Someone did the Yona et al 2018 experiment, but with a eukaryote!

The article Yona et al. 2018 (Random sequences rapidly evolve into de novo promoters) has come up here before, because it shows that random DNA sequences easily and quickly can evolve into functional promoters in bacteria.

It has been an open question how prevalent expression from random DNA sequences would be when integrated in eukaryotic chromosomes, that typically are wrapped up tightly into chromatin complexes.

A similar experiment has now been done on yeast, a eukaryotic organism, and remarkably the numbers that a random sequences can function as a promoter are surprisingly close to those in prokaryotes:

Xu, H., Li, C., Xu, C. et al. Chance promoter activities illuminate the origins of eukaryotic intergenic transcriptions. Nat Commun 14 , 1826 (2023). Chance promoter activities illuminate the origins of eukaryotic intergenic transcriptions | Nature Communications


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.

Somewhere around 40-60% of random sequences can function as active promoters, however they are on average considerably weaker promoters than in prokaryotes(to me implying that the expectation is that random promoters in yeast would have to mutate to become stronger promoters):


In summary, we found that 41–63% of 120-nucleotide random sequences have significant promoter activities in S. cerevisiae, demonstrating the easiness for a random sequence to be transcribed by chance even in eukaryotes. However, the probability is ~0.025% for a random promoter to be significantly stronger than the median promoter activity of yeast native genes, contrasting the observation in E. coli where 2.5% of random promoters are as strong as the induced lac promoter19,40, which ranks in the top 3% of all E. coli native promoters in strength. This disparity could be due to the chromatin structure in eukaryotes21 and/or the lack of consensus sequence in yeast that is analogous to the short motifs bound by the canonical σ70-RNAP in E. coli 40. Indeed, although random promoters with TATA boxes tend to be stronger than those lacking TATA boxes, a sizable fraction of the former (22.8% in YPD and 39.4% in SCD) do not have detectable activities (Fig. S21).


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Of course one should ask what the ENCODE folks will think of this.