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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: Specifically, the compensatory mutation rate and type, the molecular rescue mechanism, the genetic target, and the associated fitness cost varied across contexts.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

Compensation by loss of functionSpot dilution assay shown after 3 days of growth on SC glucose or galactose media for whole gene deletions of genes identified by genome sequencing in the thermosensitive strains. The results confirm that the loss of function of certain genes can counterweight las17-41 thermosensitivity, in a context-specific manner. The case of twf1Δ in particular is restricted to the RM genetic background as previously observed among the sequenced mutants. The deletion of bsp1 follows the same pattern, but spontaneous mutants can be observed in the BY background on glucose. It is noteworthy that the only BY bsp1 mutant recovered in the experiment was also diploid; hence, bsp1 mutations may be compensatory in this background on glucose only in combination with another mutational event.
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fig04ev: Compensation by loss of functionSpot dilution assay shown after 3 days of growth on SC glucose or galactose media for whole gene deletions of genes identified by genome sequencing in the thermosensitive strains. The results confirm that the loss of function of certain genes can counterweight las17-41 thermosensitivity, in a context-specific manner. The case of twf1Δ in particular is restricted to the RM genetic background as previously observed among the sequenced mutants. The deletion of bsp1 follows the same pattern, but spontaneous mutants can be observed in the BY background on glucose. It is noteworthy that the only BY bsp1 mutant recovered in the experiment was also diploid; hence, bsp1 mutations may be compensatory in this background on glucose only in combination with another mutational event.

Mentions: Apart from BSP1, all yeast compensatory genes have at least one human homolog (RIDDLE, FDR = 0.007), expanding the associated WAS disease pathway and illustrating the power of such experiments in identifying functionally related proteins (Fig5). Eight of the genes are likely affected by a partial or complete loss of gene function (deletion, TE insertion, frame shift, or stop codon). We investigated complete loss-of-function specificity by gene deletion in the progenitor strain and confirmed that three deletions (cnb1Δ, bsp1Δ, and twf1Δ) rescued growth of the las17-41 strain at 37°C, each in a context-specific manner (Fig EV4). Genes whose absence confers some benefit could be attractive drug targets (Kaiser, 2014). For example, the mutations affecting the calcineurin regulatory subunit CNB1 suggest that calcineurin inhibition compensates the las17-41 phenotype in the BY background. WAS and calcineurin are both involved in controlling TCR-mediated T-cell function, but since they are depicted as acting in parallel paths (Baniyash, 2004), their interconnection remains to be explored. Calcineurin function can be inhibited using cyclosporin A, an immunosuppressive drug (Singh-Babak et al, 2012). We found that cyclosporin A allows growth of BY las17-41 at 37°C on glucose (Figs6 and EV5) which mirrors the las17-41 cnb1Δ phenotypes (FigEV4) and the quantitative results obtained for cnb1 rescue mutants (Fig1C). Thus, the genetic background and metabolic state may influence the effect of a potential drug. Therefore, taking these factors into account when conducting screens to identify therapeutic targets may increase their success rate.


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)

Compensation by loss of functionSpot dilution assay shown after 3 days of growth on SC glucose or galactose media for whole gene deletions of genes identified by genome sequencing in the thermosensitive strains. The results confirm that the loss of function of certain genes can counterweight las17-41 thermosensitivity, in a context-specific manner. The case of twf1Δ in particular is restricted to the RM genetic background as previously observed among the sequenced mutants. The deletion of bsp1 follows the same pattern, but spontaneous mutants can be observed in the BY background on glucose. It is noteworthy that the only BY bsp1 mutant recovered in the experiment was also diploid; hence, bsp1 mutations may be compensatory in this background on glucose only in combination with another mutational event.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig04ev: Compensation by loss of functionSpot dilution assay shown after 3 days of growth on SC glucose or galactose media for whole gene deletions of genes identified by genome sequencing in the thermosensitive strains. The results confirm that the loss of function of certain genes can counterweight las17-41 thermosensitivity, in a context-specific manner. The case of twf1Δ in particular is restricted to the RM genetic background as previously observed among the sequenced mutants. The deletion of bsp1 follows the same pattern, but spontaneous mutants can be observed in the BY background on glucose. It is noteworthy that the only BY bsp1 mutant recovered in the experiment was also diploid; hence, bsp1 mutations may be compensatory in this background on glucose only in combination with another mutational event.
Mentions: Apart from BSP1, all yeast compensatory genes have at least one human homolog (RIDDLE, FDR = 0.007), expanding the associated WAS disease pathway and illustrating the power of such experiments in identifying functionally related proteins (Fig5). Eight of the genes are likely affected by a partial or complete loss of gene function (deletion, TE insertion, frame shift, or stop codon). We investigated complete loss-of-function specificity by gene deletion in the progenitor strain and confirmed that three deletions (cnb1Δ, bsp1Δ, and twf1Δ) rescued growth of the las17-41 strain at 37°C, each in a context-specific manner (Fig EV4). Genes whose absence confers some benefit could be attractive drug targets (Kaiser, 2014). For example, the mutations affecting the calcineurin regulatory subunit CNB1 suggest that calcineurin inhibition compensates the las17-41 phenotype in the BY background. WAS and calcineurin are both involved in controlling TCR-mediated T-cell function, but since they are depicted as acting in parallel paths (Baniyash, 2004), their interconnection remains to be explored. Calcineurin function can be inhibited using cyclosporin A, an immunosuppressive drug (Singh-Babak et al, 2012). We found that cyclosporin A allows growth of BY las17-41 at 37°C on glucose (Figs6 and EV5) which mirrors the las17-41 cnb1Δ phenotypes (FigEV4) and the quantitative results obtained for cnb1 rescue mutants (Fig1C). Thus, the genetic background and metabolic state may influence the effect of a potential drug. Therefore, taking these factors into account when conducting screens to identify therapeutic targets may increase their success rate.

Bottom Line: Specifically, the compensatory mutation rate and type, the molecular rescue mechanism, the genetic target, and the associated fitness cost varied across contexts.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