Selection for robust metabolism in domesticated yeasts is driven by adaptation to Hsp90 stress.

Protein folding both promotes and constrains adaptive evolution. We uncover this surprising duality in the role of the protein-folding chaperone heat shock protein 90 (Hsp90) in maintaining the integrity of yeast metabolism amid proteotoxic stressors within industrial domestication niches. Ethanol disrupts critical Hsp90-dependent metabolic pathways and exerts strong selective pressure for redundant duplications of key genes within these pathways, yielding the classical genomic signatures of beer and bread domestication. This work demonstrates a mechanism of adaptive canalization in an ecology of major economic importance and highlights Hsp90-dependent variation as an important source of phantom heritability in complex traits.

Genetic determinants underlying the progressive phenotype of ß-lactam/ß-lactamase inhibitor resistance in Escherichia coli.

IMPORTANCE: The increased feasibility of whole-genome sequencing has generated significant interest in using such molecular diagnostic approaches to characterize difficult-to-treat, antimicrobial-resistant (AMR) infections. Nevertheless, there are current limitations in the accurate prediction of AMR phenotypes based on existing AMR gene database approaches, which primarily correlate a phenotype with the presence/absence of a single AMR gene. Our study utilized a large cohort of cephalosporin-susceptible Escherichia coli bacteremia samples to determine how increasing the dosage of narrow-spectrum ß-lactamase-encoding genes in conjunction with other diverse ß-lactam/ß-lactamase inhibitor (BL/BLI) genetic determinants contributes to progressively more severe BL/BLI phenotypes. We were able to characterize the complexity of the genetic mechanisms underlying progressive BL/BLI resistance including the critical role of ß-lactamase encoding gene amplification. For the diverse array of AMR phenotypes with complex mechanisms involving multiple genomic factors, our study provides an example of how composite risk scores may improve understanding of AMR genotype/phenotype correlations.

Ethanol Drives Evolution of Hsp90-Dependent Robustness by Redundancy in Yeast Domestication.

Protein folding promotes and constrains adaptive evolution. We uncover this surprising duality in the role the protein-folding chaperone Hsp90 plays in mediating the interplay between proteome and the genome which acts to maintain the integrity of yeast metabolism in the face of proteotoxic stressors in anthropic niches. Of great industrial relevance, ethanol concentrations generated by fermentation in the making of beer and bread disrupt critical Hsp90-dependent nodes of metabolism and exert strong selective pressure for increased copy number of key genes encoding components of these nodes, yielding the classical genetic signatures of beer and bread domestication. This work establishes a mechanism of adaptive canalization in an ecology of major economic significance and highlights Hsp90-contingent variation as an important source of phantom heritability in complex traits.