Biology subjects

Mozzachiodi, S.

Publications and source records attributed to Mozzachiodi, S..

7 recordsLinked to original sources

bioRxiv2026

Network-scale disruption of RNA-protein interactions by a bioaccumulating small-molecule drug

Many small-molecule drugs accumulate in both host and gut microbial cells. Yet, the molecular consequences of intracellular drug accumulation are largely unknown. Here we show that the antidepressant duloxetine broadly disrupts RNA-protein interactions revealing a previously unrecognized mode of drug effect. Across phylogenetically diverse bacteria and human intestinal cells, duloxetine consistently reduced RNA-binding capacity, with approximately 80% of RNA-binding proteins responding to duloxetine in bacteria (E. coli IAI1) and human (Caco-2) cells. As a mechanistic example, we show how duloxetine disrupts interactions between the pyrimidine biosynthesis enzyme PyrB and transcripts encoding metabolically linked functions. Biochemical and structural analyses show that duloxetine competes with aspartate, the natural substrate of PyrB, weakening the enzymes binding with 3' UTR-localized stem-loop structures in its RNA partners. Overall, our results uncover the off-target disruption of RNA-protein interactions due to drug accumulation and have implications for understanding molecular basis of variation in drug efficacy and toxicity.

systems biology↗

bioRxiv2026

Laboratory evolution enhances resilience of a symbiont yeast and its honeybee host against agrochemical exposure

Yeasts are key microbial members of several ecosystems. Yet, the impact of widespread chemical pollutants on yeasts is only sparsely studied. Here we report the effect of >1000 chemical pollutants on fourteen diverse yeast species spanning the Saccharomycotina subphylum. Starmerella bombicola, a symbiont of various bee species, was the most sensitive and inhibited by several fungicides as well as by non-fungicides. To identify the molecular basis of this ultra-sensitivity, we selected resistant lineages against nine chemicals using adaptive laboratory evolution. Whole-genome-sequencing uncovered convergent evolution on YBP1, a key regulator of oxidative stress. Proteomic analysis confirmed the protective role of oxidative stress response pathways, including proteins encoded by horizontally transferred bacterial genes. We find that the evolved S. bombicola stably colonized the bee gut and ameliorated the negative effect of paclobutrazol, a plant hormone regulator, on gut microbes, sucrose responsiveness, and learning. Our findings demonstrate how laboratory evolution can be used to mitigate the negative impact of chemical pollutants on pollinators.

microbiology↗

bioRxiv2025

Interspecies interactions drive bacterial proteome reorganisation and emergent metabolism

Species in microbial communities must respond to the presence of others to stave off resource competition or to capitalise on new resources that may become available due to additional metabolic activities. Such metabolic interactions manifest in growth effects such as competitive exclusion or cooperative growth boost. However, intra-cellular molecular changes that underpin these responses are very sparsely studied, preventing mechanistic insights into community function and dynamics. Here, we analyse meta-proteomics and metabolomic responses in 104 pairwise co-cultures of 15 diverse gut bacteria in a nutrient-rich medium. These co-cultures span a diversity of ecological interactions with competition, amensalism and exploitation being prominent, and with around one in five positive interactions. The species in co-cultures feature substantial molecular responses, with typically more than 60% of the proteome changing in response to at least one partner. Even closely related species and ortholog proteins show different expression profiles in response to the same partner indicating functional diversification at both protein and species level. We show that the magnitude of these responses is determined by genome size, species abundance, and pH. Small-molecule transport and carbon metabolism are among the most responsive processes indicating pervasive metabolic interactions. Using metabolomics, we identify likely cross-fed metabolites, emergent polyamine metabolism, and niche partitioning in amino acid utilisation. Overall, our study shows how bacteria respond to the presence of other species through extensive remodelling of their proteome and metabolome.

microbiology↗

bioRxiv2021

Unlocking the functional potential of polyploid yeasts

Breeding and domestication have generated widely exploited crops, animals and microbes. However, many Saccharomyces cerevisiae industrial strains have complex polyploid genomes and are sterile, preventing genetic improvement strategies based on breeding. Here, we present a novel strain improvement approach based on the budding yeasts property to promote genetic recombination when meiosis is interrupted and cells return-to-mitotic-growth (RTG). We demonstrated that two unrelated sterile industrial strains with complex triploid and tetraploid genomes were RTG-competent and developed a visual screening for easy and high-throughput identification of recombined RTG clones based on colony phenotypes. Sequencing of the evolved clones revealed unprecedented levels of RTG-induced genome-wide recombination. We generated and extensively phenotyped a RTG library and identified clones with superior biotechnological traits. Thus, we propose the RTG-framework as a fully non-GMO workflow to rapidly improve industrial yeasts that can be easily brought to the market.

genetics↗

bioRxiv2020

Aborting meiosis overcomes hybrid sterility

Hybrids between species or diverged lineages contain fundamentally novel genetic combinations but an impaired meiosis often makes them evolutionary dead ends. Here, we explored to what extent and how an aborted meiosis followed by a return-to-growth (RTG) promotes recombination across a panel of 20 yeast diploid backgrounds with different genomic structures and levels of sterility. Genome analyses of 284 clones revealed that RTG promoted recombination and generated extensive regions of loss-of-heterozygosity in sterile hybrids with either a defective meiosis or a heavily rearranged karyotype, whereas RTG recombination was reduced by high sequence divergence between parental subgenomes. The RTG recombination preferentially occurred in regions with local sequence homology and in meiotic recombination hotspots. The loss-of-heterozygosity had a profound impact on sexual and asexual fitness, and enabled genetic mapping of phenotypic differences in sterile lineages where linkage or association analyses failed. We propose that RTG gives sterile hybrids access to a natural route for genome recombination and adaptation. One sentence summaryAborting meiosis followed by a return to mitotic growth promotes evolution by genome wide-recombination in sterile yeast hybrids.

genetics↗

bioRxiv2019

An Out-of-Patagonia dispersal explains most of the worldwide genetic distribution in Saccharomyces eubayanus

Saccharomyces eubayanus represents missing cryotolerant ancestor of lager yeast hybrid and can be found in Patagonia in association with Nothofagus forests. The limited number of isolates and associated genomes available has prevented to resolve the S. eubayanus origin and evolution. Here, we present a sampling effort at an unprecedented scale and report the isolation of 160 strains from ten sampling sites along 2,000 km distance in South America. We sequenced the genome of 82 strains and, together with other 25 available genomes, performed comprehensive phylogenetic analysis. Our results revealed the presence of three main Patagonia-B lineages together with dozens of admixed strains distributed in three mosaic clusters. The PB-1 lineage isolated from Tierra del Fuego exhibited the highest genetic diversity, lowest LD blocks and highest Fis values compared to the other lineages, suggesting a successful adaptation to cold temperatures in extreme environments and greater inbreeding rates in Tierra del Fuego. Differences between lineages and strains were found in terms of aneuploidy and pangenome content, evidencing a lateral gene transfer event in PB-2 strains from an unknown donor species. Overall, the Patagonian lineages, particularly southern populations, showed a greater global genetic diversity compared to Holarctic and Chinese lineages, supporting the scenario of a S. eubayanus colonization from Patagonia and then spread towards northern and western regions, including the Holarctic (North America and China) and New Zealand. Interestingly, fermentative capacity and maltose consumption resulted negatively correlated with latitude, indicating a better fermentative performance in norther populations. Our genome analysis together with previous reports in the sister species S. uvarum strongly suggests that the S. eubayanus ancestor could have originated in Patagonia or the Southern Hemisphere, rather than China, yet further studies are needed to resolve this conflicting scenario. Understanding S. eubayanus evolutionary history is crucial to resolve the unknown origin of the lager yeast and might open new avenues for biotechnological applications.

genomics↗

bioRxiv2018

Accurate tracking of the mutational landscape of diploid hybrid genomes reveals genetic background effects

BackgroundGenome evolution promotes diversity within a population via mutations, recombination, and whole-genome duplication. However, quantifying precisely these factors in diploid hybrid genomes is challenging. Here we present an integrated experimental and computational workflow to accurately track the mutational landscape of yeast diploid hybrids (MuLoYDH) in terms of single-nucleotide variants, small insertions/deletions, copy-number variants and loss-of-heterozygosity. ResultsHaploid Saccharomyces parents were combined into diploid hybrids with fully phased genome and controlled levels of heterozygosity. The resulting hybrids represented the ancestral state and were evolved under different laboratory protocols. Variant simulations enabled to efficiently integrate competitive and standard mapping, depending on local levels of heterozygosity and read length. Experimental validations proved high accuracy and resolution of our computational approach. Finally, applying MuLoYDH to four different diploids revealed striking genetic background effects. Homozygous S. cerevisiae showed ~4-fold higher mutation rate compared to S. paradoxus. In contrast, interspecies hybrids exhibited mutation rates similar to intraspecies hybrids despite 10-fold higher heterozygosity. MuLoYDH unveiled that a substantial fraction of the genome (~200 bp per generation) was shaped by loss-of-heterozygosity and this process was strongly inhibited by high levels of heterozygosity. ConclusionsWe report a comprehensive framework for characterizing the mutational spectrum of yeast diploid hybrids with unprecedented resolution, which can be generalised to other genetic systems. Applying MuLoYDH to laboratory-evolved hybrids provided novel quantitative insights into the evolutionary processes that mould yeast genomes.

genomics↗