Patterns of epistasis and shapes of fitness landscapes are of wide interest because of their bearings on a number of evolutionary theories. The common phenomena of slowing fitness increases during adaptations and diminishing returns from beneficial mutations are believed to reflect a concave fitness landscape and a preponderance of negative epistasis. Paradoxically, fitness drops tend to decelerate and harm from deleterious mutations shrinks during accumulation of random mutations, patterns thought to indicate a convex fitness landscape and a predominance of positive epistasis. Current theories cannot resolve this apparent contradiction. Here we show that the phenotypic effect of a mutation varies substantially depending on the specific genetic background and that this idiosyncrasy in epistasis creates all of the above trends without requiring a biased distribution of epistasis. The idiosyncratic epistasis theory explains the universalities in mutational effects and evolutionary trajectories as emerging from randomness due to biological complexity.

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Functionally related genes tend to be chromosomally clustered in eukaryotic genomes even after the exclusion of tandem duplicates, but the biological significance of this widespread phenomenon is unclear. We propose that stochastic expression fluctuations of neighboring genes resulting from chromatin dynamics are more or less synchronized such that their expression ratio is more stable than that for unlinked genes. Consequently, chromosomal clustering could be advantageous when the expression ratio of the clustered genes needs to stay constant, for example, because of the accumulation of toxic compounds when this ratio is altered. Evidence from manipulative experiments on the yeast GAL cluster, comprising three chromosomally adjacent genes encoding enzymes catalyzing consecutive reactions in galactose catabolism, unequivocally supports this hypothesis and elucidates how disorder in one biological phenomenon-gene expression noise-could prompt the emergence of order in another-genome organization.

Shenhav and Zeevi conclude in a recent article (Science 370:683-687) that the universal genetic code (UGC) is optimized for resource conservation because mutations are less likely to increase proteomic nitrogen and carbon uses under the UGC than under random genetic codes (RGCs). Their finding results from miscalculating mutational effects and benchmarking against biased RGCs. Our reanalysis refutes their conclusion.

It is debated whether the pervasive intergenic transcription from eukaryotic genomes has functional significance or simply reflects the promiscuity of RNA polymerases. We approach this question by comparing chance promoter activities with the expression levels of intergenic regions in the model eukaryote Saccharomyces cerevisiae. We build a library of over 105 strains, each carrying a 120-nucleotide, chromosomally integrated, completely random sequence driving the potential transcription of a barcode. Quantifying the RNA concentration of each barcode in two environments reveals that 41–63% of random sequences have significant, albeit usually low, promoter activities. Therefore, even in eukaryotes, where the presence of chromatin is thought to repress transcription, chance transcription is prevalent. We find that only 1–5% of yeast intergenic transcriptions are unattributable to chance promoter activities or neighboring gene expressions, and these transcriptions exhibit higher-than-expected environment-specificity. These findings suggest that only a minute fraction of intergenic transcription is functional in yeast.