Ancient Evolutionary Trade-Offs between Yeast Ploidy States

<div><p>The number of chromosome sets contained within the nucleus of eukaryotic organisms is a fundamental yet evolutionarily poorly characterized genetic variable of life. Here, we mapped the impact of ploidy on the mitotic fitness of baker's yeast and its never domesticated relative <i>Saccharomyces paradoxus</i> across wide swaths of their natural genotypic and phenotypic space. Surprisingly, environment-specific influences of ploidy on reproduction were found to be the rule rather than the exception. These ploidy–environment interactions were well conserved across the 2 billion generations separating the two species, suggesting that they are the products of strong selection. Previous hypotheses of generalizable advantages of haploidy or diploidy in ecological contexts imposing nutrient restriction, toxin exposure, and elevated mutational loads were rejected in favor of more fine-grained models of the interplay between ecology and ploidy. On a molecular level, cell size and mating type locus composition had equal, but limited, explanatory power, each explaining 12.5%–17% of ploidy–environment interactions. The mechanism of the cell size–based superior reproductive efficiency of haploids during Li⁺ exposure was traced to the Li⁺ exporter <i>ENA</i>. Removal of the Ena transporters, forcing dependence on the Nha1 extrusion system, completely altered the effects of ploidy on Li⁺ tolerance and evoked a strong diploid superiority, demonstrating how genetic variation at a single locus can completely reverse the relative merits of haploidy and diploidy. Taken together, our findings unmasked a dynamic interplay between ploidy and ecology that was of unpredicted evolutionary importance and had multiple molecular roots.</p> </div

Ploidy–environments interactions are conserved since before the <i>S. cerevisae</i> and <i>S. paradoxus</i> radiation.

<p>A) Fitness component measures with a significant (FDR, α = 0.05) difference in performance between haploids and diploids in <i>S. cerevisiae</i>, in <i>S. paradoxus</i> or in both species. To compare haploid and diploid asexual proliferative capacity, a mean of the log(2) relative performance of the two haploid mating types (each n = 2) was used to derive a single measure of haploid performance. This was compared to that of the diploid (n = 4), by calculating the mean difference between haploid and diploid phenotypes. Each species was treated separately. Error bars represent the SEM (n = 24 for <i>S. cerevisiae</i>, n = 27 for <i>S. paradoxus</i>). B) Left panels show pairwise Pearson correlation coefficients, based on ploidy effects over all mitotic traits, between strains belonging to the same (627 pairs) or different (648 pairs) species, the same (43 pairs) or different (233 pairs) <i>S. cerevisiae</i> population and the same (65 pairs) or different (211 pairs) <i>S. cerevisiae</i> source environment. Species, population and source environment, all have significant impact on ploidy effects (ANOVA F-test; p-values displayed, note the large sample size for the between/within species comparison, and the correspondingly low SEM), but explained only 2.5%, 9.3% and 1.8% of the overall variation in correlation coefficients (R2-adj). Right panels resolve <i>S. cerevisiae</i> populations into the Malaysian, European, African and North American populations and <i>S. cerevisiae</i> sources into Clinical, Fermentation, Lab and Wild strains. Top and bottom of boxes represent 25th and 75th quartiles, bands represent medians, whiskers show the lowest and highest data point still within 1.5 interquartile range of the lower and upper quartile respectively and filled circles represent data points outside this range.</p

Patterns of ploidy–environment interactions refute generalizing hypotheses on the effects of mutational load, toxin exposure, and nutrient restriction.

<p>Performance of haploid (n = 4) and diploid (n = 2) versions of individual <i>S. cerevisiae</i> (blue) and <i>S. paradoxus</i> (red) strains in DNA damage inducing environments and nitrogen restricted environments. Note that data is shown on a log(2) scale. Broken lines indicate the 1∶1 correlation (null hypothesis expectation).</p

Cell size partially explains ploidy–environment interactions.

<p>A–B) Fitness components measures with a significant (FDR, α = 0.05) difference, both between large (n = 10) and small (n = 10) S288c haploids and between large (n = 29) and small (n = 20) S288c diploids. Large and small cells were constructed through individual deletion of different cell size defining genes. Note that data is shown on a log(2) scale. rror bars represent SEM. A) Performance of large and small diploid cells. B) Performance of large and small haploid cells. C) The tandem genes encoding the Li⁺ exporters <i>ENA1</i>,<i>2</i> and <i>5</i>, were deleted in the haploid S288c derivative BY4741 and the haploid deletion strain was autodiploidized through mating type switching. The total change in density (the efficiency) of mitotically reproducing populations exposed to 30 mM LiCl was obtained for <i>ena1</i>Δ<i>2</i>Δ<i>5</i>Δ haploids (n = 8) and diploids (n = 56) and compared to that of WT haploids (n = 16) and diploids (n = 16) in presence of 225 mM LiCl. Note that data is shown on a log(2) scale. Error bars represent SEM, p-values = Student's t-test. D) Growth efficiency of haploid and diploid versions of individual <i>S. cerevisiae</i> and <i>S. paradoxus</i> strains. Broken lines represent 1∶1 correlation (null hypothesis expectation).</p

Ploidy–environment interactions are the rule rather than the exception in yeast and favor haploidy and diploidy equally.

<p>A) The mitotic fitness components lag (time to initiate proliferation), rate (population doubling time) and efficiency (total change in population density) of asexual reproduction were extracted from high density growth curves of 24 <i>S. cerevisiae</i> and 27 <i>S. paradoxus</i> strains cultivated as haploids (n = 4) and diploids (n = 2) in an array of environmental contexts. Performance was log(2) transformed and normalized to that of the universal reference strain S288c, providing relative performance measures. B) The performances of haploids and diploids were compared over all species, strains, mitotic fitness components and environments. Line indicates the 1∶1 correlation. C) The performance of haploids and diploids over all strains and environments. Note that performance is on a log(2) scale. No significant difference between the two ploidy states (FDR, α = 0.05) were found. Error bars represent SEM.</p

Table1_Circulating serum miR-362-3p and miR-6721-5p as potential biomarkers for classification patients with adult-type diffuse glioma.docx

According to the fifth edition of the WHO Classification of Tumours of the Central Nervous System (CNS) published in 2021, grade 4 gliomas classification includes IDH-mutant astrocytomas and wild-type IDH glioblastomas. Unfortunately, despite precision oncology development, the prognosis for patients with grade 4 glioma remains poor, indicating an urgent need for better diagnostic and therapeutic strategies. Circulating miRNAs besides being important regulators of cancer development could serve as promising diagnostic biomarkers for patients with grade 4 glioma. Here, we propose a two-miRNA miR-362-3p and miR-6721-5p screening signature for serum for non-invasive classification of identified glioma cases into the highest-grade 4 and lower-grade gliomas. A total of 102 samples were included in this study, comprising 78 grade 4 glioma cases and 24 grade 2–3 glioma subjects. Using the NanoString platform, seven miRNAs were identified as differentially expressed (DE), which was subsequently confirmed via RT-qPCR analysis. Next, numerous combinations of DE miRNAs were employed to develop classification models. The dual panel of miR-362-3p and miR-6721-5p displayed the highest diagnostic value to differentiate grade 4 patients and lower grade cases with an AUC of 0.867. Additionally, this signature also had a high AUC = 0.854 in the verification cohorts by RT-qPCR and an AUC = 0.842 using external data from the GEO public database. The functional annotation analyses of predicted DE miRNA target genes showed their primary involvement in the STAT3 and HIF-1 signalling pathways and the signalling pathway of pluripotency of stem cells and glioblastoma-related pathways. For additional exploration of miRNA expression patterns correlated with glioma, we performed the Weighted Gene-Co Expression Network Analysis (WGCNA). We showed that the modules most associated with glioma grade contained as many as six DE miRNAs. In conclusion, this study presents the first evidence of serum miRNA expression profiling in adult-type diffuse glioma using a classification based on the WHO 2021 guidelines. We expect that the discovered dual miR-362-3p and miR-6721-5p signatures have the potential to be utilised for grading gliomas in clinical applications.</p

COVID-19 Host Genetics Initiative. A first update on mapping the human genetic architecture of COVID-19

The COVID-19 pandemic continues to pose a major public health threat, especially in countries with low vaccination rates. To better understand the biological underpinnings of SARS-CoV-2 infection and COVID-19 severity, we formed the COVID-19 Host Genetics Initiative1. Here we present a genome-wide association study meta-analysis of up to 125,584 cases and over 2.5 million control individuals across 60 studies from 25 countries, adding 11 genome-wide significant loci compared with those previously identified2. Genes at new loci, including SFTPD, MUC5B and ACE2, reveal compelling insights regarding disease susceptibility and severity.</p