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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

Sequence alignment of WASP and its homologsThe conserved W64 residue is shown in bold. Sequences were obtained from the Ensembl database and aligned with Geneious 6.1.6.
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fig01ev: Sequence alignment of WASP and its homologsThe conserved W64 residue is shown in bold. Sequences were obtained from the Ensembl database and aligned with Geneious 6.1.6.

Mentions: Here, we use an experimental evolution approach to identify a target-oriented network of genetic remedies to a deleterious mutation in a combination of genetic and environmental conditions. We used the budding yeast as a model for the study of the Wiskott–Aldrich syndrome (WAS). WAS is a rare X-linked primary immunodeficiency and blood platelet disorder classically characterized by the triad of recurrent infections, abnormal bleeding caused by a reduced number of platelets, and skin eczema (Albert et al, 2011). The syndrome is caused by mutations in the gene encoding the scaffolding protein WAS (WASP) involved in actin assembly (Thrasher & Burns, 2010). WASP is a functional homolog of Saccharomyces cerevisiae Las17 and it can complement the growth defect of the las17Δ strain when co-expressed with the WAS-interacting protein (WIP), the yeast Vrp1 homolog (Rajmohan et al, 2009). The yeast las17-41 allele encodes a W41R mutation that is homologous to the W64R mutation in the WH1 domain of WASP (FigEV1). This mutation causes classic WAS symptoms (Fillat et al, 2000; Jin et al, 2004). The growth of a yeast strain carrying this allele is completely impaired at 37°C and above, while it is normal at 22°C (FigEV2). The las17-41 allele therefore provides a tractable system to study how this mutation could be corrected genetically or pharmacologically. We experimentally explored the genetic rescue by compensatory mutation to WAS in four different contexts, using two las17-41 strains with different genetic backgrounds, referred to as BY and RM, each on two carbon sources, glucose and galactose, which induce distinct metabolic states in yeast (Fendt & Sauer, 2010). We find that the mutation rate and up to 80% of rescue mutation targets could be constrained by the genetic and/or environmental context. We experimentally exemplify that interactions between these factors, that is, higher-order effects, can have critical consequences on treatment outcome.


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)

Sequence alignment of WASP and its homologsThe conserved W64 residue is shown in bold. Sequences were obtained from the Ensembl database and aligned with Geneious 6.1.6.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig01ev: Sequence alignment of WASP and its homologsThe conserved W64 residue is shown in bold. Sequences were obtained from the Ensembl database and aligned with Geneious 6.1.6.
Mentions: Here, we use an experimental evolution approach to identify a target-oriented network of genetic remedies to a deleterious mutation in a combination of genetic and environmental conditions. We used the budding yeast as a model for the study of the Wiskott–Aldrich syndrome (WAS). WAS is a rare X-linked primary immunodeficiency and blood platelet disorder classically characterized by the triad of recurrent infections, abnormal bleeding caused by a reduced number of platelets, and skin eczema (Albert et al, 2011). The syndrome is caused by mutations in the gene encoding the scaffolding protein WAS (WASP) involved in actin assembly (Thrasher & Burns, 2010). WASP is a functional homolog of Saccharomyces cerevisiae Las17 and it can complement the growth defect of the las17Δ strain when co-expressed with the WAS-interacting protein (WIP), the yeast Vrp1 homolog (Rajmohan et al, 2009). The yeast las17-41 allele encodes a W41R mutation that is homologous to the W64R mutation in the WH1 domain of WASP (FigEV1). This mutation causes classic WAS symptoms (Fillat et al, 2000; Jin et al, 2004). The growth of a yeast strain carrying this allele is completely impaired at 37°C and above, while it is normal at 22°C (FigEV2). The las17-41 allele therefore provides a tractable system to study how this mutation could be corrected genetically or pharmacologically. We experimentally explored the genetic rescue by compensatory mutation to WAS in four different contexts, using two las17-41 strains with different genetic backgrounds, referred to as BY and RM, each on two carbon sources, glucose and galactose, which induce distinct metabolic states in yeast (Fendt & Sauer, 2010). We find that the mutation rate and up to 80% of rescue mutation targets could be constrained by the genetic and/or environmental context. We experimentally exemplify that interactions between these factors, that is, higher-order effects, can have critical consequences on treatment outcome.

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