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Evolutionary rescue by compensatory mutations is constrained by genomic and environmental backgrounds.

Filteau M, Hamel V, Pouliot MC, Gagnon-Arsenault I, Dubé AK, Landry CR - Mol. Syst. Biol. (2015)

Bottom Line: We found that multiple aspects of the evolutionary rescue outcome depend on the genotype, the environment, or a combination thereof.The course of compensatory evolution is therefore highly contingent on the initial conditions in which the deleterious mutation occurs.Our results experimentally illustrate the importance of epistasis and environmental evolutionary constraints that shape the adaptive landscape and evolutionary rate of molecular networks.

View Article: PubMed Central - PubMed

Affiliation: Département de Biologie, PROTEO and Institut de Biologie Intégrative et des Systèmes (IBIS) Université Laval, Québec, Qc, Canada.

No MeSH data available.


Related in: MedlinePlus

Network of protein-coding rescue genesEmpty circles regroup targets that were found in a particular context. Nodes are colored by their function and edges represent protein–protein interactions reported in Biogrid 3.3.122 (Chatr-Aryamontri et al, 2015). Protein-coding compensatory genes are strongly associated with Las17 at the network level as they show 15-fold enrichment in protein–protein interactions among themselves (Fisher's exact test, P-value < 1e-16). Ten of these proteins physically interact with Las17, a significant enrichment (Fisher's exact test, P-value = 3e-14), suggesting that interacting proteins are prime candidates for rescue mutations. Interestingly, in case where an interaction interface with Las17 has been identified, the mutations found do not coincide with the interacting residues (Chereau et al, 2005; Ti et al, 2011), suggesting more complex compensatory mechanisms than direct physical interactions with the altered interface of Las17. These interactors also have a smaller shortest path to one another than expected by randomly sampling the Las17 interactome (left-sided P-value = 0.03), showing that this subset is intimately connected to the essential function of LAS17. In agreement with this observation, these 13 genes are enriched in GO terms related to Las17 functions, for example, actin filament polymerization (GO:0030041, Holm–Bonferroni corrected P-value = 3e-14).
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fig03: Network of protein-coding rescue genesEmpty circles regroup targets that were found in a particular context. Nodes are colored by their function and edges represent protein–protein interactions reported in Biogrid 3.3.122 (Chatr-Aryamontri et al, 2015). Protein-coding compensatory genes are strongly associated with Las17 at the network level as they show 15-fold enrichment in protein–protein interactions among themselves (Fisher's exact test, P-value < 1e-16). Ten of these proteins physically interact with Las17, a significant enrichment (Fisher's exact test, P-value = 3e-14), suggesting that interacting proteins are prime candidates for rescue mutations. Interestingly, in case where an interaction interface with Las17 has been identified, the mutations found do not coincide with the interacting residues (Chereau et al, 2005; Ti et al, 2011), suggesting more complex compensatory mechanisms than direct physical interactions with the altered interface of Las17. These interactors also have a smaller shortest path to one another than expected by randomly sampling the Las17 interactome (left-sided P-value = 0.03), showing that this subset is intimately connected to the essential function of LAS17. In agreement with this observation, these 13 genes are enriched in GO terms related to Las17 functions, for example, actin filament polymerization (GO:0030041, Holm–Bonferroni corrected P-value = 3e-14).

Mentions: Aside from suppressor mutations and reversions, we identified compensatory mutations in 13 protein-coding genes that belong to major functional modules: the actin filament and actin cortical patch, the ARP2/3 complex, and the Ca2+/calmodulin signaling pathway, the latter two being found in specific contexts (Fig3). We find that the context has a significant effect on the functional targets recovered (nominal logistic model, df = 9, P-value = 7e-6). To investigate the specificity of the identified compensatory mutations, selected alleles were cloned on a low copy number plasmid and transformed into the thermosensitive strains. Growth of transformed colonies at 37°C would confirm that the compensatory mechanism consists in a dominant gain of function. This was the case for most alleles tested, but the effect of each individual mutation was variable among contexts, sometimes even within the same gene (Fig4A). For example, on glucose, a clear gain of function could be observed for only one cap1 allele in RM, where it was recovered, but no clear gain of function was observed in BY. In line with their context-specific recovery, alleles of genes in the ARP2/3 complex were consistently compensatory only in the RM background on galactose. This again supports that compensatory rescue depends on higher-order interactions and also suggests that mutations involving the same gene may not compensate via the same mechanism, that is, gain of function at the protein sequence level or gene dosage. The actin gene is a prime example supporting this conclusion, as increasing gene dosage of actin with a wild-type allele was able to compensate las17-41 thermosensitivity specifically in the RM background on glucose, whereas some point mutations in actin were compensatory in all contexts (Fig4A and B). Thus, the increased gene dosage of actin may be the compensatory mechanism explaining the high frequency of ChrVI trisomia. This result parallels the report that the loss of function of the WIP homolog Vrp1 can be suppressed by increased amounts of monomeric actin, but not filamentous actin (Haarer et al, 2013). In humans, the WH1 domain where the W41R mutation lies interacts with WIP, and loss of WASP–WIP complex activity has been hypothesized to be causal to the disease (Rajmohan et al, 2009). However, we did not encounter compensatory mutations in VRP1, suggesting that the interaction could either not be restored in a single step or may not contribute to Las17 essential function at restrictive temperature.


Evolutionary rescue by compensatory mutations is constrained by genomic and environmental backgrounds.

Filteau M, Hamel V, Pouliot MC, Gagnon-Arsenault I, Dubé AK, Landry CR - Mol. Syst. Biol. (2015)

Network of protein-coding rescue genesEmpty circles regroup targets that were found in a particular context. Nodes are colored by their function and edges represent protein–protein interactions reported in Biogrid 3.3.122 (Chatr-Aryamontri et al, 2015). Protein-coding compensatory genes are strongly associated with Las17 at the network level as they show 15-fold enrichment in protein–protein interactions among themselves (Fisher's exact test, P-value < 1e-16). Ten of these proteins physically interact with Las17, a significant enrichment (Fisher's exact test, P-value = 3e-14), suggesting that interacting proteins are prime candidates for rescue mutations. Interestingly, in case where an interaction interface with Las17 has been identified, the mutations found do not coincide with the interacting residues (Chereau et al, 2005; Ti et al, 2011), suggesting more complex compensatory mechanisms than direct physical interactions with the altered interface of Las17. These interactors also have a smaller shortest path to one another than expected by randomly sampling the Las17 interactome (left-sided P-value = 0.03), showing that this subset is intimately connected to the essential function of LAS17. In agreement with this observation, these 13 genes are enriched in GO terms related to Las17 functions, for example, actin filament polymerization (GO:0030041, Holm–Bonferroni corrected P-value = 3e-14).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4631203&req=5

fig03: Network of protein-coding rescue genesEmpty circles regroup targets that were found in a particular context. Nodes are colored by their function and edges represent protein–protein interactions reported in Biogrid 3.3.122 (Chatr-Aryamontri et al, 2015). Protein-coding compensatory genes are strongly associated with Las17 at the network level as they show 15-fold enrichment in protein–protein interactions among themselves (Fisher's exact test, P-value < 1e-16). Ten of these proteins physically interact with Las17, a significant enrichment (Fisher's exact test, P-value = 3e-14), suggesting that interacting proteins are prime candidates for rescue mutations. Interestingly, in case where an interaction interface with Las17 has been identified, the mutations found do not coincide with the interacting residues (Chereau et al, 2005; Ti et al, 2011), suggesting more complex compensatory mechanisms than direct physical interactions with the altered interface of Las17. These interactors also have a smaller shortest path to one another than expected by randomly sampling the Las17 interactome (left-sided P-value = 0.03), showing that this subset is intimately connected to the essential function of LAS17. In agreement with this observation, these 13 genes are enriched in GO terms related to Las17 functions, for example, actin filament polymerization (GO:0030041, Holm–Bonferroni corrected P-value = 3e-14).
Mentions: Aside from suppressor mutations and reversions, we identified compensatory mutations in 13 protein-coding genes that belong to major functional modules: the actin filament and actin cortical patch, the ARP2/3 complex, and the Ca2+/calmodulin signaling pathway, the latter two being found in specific contexts (Fig3). We find that the context has a significant effect on the functional targets recovered (nominal logistic model, df = 9, P-value = 7e-6). To investigate the specificity of the identified compensatory mutations, selected alleles were cloned on a low copy number plasmid and transformed into the thermosensitive strains. Growth of transformed colonies at 37°C would confirm that the compensatory mechanism consists in a dominant gain of function. This was the case for most alleles tested, but the effect of each individual mutation was variable among contexts, sometimes even within the same gene (Fig4A). For example, on glucose, a clear gain of function could be observed for only one cap1 allele in RM, where it was recovered, but no clear gain of function was observed in BY. In line with their context-specific recovery, alleles of genes in the ARP2/3 complex were consistently compensatory only in the RM background on galactose. This again supports that compensatory rescue depends on higher-order interactions and also suggests that mutations involving the same gene may not compensate via the same mechanism, that is, gain of function at the protein sequence level or gene dosage. The actin gene is a prime example supporting this conclusion, as increasing gene dosage of actin with a wild-type allele was able to compensate las17-41 thermosensitivity specifically in the RM background on glucose, whereas some point mutations in actin were compensatory in all contexts (Fig4A and B). Thus, the increased gene dosage of actin may be the compensatory mechanism explaining the high frequency of ChrVI trisomia. This result parallels the report that the loss of function of the WIP homolog Vrp1 can be suppressed by increased amounts of monomeric actin, but not filamentous actin (Haarer et al, 2013). In humans, the WH1 domain where the W41R mutation lies interacts with WIP, and loss of WASP–WIP complex activity has been hypothesized to be causal to the disease (Rajmohan et al, 2009). However, we did not encounter compensatory mutations in VRP1, suggesting that the interaction could either not be restored in a single step or may not contribute to Las17 essential function at restrictive temperature.

Bottom Line: We found that multiple aspects of the evolutionary rescue outcome depend on the genotype, the environment, or a combination thereof.The course of compensatory evolution is therefore highly contingent on the initial conditions in which the deleterious mutation occurs.Our results experimentally illustrate the importance of epistasis and environmental evolutionary constraints that shape the adaptive landscape and evolutionary rate of molecular networks.

View Article: PubMed Central - PubMed

Affiliation: Département de Biologie, PROTEO and Institut de Biologie Intégrative et des Systèmes (IBIS) Université Laval, Québec, Qc, Canada.

No MeSH data available.


Related in: MedlinePlus