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Polyploidy is observed across the tree of life, yet its influence on evolution remains incompletely understood (1-4). Polyploidy, usually whole-genome duplication, is proposed to alter the rate of evolutionary adaptation. This could occur through complex effects on the frequency or fitness of beneficial mutations (2, 5-7). For example, in diverse cell types and organisms, immediately after a whole-genome duplication, newly formed polyploids missegregate chromosomes and undergo genetic instability (8-13). The instability following whole-genome duplications is thought to provide adaptive mutations in microorganisms (13, 14) and can promote tumorigenesis in mammalian cells (11, 15). Polyploidy may also affect adaptation independently of beneficial mutations through ploidy-specific changes in cell physiology (16). Here we perform in vitro evolution experiments to test directly whether polyploidy can accelerate evolutionary adaptation. Compared with haploids and diploids, tetraploids undergo significantly faster adaptation. Mathematical modelling suggests that rapid adaptation of tetraploids is driven by higher rates of beneficial mutations with stronger fitness effects, which is supported by whole-genome sequencing and phenotypic analyses of evolved clones. Chromosome aneuploidy, concerted chromosome loss, and point mutations all provide large fitness gains. We identify several mutations whose beneficial effects are manifest specifically in the tetraploid strains. Together, these results provide direct quantitative evidence that in some environments polyploidy can accelerate evolutionary adaptation., To determine how polyploidy affects the rate of adaptation, we performed hundreds of independent passaging experiments in a poor carbonsource medium (raffinose, Fig. 1a), comparing isogenic haploid (1N), diploid (2N), [...]

Work from our laboratory and others has demonstrated that activation of the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) inhibits transformed growth of non-small cell lung cancer (NSCLC) cell lines in vitro and in vivo. We have demonstrated that activation of PPARgamma promotes epithelial differentiation of NSCLC by increasing expression of E-cadherin, as well as inhibiting expression of COX-2 and nuclear factor-kappaB. The Snail family of transcription factors, which includes Snail (Snail1), Slug (Snail2), and ZEB1, is an important regulator of epithelial-mesenchymal transition, as well as cell survival. The goal of this study was to determine whether the biological responses to rosiglitazone, a member of the thiazolidinedione family of PPARgamma activators, are mediated through the regulation of Snail family members. Our results indicate that, in two independent NSCLC cell lines, rosiglitazone specifically decreased expression of Snail, with no significant effect on either Slug or ZEB1. Suppression of Snail using short hairpin RNA silencing mimicked the effects of PPARgamma activation, in inhibiting anchorage-independent growth, promoting acinar formation in three-dimensional culture, and inhibiting invasiveness. This was associated with the increased expression of E-cadherin and decreased expression of COX-2 and matrix metaloproteinases. Conversely, overexpression of Snail blocked the biological responses to rosiglitazone, increasing anchorage-independent growth, invasiveness, and promoting epithelial-mesenchymal transition. The suppression of Snail expression by rosiglitazone seemed to be independent of GSK-3 signaling but was rather mediated through suppression of extracellular signal-regulated kinase activity. These findings suggest that selective regulation of Snail may be critical in mediating the antitumorigenic effects of PPARgamma activators.