1001321#pgen-1001321-g002\" target=\"_blank\">Figure 2B</a> for details.</p>", "links"=>[], "tags"=>["substitutions", "evolved", "tem", "double-mutants"], "article_id"=>464317, "categories"=>["Evolutionary Biology", "Genetics"], "users"=>["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"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1001321.g005"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Amino_acid_substitutions_in_evolved_TEM_double_mutants_R164S_G238S_and_A237T_G238S_/464317", "title"=>"Amino acid substitutions in evolved TEM double-mutants R164S/G238S and A237T/G238S.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-03-03 01:11:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/794089"], "description"=>"<p>The kinetic were acquired <i>in vitro</i> with purified proteins. The <i>T<sub>m</sub></i> and <i>m</i> values (indicating the cooperativity of unfolding) were extracted from heat denaturation. N.D.; not determined. Errors shown are standard deviations. Because of the high TEM-1 levels under induction, MIC assays for ampicillin were determined without the addition of IPTG. For additional details see <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1001321#pgen.1001321.s002\" target=\"_blank\">Figures S2</a> and <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1001321#pgen.1001321.s003\" target=\"_blank\">S3</a>.</p>a<p>Median value across three replicates (see <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1001321#pgen.1001321.s006\" target=\"_blank\">Table S3</a> for replicate measurements).</p>b<p>The error ranges for TEM-1 and mutants R164S and R164S/G238S were determined from two independent measurements with two different protein preparations; error ranges for the remaining variant are estimated to be within the same range.</p>", "links"=>[], "tags"=>["kinetic", "parameters", "mutants", "r164s", "mutant"], "article_id"=>464454, "categories"=>["Evolutionary Biology", "Genetics"], "users"=>["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"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1001321.t001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_MIC_values_and_kinetic_and_stability_parameters_of_TEM_1_single_mutants_R164S_and_G238S_and_double_mutant_R164S_G238S_/464454", "title"=>"MIC values and kinetic and stability parameters of TEM-1, single mutants R164S and G238S, and double mutant R164S/G238S.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-03-03 01:14:14"}

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Relative Metric

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