Adaptation of the yeast gene knockout collection is near-perfectly predicted by fitness and diminishing return epistasis.
Karl PerssonSimon StenbergMarkus J TamásJonas WarringerPublished in: G3 (Bethesda, Md.) (2022)
Adaptive evolution of clonally dividing cells and microbes is the ultimate cause of cancer and infectious diseases. The possibility of constraining the adaptation of cell populations, by inhibiting proteins enhancing the evolvability, has therefore attracted interest. However, our current understanding of how genes influence adaptation kinetics is limited, partly because accurately measuring adaptation for many cell populations is challenging. We used a high-throughput adaptive laboratory evolution platform to track the adaptation of >18,000 cell populations corresponding to single-gene deletion strains in the haploid yeast deletion collection. We report that the preadaptation fitness of gene knockouts near-perfectly (R2= 0.91) predicts their adaptation to arsenic, leaving at the most a marginal role for dedicated evolvability gene functions. We tracked the adaptation of another >23,000 gene knockout populations to a diverse range of selection pressures and generalized the almost perfect (R2=0.72-0.98) capacity of preadaptation fitness to predict adaptation. We also reconstructed mutations in FPS1, ASK10, and ARR3, which together account for almost all arsenic adaptation in wild-type cells, in gene deletions covering a broad fitness range and show that the predictability of arsenic adaptation can be understood as a by global epistasis, where excluding arsenic is more beneficial to arsenic unfit cells. The paucity of genes with a meaningful evolvability effect on adaptation diminishes the prospects of developing adjuvant drugs aiming to slow antimicrobial and chemotherapy resistance.
Keyphrases
- genome wide
- genome wide identification
- high throughput
- copy number
- induced apoptosis
- drinking water
- physical activity
- single cell
- body composition
- heavy metals
- cell cycle arrest
- early stage
- stem cells
- wild type
- genome wide analysis
- staphylococcus aureus
- escherichia coli
- radiation therapy
- dna methylation
- gene expression
- cell death
- drug induced
- cell wall
- bone marrow
- embryonic stem cells