Natural proteome diversity links aneuploidy tolerance to protein turnover.

Accessing the natural genetic diversity of species unveils hidden genetic traits, clarifies gene functions and allows the generalizability of laboratory findings to be assessed. One notable discovery made in natural isolates of Saccharomyces cerevisiae is that aneuploidy-an imbalance in chromosome copy numbers-is frequent1,2 (around 20%), which seems to contradict the substantial fitness costs and transient nature of aneuploidy when it is engineered in the laboratory3-5. Here we generate a proteomic resource and merge it with genomic1 and transcriptomic6 data for 796 euploid and aneuploid natural isolates. We find that natural and lab-generated aneuploids differ specifically at the proteome. In lab-generated aneuploids, some proteins-especially subunits of protein complexes-show reduced expression, but the overall protein levels correspond to the aneuploid gene dosage. By contrast, in natural isolates, more than 70% of proteins encoded on aneuploid chromosomes are dosage compensated, and average protein levels are shifted towards the euploid state chromosome-wide. At the molecular level, we detect an induction of structural components of the proteasome, increased levels of ubiquitination, and reveal an interdependency of protein turnover rates and attenuation. Our study thus highlights the role of protein turnover in mediating aneuploidy tolerance, and shows the utility of exploiting the natural diversity of species to attain generalizable molecular insights into complex biological processes.

The pseudoentropy of allele frequency trajectories, the persistence of variation, and the effective population size.

To concisely describe how genetic variation, at individual loci or across whole genomes, changes over time, and to follow transitory allelic changes, we introduce a quantity related to entropy, that we term pseudoentropy. This quantity emerges in a diffusion analysis of the mean time a mutation segregates in a population. For a neutral locus with an arbitrary number of alleles, the mean time of segregation is generally proportional to the pseudoentropy of initial allele frequencies. After the initial time point, pseudoentropy generally decreases, but other behaviours are possible, depending on the genetic diversity and selective forces present. For a biallelic locus, pseudoentropy and entropy coincide, but they are distinct quantities with more than two alleles. Thus for populations with multiple biallelic loci, the language of entropy suffices. Then entropy, combined across loci, serves as a concise description of genetic variation. We used individual based simulations to explore how this entropy behaves under different evolutionary scenarios. In agreement with predictions, the entropy associated with unlinked neutral loci decreases over time. However, deviations from free recombination and neutrality have clear and informative effects on the entropy's behaviour over time. Analysis of publicly available data of a natural D. melanogaster population, that had been sampled over seven years, using a sliding-window approach, yielded considerable variation in entropy trajectories of different genomic regions. These mostly follow a pattern that suggests a substantial effective population size and a limited effect of positive selection on genome-wide diversity over short time scales.