Pal T, Cisneros AF, and Landry CR

Abstract

Mendelian genetics provides us with a framework for studying allelic dominance relationships at a locus at the phenotypic level. These dominance relationships result from different molecular factors, including the mapping of fitness onto molecular activity. For homomeric proteins, physical interactions between alleles could affect protein activity, providing a mechanism for dominance. Here, we examine the molecular underpinnings of dominance using a model in which fitness is determined by the activities of monomeric and dimeric proteins. Our model recapitulates previous observations that monomeric proteins can show phenotypic dominance due to the underlying fitness function in the absence of molecular dominance. In turn, the landscape of phenotypic dominance for the dimer system results from the interplay of the fitness function, molecular dominance, and the selective homo- or heteromerization of the two alleles. Our results show the complex relationships between molecular and phenotypic dominance and highlight the fundamental difference in dominance landscapes for monomeric and homomeric proteins.

Read more on bioRxiv

Lemieux P, Dubé AK, and Landry CR

Abstract

Scaffolds are powerful tools in synthetic biology for various applications, from increasing yield to optimizing signalling specificity. Scaffolds can be built by fusing peptide binding domains (PBD) and attaching the peptide they bind to the enzymes inducing spatial proximity. Only a few PBD-peptide combinations have been tested in this context, and no combination produced a high yield in yeast, an important chassis in biotechnology. Therefore, there is a need for more exploration of PBD-peptide pairs to be used in yeast. Scaffold characterization is challenging because it is often dependent on a model pathway with an output that is difficult to measure quantitatively. Here, we use a protein-fragment complementation assay (PCA) to study scaffold efficiency in yeast that allows to couple scaffold efficiency with growth rate. First, we characterize PBD-peptide interaction (PPI) strength and their binding availability. Then, we test different scaffold architectures and expression levels to quantify the simultaneous binding of peptide pairs to the scaffold. We show that PPI strength of the weakest binding PDB-peptide pair is critical for scaffold efficiency and that PPI strength is limited by low binding availability of some peptides. Also, we find that slight architectural variations and expression levels have a significant impact on scaffold efficiency detected by DHFR PCA. In the future, DHFR PCA method will enable testing in a high throughput manner scaffold variants in yeast through its easy to read scaffolding efficiency signal.

Read more on bioRxiv

Durand R, Pageau A, and Landry CR

Abstract

Deep-mutational scanning (DMS) is a powerful technique that allows screening large libraries of mutants at high throughput. It has been used in many applications, including to estimate the fitness impact of all single mutants of entire proteins, to catalog drug resistance mutations and even to predict protein structure. Here, we present gyōza, a Snakemake-based workflow to analyze DMS data. gyōza requires little programming knowledge and comes with comprehensive documentation to help the user go from raw sequencing data to functional impact scores. Complete with quality control and an automatically generated HTML report, this new pipeline should facilitate the analysis of any DMS experiment. gyōza is freely available on GitHub (https://github.com/durr1602/gyoza).

Read more on bioRxiv

Mallik S, Cisneros AF, Landry CR, and Levy ED

Abstract

Homomeric proteins are ubiquitous and mediate myriads of cellular functions. When a gene encoding a homomer duplicates, the resulting paralogs can either form distinct homomers, or evolve into a heteromer containing both paralogs. While such events have extensively shaped proteomes, the molecular mechanisms driving these fates and their associated functional consequences remain largely unknown. Here, we conducted a comprehensive phylogenomic analysis tracing gene duplication histories of 7,377 human paralogs across the eukaryotic lineage and identified their fates using protein interaction data. Simulations and data analyses show that cellular constraints must act as barriers to disfavor heteromerization and promote homomerization. We found that multiple cellular and molecular constraints can serve as barriers, including the lack of co-expression and co-localization. The main barrier, however, is co-translational assembly, which naturally promotes the self-assembly of each paralog from its corresponding mRNA, thus hindering heteromerization. We further established that heteromerization constrains functional divergence, with homomeric paralogs exhibiting stronger signatures of adaptive evolution and functional divergence compared to heteromeric paralogs. Together, these findings identify key biochemical and cellular properties that explain protein function diversification following gene duplication.

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Bedard C, Pageau A, Fijarczyk A, Mendoza-Salido D, Alcaniz A, Despres P, Durand R, Plante S, Alexander E, Rouleau FD, Giguere M, Bernier M, Sharma J, Maroc L, Gervais N, Menon A, Gagnon-Arsenault I, Bakker S, Rhodes J, Dufresne P, Bharat A, Sellam A, Luca DD, Gerstein A, Shapiro RS, Quijada N, and Landry CR

Abstract

Antimicrobial resistance (AMR) is a global threat. To optimize the use of our antifungal arsenal, we need rapid detection and monitoring tools that rely on high-quality AMR mutation data. Here, we performed a thorough manual curation of published AMR mutations in fungal pathogens to produce the FungAMR reference dataset. A total of 462 papers were curated, leading to 54,666 mutation entries all classified with the degree of evidence that supports their role in resistance. FungAMR covers 92 species, 202 genes and 184 drugs. We combined variant effect predictors with FungAMR resistance mutations and showed that these tools could be used to help predict the potential impact of mutations on AMR. Additionally, a comparative analysis among species revealed a high level of convergence in the molecular basis of resistance, revealing some potentially universal resistance mutations. The analysis also showed that a significant number of resistance mutations lead to cross-resistance within antifungals of a class, as well as between classes for certain mutated genes. The acquisition of fungal resistance in the clinic and the field is an urging concern. Finally, we provide a computational tool, ChroQueTas, that leverages FungAMR to screen fungal genomes for AMR mutations. These resources are anticipated to have great utility for researchers in the fight against antifungal resistance.

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Durand R, Torbey AG, Giguere M, Pageau A, Dubé AK, Lagüe P and Landry CR

Abstract

One of the front-line drug classes used to treat invasive fungal infections is echinocandins, which target the fungal-specific beta-glucan synthase (Fks). Treatment failure due to resistance often coincides with mutations in two protein regions known as hotspots. The biophysical bases by which such mutations confer resistance and cross-resistance among echinocandins are largely unknown. Here, we use deep-mutational scanning to quantify the resistance level of 660 mutations in the hotspots of two homologous Fks. We detail the constraints acting on drug binding and explain the resistance specificity for some mutations using the drug-protein interactions from our molecular models. Our findings will enable DNA sequence-based predictions of resistance to this important drug family and the improvement of future molecules that could overcome current resistance mutations.

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Jordan DF, Dubé AK, Dionne U, Bradley D, and Landry CR

Abstract

In signaling networks, many protein-protein interactions are mediated by modular domains that bind short linear motifs. The motifs’ sequences modulate many factors, among them affinity and specificity, or the ability to bind strongly and to bind the appropriate partners. Previous studies have proposed a trade-off between affinity and specificity, suggesting that motifs with high affinity are less capable of differentiating between domains with similar sequences and structures. Using Deep Mutational Scanning to create a mutant library of a well characterized binding motif, and protein complementation assays to measure protein-protein interactions, we tested this trade-off in vivo for the first time. We measured the binding strength and specificity of a library of mutants of a binding motif on the MAP kinase kinase Pbs2, which binds the SH3 domain of the osmosensor protein Sho1 in Saccharomyces cerevisiae. We find that many mutations in the region surrounding the binding motif modulate binding strength, but that few mutations have a strong impact on specificity. Moreover, we find no systematic relationship between affinity and specificity as measured in vivo. Interestingly, all Pbs2 mutations which increase affinity or specificity are situated outside of the Pbs2 residues that interact with the canonical SH3-binding pocket, suggesting that other surfaces on Sho1 contribute to binding. We use predicted structures to propose a model of binding which involves residues neighboring the core Pbs2 motif binding outside of the canonical SH3-binding pocket, allowing affinity and specificity to be determined by a broader range of sequences than what has previously been considered.

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Belda H, Bradley D, Christodoulou E, Nofal SD, Broncel M, Jones D, Davies H, Bertran MT, Purkiss AG, Ogrodowicz RW, Joshi D, O’Reilly N, Walport L, Claessens A, Powell A, House D, Kjaer S, Landry CR, and Treeck M

Abstract

Among the ∼200 Plasmodium species that infect vertebrates, six infect humans. Of these, P. falciparum causes >95% of all ∼500,000 annual fatalities. Phylogenetically, P. falciparumbelongs to the Laverania subgenus, a group of Plasmodium species that infect great apes. Common to Laverania species is the family of FIKK kinases. One million years ago, a single FIKK kinase conserved in all Plasmodium species gained an export element in the Laveraniasubgenus and expanded into the family of ∼20 atypical FIKK kinases, most of which are exported into the host cell. The fikk genes are conserved in syntenic loci across the Laverania, arguing for a rapid expansion controlling important functions in host cell remodelling and pathogenesis. We provide evidence that the FIKK paralogues evolved specific and mutually exclusive phosphorylation motif preferences, conserved across their Laverania orthologues, in a short evolutionary timeframe. Surprisingly, we find that FIKK13 has evolved exclusive tyrosine-phosphorylation preference, which was thought to be absent in Plasmodium species. Combining a crystal structure with AlphaFold2 predictions, we identify residues that determine kinase-specificity within the FIKK family in a fast-evolving flexible loop. Finally, we show that all expressed members of the FIKK kinase family can be chemically inhibited in vitro using a single compound. Such a pan-specific inhibitor of this kinase family important for virulence could reduce the ability of the parasite to gain escape-mutations and resistance.

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Fijarczyk A, Hessenauer P, Hamelin RC, and Landry CR

Abstract

Fungi have a wide range of lifestyles and hosts. We still know little about the impact of lifestyles on their genome architecture. Here, we combined and annotated 562 fungal genomes from the class Sordariomycetes and examined the coevolution between 12 genomic and two lifestyle traits: pathogenicity and insect association. We found that pathogens tend to evolve a larger number of protein-coding genes, tRNA genes, and have larger non-repetitive genome sizes than non-pathogenic species. In contrast, species with a pathogenic or symbiotic relationship with insects have smaller genome sizes and genes with longer exons; they also have fewer genes if they are vectored by insects, compared to species not associated with insects. Our study demonstrates that pathogen genome size and complexity are the result of an interplay between drift, imposed by symbiosis and small effective population size, which leads to genome contraction, and the adaptive role of gene amplification, which leads to genome expansion.

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Nguyen Q G, Jain M, Landry CR and M Filteau

Abstract

Microbial interactions contribute to shape ecosystems and their functions. The interplay between microorganisms also shapes the evolutionary trajectory of each species, by imposing metabolic and physiological selective pressures. The mechanisms underlying these interactions are thus of interest to improve our understanding of microbial evolution at the genetic level. Here we applied a functional genomics approach in the model yeast Saccharomyces cerevisiae to identify the fitness determinants of naïve biotic interactions. We used a barcoded prototroph yeast deletion collection to perform pooled fitness competitions in co-culture with seven Pseudomonas spp natural isolates. We found that co-culture had a positive impact on fitness profiles, as in general the deleterious effects of loss of function in our nutrient-poor media were mitigated. In total, 643 genes showed a fitness difference in co-culture, most of which can be explained by a media diversification procured by bacterial metabolism. However, a large fraction (36%) of gene-microbe interactions could not be recaptured in cell-free supernatant experiments, showcasing that feedback mechanisms or physical contacts modulate these interactions. Also, the gene list of some co-cultures was enriched with homologs in other eukaryote species, suggesting a variable degree of specificity underlying the mechanisms of biotic interactions and that these interactions could also exist in other organisms. Our results illustrate how microbial interactions can contribute to shape the interplay between genomes and species interactions, and that S. cerevisiae is a powerful model to study the impact of biotic interactions.

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Cisneros AF, and Landry CR

Read more in Proceedings of the National Academy of Sciences

Dibyachintan S, Dubé AK, Bradley D, Lemieux P, Dionne U, and Landry CR

Abstract

Paralogous genes are often functionally redundant for long periods of time. While their functions are preserved, paralogs accumulate cryptic changes in sequence and expression, which could modulate the impact of future mutations through epistasis. We examine the impact of mutations on redundant myosin proteins that have maintained the same binding preference despite having accumulated differences in expression levels and amino acid substitutions in the last 100 million years. By quantifying the impact of all single-amino acid substitutions in their SH3 domains on the physical interaction with their interaction partners, we show that the same mutations in the paralogous SH3s change binding in a paralog-specific and interaction partner-specific manner. This contingency is explained by the difference in promoter strength of the two paralogous myosin genes and epistatic interactions between the mutations introduced and cryptic divergent sites within the SH3s. One significant consequence of this contingency is that while some mutations would be sufficient to nonfunctionalize one paralog, they would have minimal impact on the other. Our results reveal how cryptic divergence, which accumulates while maintaining functional redundancy in cellular networks, could bias gene duplicates to specific fates.

Read more in Nature Communications

Jay A, Jordan DF, Gerstein A  and Landry CR

Abstract

Faced with the burden of increasing resistance to antifungals in many fungal pathogens and the constant emergence of new drug-resistant strains, it is essential to assess the importance of various resistance mechanisms. Fungi have relatively plastic genomes and can tolerate genomic copy number variation (CNV) caused by aneuploidy and gene amplification or deletion. In many cases, these genomic changes lead to adaptation to stressful conditions, including those caused by antifungal drugs. Here, we specifically examine the contribution of CNVs to antifungal resistance. We undertook a thorough literature search, collecting reports of antifungal resistance caused by a CNV, and classifying the examples of CNV-conferred resistance into four main mechanisms. We find that in human fungal pathogens, there is little evidence that gene copy number plays a major role in the emergence of antifungal resistance compared to other types of mutations. We discuss why we might be underestimating their importance and new approaches being used to study them.

Read more in npj Antimicrobials and Resistance

Aubé S,  and Landry CR

Abstract

Experiments in budding yeast reveal how the effects of mutations on phenotype and fitness vary across environments.

Read more in Nature Ecology and Evolution

Bautista C, Gagnon-Arsenault I, Utrobina M, Fijarczyk A, Bendixsen DP, Stelkens R, and Landry CR

Abstract

Hybrids between species exhibit plastic genomic architectures that could foster or slow down their adaptation. When challenged to evolve in an environment containing a UV mimetic drug, yeast hybrids have reduced adaptation rates compared to parents. We find that hybrids and their parents converge onto similar molecular mechanisms of adaptation by mutations in pleiotropic transcription factors, but at a different pace. After 100 generations, mutations in these genes tend to be homozygous in the parents but heterozygous in the hybrids. We hypothesize that a lower rate of loss of heterozygosity (LOH) in hybrids could limit fitness gain. Using genome editing, we first demonstrate that mutations display incomplete dominance, requiring homozygosity to show full impact and to entirely circumvent Haldane’s sieve, which favors the fixation of dominant mutations. Second, tracking mutations in earlier generations confirmed a different rate of LOH in hybrids. Together, these findings show that Haldane’s sieve slows down adaptation in hybrids, revealing an intrinsic constraint of hybrid genomic architecture that can limit the role of hybridization in adaptive evolution.

Read more in Nature Communications

Agyare-Tabbi MR, Uthayakumar D, Francis D, Maroc L, Grant C, McQueen P, Westmacott G, Shaker H, Skulska I, Gagnon-Arsenault I, Boisvert J, Landry CR, and Shapiro RS

Abstract

Antimicrobial-induced DNA damage, and subsequent repair via upregulation of DNA repair factors, including error-prone translesion polymerases, can lead to the increased accumulation of mutations in the microbial genome, and ultimately increased risk of acquired mutations associated with antimicrobial resistance. While this phenotype is well described in bacterial species, it is less thoroughly investigated amongst microbial fungi. Here, we monitor DNA damage induced by antifungal agents in the fungal pathogen Candida albicans, and find that commonly used antifungal drugs are able to induce DNA damage, leading to the upregulation of transcripts encoding predicted error-prone polymerases and related factors. We focus on REV1, encoding a putative error-prone polymerase, and find that while deleting this gene in C. albicans leads to increased sensitivity to DNA damage, it also unexpectedly renders cells more likely to incur mutations and evolve resistance to antifungal agents. We further find that deletion of REV1 leads to a significant depletion in the uncharacterized protein Shm1, which itself plays a role in fungal mutagenesis. Together, this work lends new insight into previously uncharacterized factors with important roles in the DNA damage response, mutagenesis, and the evolution of antifungal drug resistance.

Read more in npj Antimicrobials and Resistance

Bédard C, Gagnon-Arsenault I, Boisvert J, Plante S, Dubé AK, Pageau A, Sharma J, Maroc L, Shapiro RS, and Landry CR

Abstract

Azole antifungals are the main drugs used to treat fungal infections. Amino acid substitutions in the drug target Erg11 (Cyp51) are a common resistance mechanism in pathogenic yeasts. How many and which mutations confer resistance is, however, largely unknown. Here we measure the impact of nearly 4,000 amino acid variants of Candida albicans Erg11 on the susceptibility to six clinical azoles. This was achieved by deep mutational scanning of CaErg11 expressed in Saccharomyces cerevisiae. We find that a large fraction of mutations lead to resistance (33%), most resistance mutations confer cross-resistance (88%) and only a handful of resistance mutations show a significant fitness cost (9%). Our results reveal that resistance to azoles can arise through a large set of mutations and this will probably lead to azole pan-resistance, with little evolutionary compromise. This resource will help inform treatment choices in clinical settings and guide the development of new drugs.

Read more in Nature Microbiology

Bradley D*, Hogrebe A*, Dandage R, Dubé AK, Leutert M, Dionne U, Chang A, Villen J, and Landry CR

Abstract

The fidelity of signal transduction requires the binding of regulatory molecules to their cognate targets. However, the crowded cell interior risks off-target interactions between proteins that are functionally unrelated. How such off-target interactions impact fitness is not generally known. Here, we use Saccharomyces cerevisiae to inducibly express tyrosine kinases. Because yeast lacks bona fide tyrosine kinases, the resulting tyrosine phosphorylation is biologically spurious. We engineered 44 yeast strains each expressing a tyrosine kinase, and quantitatively analysed their phosphoproteomes. This analysis resulted in ~30,000 phosphosites mapping to ~3500 proteins. The number of spurious pY sites generated correlates strongly with decreased growth, and we predict over 1000 pY events to be deleterious. However, we also find that many of the spurious pY sites have a negligible effect on fitness, possibly because of their low stoichiometry. This result is consistent with our evolutionary analyses demonstrating a lack of phosphotyrosine counter-selection in species with tyrosine kinases. Our results suggest that, alongside the risk for toxicity, the cell can tolerate a large degree of non-functional crosstalk as interaction networks evolve.

Read more in The EMBO Journal

Després PC, Dubé AK, Picard ME, Grenier J, Shi R, and Landry CR

Abstract

The functions of proteins generally depend on their assembly into complexes. During evolution, some complexes have transitioned from homomers encoded by a single gene to heteromers encoded by duplicate genes. This transition could occur without adaptive evolution through intermolecular compensatory mutations. Here, we experimentally duplicated and evolved a homodimeric enzyme to determine whether and how this could happen. We identified hundreds of deleterious mutations that inactivate individual homodimers but produce functional enzymes when coexpressed as duplicated proteins that heterodimerize. The structure of one such heteromer reveals how both losses of function are buffered through the introduction of asymmetry in the complex that allows them to subfunctionalize. Constructive neutral evolution can thus occur by gene duplication followed by only one deleterious mutation per duplicate.

Read more in Science

Bradley D, Garand C, Belda H, Gagnon-Arsenault I, Treeck M, Elowe S, and Landry CR

Abstract

Most biological processes are regulated by signaling modules that bind to short linear motifs. For protein kinases, substrates may have full or only partial matches to the kinase recognition motif, a property known as “substrate quality.” However, it is not clear whether differences in substrate quality represent neutral variation or if they have functional consequences. We examine this question for the kinase CK2, which has many fundamental functions. We show that optimal CK2 sites are phosphorylated at maximal stoichiometries and found in many conditions, whereas minimal substrates are more weakly phosphorylated and have regulatory functions. Optimal CK2 sites tend to be more conserved, and substrate quality is often tuned by selection. For intermediate sites, increases or decreases in substrate quality may be deleterious, as we demonstrate for a CK2 substrate at the kinetochore. The results together suggest a strong role for substrate quality in phosphosite function and evolution.

Read more in Cell Systems

Landry CR

Abstract

As a starting biology student in the late 1990s, I was taught how the interior of cells is physically organized in space and time. When looking at sketches of cells, we did not need to know which species we talked about because what we were learning was considered universal. By contrast, classes in evolutionary biology embraced the diversity of forms, behaviors, and physiology of plants, animals, and microbes. In retrospect, why would we expect to see diversity at the organism level but not at the intracellular level? This contrasting view of biology was due to historical reasons, some of which I discovered as my career progressed. On one side of history, evolutionary biologists were testing hypotheses about what they could measure, which meant mainly in the visible world. For cell biologists, tools were not sufficiently widely accessible to allow for probing the inner life of cells in a large diversity of species. More importantly, the changes in time or in response to stimuli for any given model cell already provided plenty of material for investigation. In addition, the study of a handful of models was deemed sufficient to extract the core principles of cellular life. Things have dramatically changed in the past 30 years; functional genomics and systems biology approaches can now be applied within and among species to measure how cells are organized physically and dynamically through time. This gives us more diversity to explain.

Read more in Trends in Ecology & Evolution

Rouleau FD, Dubé AK, Gagnon-Arsenault I, Dibyachintan S, Pageau A, Després PC, Lagüe P, and Landry CR

Abstract

Pneumocystis jirovecii is a fungal pathogen that causes pneumocystis pneumonia, a disease that mainly affects immunocompromised individuals. This fungus has historically been hard to study because of our inability to grow it in vitro. One of the main drug targets in P. jirovecii is its dihydrofolate reductase (PjDHFR). Here, by using functional complementation of the baker’s yeast ortholog, we show that PjDHFR can be inhibited by the antifolate methotrexate in a dose-dependent manner. Using deep mutational scanning of PjDHFR, we identify mutations conferring resistance to methotrexate. Thirty-one sites spanning the protein have at least one mutation that leads to resistance, for a total of 355 high-confidence resistance mutations. Most resistance-inducing mutations are found inside the active site, and many are structurally equivalent to mutations known to lead to resistance to different antifolates in other organisms. Some sites show specific resistance mutations, where only a single substitution confers resistance, whereas others are more permissive, as several substitutions at these sites confer resistance. Surprisingly, one of the permissive sites (F199) is without direct contact to either ligand or cofactor, suggesting that it acts through an allosteric mechanism. Modeling changes in binding energy between F199 mutants and drug shows that most mutations destabilize interactions between the protein and the drug. This evidence points towards a more important role of this position in resistance than previously estimated and highlights potential unknown allosteric mechanisms of resistance to antifolate in DHFRs. Our results offer unprecedented resources for the interpretation of mutation effects in the main drug target of an uncultivable fungal pathogen.

Read more in PLOS Genetics

Cisneros AF, Nielly-Thibault N, Malik S, Levy ED, and Landry CR

Abstract

Biological systems can gain complexity over time. While some of these transitions are likely driven by natural selection, the extent to which they occur without providing an adaptive benefit is unknown. At the molecular level, one example is heteromeric complexes replacing homomeric ones following gene duplication. Here, we build a biophysical model and simulate the evolution of homodimers and heterodimers following gene duplication using distributions of mutational effects inferred from available protein structures. We keep the specific activity of each dimer identical, so their concentrations drift neutrally in the absence of new functions. We show that for more than 60% of tested dimer structures, the relative concentration of the heteromer increases over time due to mutational biases that favor the heterodimer. However, allowing mutational effects on synthesis rates and differences in the specific activity of homodimers and heterodimers can limit or reverse the observed bias toward heterodimers. Our results show that the accumulation of more complex protein quaternary structures is likely under neutral evolution, and that natural selection would be needed to reverse this tendency.

Read more in Molecular Systems Biology

Evans-Yamamoto D*, Dubé AK*, Saha G*, Plante S, Bradley D, Gagnon-Arsenault I, and Landry CR

Abstract

Whole genome duplication (WGD) followed by speciation allows us to examine the parallel evolution of ohnolog pairs. In the yeast family Saccharomycetaceae, HRR25 is a rare case of repeated ohnolog maintenance. This gene has reverted to a single copy in S. cerevisiae where it is now essential, but has been maintained as pairs in at least 7 species post WGD. In S. cerevisiae, HRR25 encodes the casein kinase (CK) 1δ/ε and plays a role in a variety of functions through its kinase activity and protein-protein interactions (PPIs). We hypothesized that the maintenance of duplicated HRR25 ohnologs could be a result of repeated subfunctionalization. We tested this hypothesis through a functional complementation assay in S. cerevisiae, testing all pairwise combinations of 25 orthologs (including 7 ohnolog pairs). Contrary to our expectations, we observed no cases of pair-dependent complementation, which would have supported the subfunctionalization hypothesis. Instead, most post-WGD species have one ohnolog that failed to complement, suggesting their nonfunctionalization or neofunctionalization. The ohnologs incapable of complementation have undergone more rapid protein evolution, lost most PPIs that were observed for their functional counterparts and singletons from post and non-WGD species, and have non-conserved cellular localization, consistent with their ongoing loss of function. The analysis in N. castelli shows that the non-complementing ohnolog is expressed at a lower level and has become non-essential. Taken together, our results indicate that HRR25 orthologs are undergoing gradual nonfunctionalization.

Read more in Molecular Biology and Evolution

Lemieux P, Bradley D, Dubé AK, Dionne U, and Landry CR

Abstract

Protein-protein interactions drive many cellular processes. Some interactions are directed by Src homology 3 (SH3) domains that bind proline-rich motifs on other proteins. The evolution of the binding specificity of SH3 domains is not completely understood, particularly following gene duplication. Paralogous genes accumulate mutations that can modify protein functions and, for SH3 domains, their binding preferences. Here, we examined how the binding of the SH3 domains of two paralogous yeast type I myosins, Myo3 and Myo5, evolved following duplication. We found that the paralogs have subtly different SH3-dependent interaction profiles. However, by swapping SH3 domains between the paralogs and characterizing the SH3 domains freed from their protein context, we find that very few of the differences in interactions, if any, depend on the SH3 domains themselves. We used ancestral sequence reconstruction to resurrect the pre-duplication SH3 domains and examined, moving back in time, how the binding preference changed. Although the closest ancestor of the two domains had a very similar binding preference as the extant ones, older ancestral domains displayed a gradual loss of interaction with the modern interaction partners when inserted in the extant paralogs. Molecular docking and experimental characterization of the free ancestral domains showed that their affinity with the proline motifs is likely not the cause for this loss of binding. Taken together, our results suggest that the SH3 and its host protein could create intramolecular or allosteric interactions essential for the SH3-dependent PPIs, making domains not functionally equivalent even when they have the same binding specificity.

Read more in Genetics

Durand R, Jalber-Ross J, Fijarczyk A, Dubé AK, and Landry CR

Abstract

Pathogenic fungi are a cause of growing concern. Developing an efficient and safe antifungal is challenging because of the similar biological properties of fungal and host cells. Consequently, there is an urgent need to better understand the mechanisms underlying antifungal resistance to prolong the efficacy of current molecules. A major step in this direction would be to be able to predict or even prevent the acquisition of resistance. We leverage the power of experimental evolution to quantify the diversity of paths to resistance to the antifungal 5-fluorocytosine (5-FC), commercially known as flucytosine. We generated hundreds of independent 5-FC resistant mutants derived from two genetic backgrounds from wild isolates of Saccharomyces cerevisiae. Through automated pin-spotting, whole-genome and amplicon sequencing, we identified the most likely causes of resistance for most strains. Approximately a third of all resistant mutants evolved resistance through a pleiotropic drug response, a potentially novel mechanism in response to 5-FC, marked by cross-resistance to fluconazole. These cross-resistant mutants are characterized by a loss of respiration and a strong tradeoff in drug-free media. For the majority of the remaining two thirds, resistance was acquired through loss-of-function mutations in FUR1, which encodes an important enzyme in the metabolism of 5-FC. We describe conditions in which mutations affecting this particular step of the metabolic pathway are favored over known resistance mutations affecting a step upstream, such as the well-known target cytosine deaminase encoded by FCY1. This observation suggests that ecological interactions may dictate the identity of resistance hotspots.

Read more on PLOS Genetics

Hénault M, Marsit S, Charron G, and Landry CR

Abstract

Transposable elements (TEs) are major contributors to structural genomic variation by creating interspersed duplications of themselves. In return, structural variants (SVs) can affect the genomic distribution of TE copies and shape their load. One long-standing hypothesis states that hybridization could trigger TE mobilization and thus increase TE load in hybrids. We previously tested this hypothesis by performing a large-scale evolution experiment by mutation accumulation (MA) on multiple hybrid genotypes within and between wild populations of the yeasts Saccharomyces paradoxus and Saccharomyces cerevisiae. Using aggregate measures of TE load with short-read sequencing, we found no evidence for TE load increase in hybrid MA lines. Here, we resolve the genomes of the hybrid MA lines with long-read phasing and assembly to precisely characterize the role of SVs in shaping the TE landscape. Highly contiguous phased assemblies of 127 MA lines revealed that SV types like polyploidy, aneuploidy and loss of heterozygosity have large impacts on the TE load. We characterized 18 de novo TE insertions, indicating that transposition only has a minor role in shaping the TE landscape in MA lines. Because the scarcity of TE mobilization in MA lines provided insufficient resolution to confidently dissect transposition rate variation in hybrids, we adapted an in vivo assay to measure transposition rates in various S. paradoxus hybrid backgrounds. We found that transposition rates are not increased by hybridization, but are modulated by many genotype-specific factors including initial TE load, TE sequence variants and mitochondrial DNA inheritance. Our results show the multiple scales at which TE load is shaped in hybrid genomes, being highly impacted by SV dynamics and finely modulated by genotype-specific variation in transposition rates.

Read more on eLife

Aubé S, Nielly-Thibault L, and Landry CR

Abstract

How changes in the different steps of protein synthesis—transcription, translation and degradation—contribute to differences of protein abundance among genes is not fully understood. There is however accumulating evidence that transcriptional divergence might have a prominent role. Here, we show that yeast paralogous genes are more divergent in transcription than in translation. We explore two causal mechanisms for this predominance of transcriptional divergence: an evolutionary trade-off between the precision and economy of gene expression and a larger mutational target size for transcription. Performing simulations within a minimal model of post-duplication evolution, we find that both mechanisms are consistent with the observed divergence patterns. We also investigate how additional properties of the effects of mutations on gene expression, such as their asymmetry and correlation across levels of regulation, can shape the evolution of paralogs. Our results highlight the importance of fully characterizing the distributions of mutational effects on transcription and translation. They also show how general trade-offs in cellular processes and mutation bias can have far-reaching evolutionary impacts.

Read more in PLoS Genetics

Kienzle L, Bettinazzi S, Choquette T, Brunet M, Hosseini Khorami H,  Jacques JF, Moreau M, Roucou X, Landry CR, Angers A, and Breton S

Abstract

Mitochondria have a central role in cellular functions, aging, and in certain diseases. They possess their own genome, a vestige of their bacterial ancestor. Over the course of evolution, most of the genes of the ancestor have been lost or transferred to the nucleus. In humans, the mtDNA is a very small circular molecule with a functional repertoire limited to only 37 genes. Its extremely compact nature with genes arranged one after the other and separated by short non-coding regions suggests that there is little room for evolutionary novelties. This is radically different from bacterial genomes, which are also circular but much larger, and in which we can find genes inside other genes. These sequences, different from the reference coding sequences, are called alternatives open reading frames or altORFs, and they are involved in key biological functions. However, whether altORFs exist in mitochondrial protein-coding genes or elsewhere in the human mitogenome has not been fully addressed. We found a downstream alternative ATG initiation codon in the + 3 reading frame of the human mitochondrial nd4 gene. This newly characterized altORF encodes a 99-amino-acid-long polypeptide, MTALTND4, which is conserved in primates. Our custom antibody, but not the pre-immune serum, was able to immunoprecipitate MTALTND4 from HeLa cell lysates, confirming the existence of an endogenous MTALTND4 peptide. The protein is localized in mitochondria and cytoplasm and is also found in the plasma, and it impacts cell and mitochondrial physiology. Many human mitochondrial translated ORFs might have so far gone unnoticed. By ignoring mtaltORFs, we have underestimated the coding potential of the mitogenome. Alternative mitochondrial peptides such as MTALTND4 may offer a new framework for the investigation of mitochondrial functions and diseases. 

Read more on BMC Biology

Plante S, Moon KM, Lemieux P, Foster LJ, and Landry CR

Abstract

The biophysical properties of the cytoplasm are major determinants of key cellular processes and adaptation. Many yeasts produce dormant spores that can withstand extreme conditions. We show that spores of Saccharomyces cerevisiae exhibit extraordinary biophysical properties, including a highly viscous and acidic cytosol. These conditions alter the solubility of more than 100 proteins such as metabolic enzymes that become more soluble as spores transit to active cell proliferation upon nutrient repletion. A key regulator of this transition is the heat shock protein, Hsp42, which shows transient solubilization and phosphorylation, and is essential for the transformation of the cytoplasm during germination. Germinating spores therefore return to growth through the dissolution of protein assemblies, orchestrated in part by Hsp42 activity. The modulation of spores’ molecular properties are likely key adaptive features of their exceptional survival capacities.

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Biot-Pelletier D, Bettinazzi S, Gagnon-Arsenault I, Dubé AK, Bédard C, Nguyen THM, Fiumera HL, Breton S, and Landry CR

Abstract

Cisneros AF*, Gagnon-Arsenault I*, Dubé AKD, Després PC, Kumar P, Lafontaine K, Pelettier JN, and Landry CR

Abstract

Peris D, Ubbelholde EJ, Kuang MC, Kominek J, Langdon QK, Adams M, Koshalek JA, Hulfachor AB, Opulente DA, Hall DJ, Hyma K, Fay JC, Leduq JB, Charron G, Landry CR, Libkind D,  Goncalves C, Goncalves P, Sampaio JP, Wang QM, Bai FY, Wrobel RL, and Hittinger CT.

Abstract

Evans-Yamamoto D, Rouleau FD, Nanda P, Makanae K, Liu Y, Després PC, Matsuo H, Seki M, Dubé AK, Ascencio D, Yachie N, Landry CR. Barcode fusion genetics-protein-fragment complementation assay (BFG-PCA): tools and resources that expand the potential for binary protein interaction discovery. Nucleic Acids Research 50 (9), e54

Mozzachiodi S, Bai FY, Baldrian P, Bell G, Boundy-Mills K, Buzzini P. Čadež N, Cubillos FA, Dashko S, Dimitrov R, Fisher KJ, Gibson B, Gouliamova D, Greig D, Heistinger L, Hittinger CT, Jecmenica M, Koufopanou V, Landry CR, Mašínová T, Naumova ES, Opulente D, Peña JJ, Petrovič U, Tsai IJ,  Turchetti B, Villarreal P, Yurkov A, Liti G, Boynton, P. Yeasts from temperate forests. Yeast 39 (1-2), 4-24

Dionne U, Percival LJ, Chartier FJM,  Landry CR, Bisson N. SRC homology 3 domains: multifaceted binding modules. Trends in Biochemical Sciences 47 (9), 772-784

Dubé AK, Dandage R, Dibyachintan S, Dionne U, Després PC, Landry CR. Deep mutational scanning of PPIs between partners expressed from their endogenous loci in vivo. Yeast Functional Genomics: Methods and Protocols, 237-259

Després PC, Dubé AK, Yachie N, Landry CR. High-throughput gene mutagenesis screening using base editing. Yeast Functional Genomics: Methods and Protocols, 331-348

Bradley D. The evolution of post-translational modifications. Current Opinion in Genetics & Development 76, 101956

Bautista C, Alfuraiji N,  Drangowka-Way A, Gangwani K, de Flamingh A, Bourne PE. Ten simple rules for improving communication among scientists. PLoS Computational Biology 18 (6), e1010130

Després PC, Cisneros AF, Alexander EMM, Sonigara R, Gagné-Thivierge C, Dubé AK, Landry CR. Asymmetrical dose responses shape the evolutionary trade-off between antifungal resistance and nutrient use. Nature Ecology & Evolution 6 (10), 1501-1515

Bédard C*, Cisneros AF*, Jordan D, Landry CR. Correlation between protein abundance and sequence conservation: what do recent experiments say? Current Opinion in Genetics & Development 77, 101984

Hénault M, Marsit S, Charron G, Landry CR. Hybridization drives mitochondrial DNA degeneration and metabolic shift in a species with biparental mitochondrial inheritance. Genome Research 32 (11-12), 2043-2056

Evans-Yamamoto D, Rouleau FD, Nanda P, Makanae K, Liu Y, Després PC, Matsuo H, Seki M, Dubé AK, Ascencio D, Yachie N, Landry CR. Barcode fusion genetics-protein-fragment complementation assay (BFG-PCA): tools and resources that expand the potential for binary protein interaction discovery. Nucleic Acids Research 50 (9), e54

Mozzachiodi S, Bai FY, Baldrian P, Bell G, Boundy-Mills K, Buzzini P. Čadež N, Cubillos FA, Dashko S, Dimitrov R, Fisher KJ, Gibson B, Gouliamova D, Greig D, Heistinger L, Hittinger CT, Jecmenica M, Koufopanou V, Landry CR, Mašínová T, Naumova ES, Opulente D, Peña JJ, Petrovič U, Tsai IJ,  Turchetti B, Villarreal P, Yurkov A, Liti G, Boynton, P. Yeasts from temperate forests. Yeast 39 (1-2), 4-24

Dionne U, Percival LJ, Chartier FJM,  Landry CR, Bisson N. SRC homology 3 domains: multifaceted binding modules. Trends in Biochemical Sciences 47 (9), 772-784

Dubé AK, Dandage R, Dibyachintan S, Dionne U, Després PC, Landry CR. Deep mutational scanning of PPIs between partners expressed from their endogenous loci in vivo. Yeast Functional Genomics: Methods and Protocols, 237-259

Després PC, Dubé AK, Yachie N, Landry CR. High-throughput gene mutagenesis screening using base editing. Yeast Functional Genomics: Methods and Protocols, 331-348

Bradley D. The evolution of post-translational modifications. Current Opinion in Genetics & Development 76, 101956

Bautista C, Alfuraiji N,  Drangowka-Way A, Gangwani K, de Flamingh A, Bourne PE. Ten simple rules for improving communication among scientists. PLoS Computational Biology 18 (6), e1010130

Després PC, Cisneros AF, Alexander EMM, Sonigara R, Gagné-Thivierge C, Dubé AK, Landry CR. Asymmetrical dose responses shape the evolutionary trade-off between antifungal resistance and nutrient use. Nature Ecology & Evolution 6 (10), 1501-1515

Bédard C*, Cisneros AF*, Jordan D, Landry CR. Correlation between protein abundance and sequence conservation: what do recent experiments say? Current Opinion in Genetics & Development 77, 101984

Hénault M, Marsit S, Charron G, Landry CR. Hybridization drives mitochondrial DNA degeneration and metabolic shift in a species with biparental mitochondrial inheritance. Genome Research 32 (11-12), 2043-2056

Fijarczyk A, Hénault M, Marsit S, Charron G, Landry CR. Heterogeneous mutation rates and spectra in yeast hybrids. Genome Biology and Evolution 13 (12), evab282

Dandage R, Landry CR. Identifying features of genome evolution to exploit cancer vulnerabilities. Cell Systems 12 (12), 1127-1130

Berger CS, Laroche J, Maaroufi H, Martin H, Moon KM, Landry CR, Foster LF, Aubin-Horth N. The parasite Schistocephalus solidus secretes proteins with putative host manipulation functions. Parasites & vectors 14 (1), 1-20

Drouin M, Hénault M, Hallin J, Landry CR. Testing the genomic shock hypothesis using transposable element expression in yeast hybrids. Frontiers in Fungal Biology 2, 729264

Suzuki G, Saito Y, Seki M, Evans-Yamamoto D, Negishi M, Kakoi K, Kawai H, Landry CR, Yachie N, Mitsuyama T. Machine learning approach for discrimination of genotypes based on bright-field cellular images. npj Systems Biology and Applications 7 (1), 31  

Marsit S, Hénault M, Charron G, Fijarczyk A, Landry CR. The neutral rate of whole-genome duplication varies among yeast species and their hybrids. Nature Communications 12 (1), 3126

Berger CM, Landry CR.  Yeast proteins do not practice social distancing as species hybridize. Current Genetics 67 (5), 755-759

Hénault M. The challenge of predicting transposable activity in hybrids. Current Genetics 67 (4), 567-572

Dionne U, Bourgault E, Dubé AK, Bradley D, Chartier FJM, Dandage R, Dibyachintan S, Després PC, Gish GD, Pham NTH, Létourneau M, Lambert JP, Doucet N, Bisson N, Landry CR. Protein context shapes the specificity of SH3 domain-mediated interactions in vivo. Nature communications 12 (1), 1597

Ascencio D, Diss G, Gagnon-Arsenault I, Dubé AK, DeLuna A, Landry CR. Expression attenuation as a mechanism of robustness against gene duplication. Proceedings of the National Academy of Sciences 118 (6), e2014345118

Dandage R*, Berger CM*,  Gagnon-Arsenault I, Moon KM, Stacey RG, Foster LJ, & Landry CR. Frequent Assembly of Chimeric Complexes in the Protein Interaction Network of an Interspecies Yeast Hybrid . Molecular Biology and Evolution 38 (4), 1384-1401

Bautista C, Marsit S, & Landry CR. Interspecific hybrids show a reduced adaptive potential under DNA damaging conditions. Evolutionary Applications 14 (3), 758-769.

Samuel Plante and Christian R Landry (2020). Closely related budding yeast species respond to different ecological signals for spore activation. Yeast 38 (1), 81-89

Gama Braga L, Cisneros A, Mathieu M, Clerc M, Garcia P, Lottin B, Garand C, Thebault P, Landry CR, & Elowe S. The BUBR1 pseudokinase domain promotes efficient kinetochore PP2A-B56 recruitment to regulate spindle checkpoint silencing and chromosome alignment. Cell Reports 33 (7), 108397 (2020) 

Hénault M, Marsit S, Charron G & Landry CR. The effect of hybridization on transposable element accumulation in an undomesticated fungal species. eLife 9, e60474 (2020)

Samuel Plante and Christian R Landry. Purification of yeast spores to investigate their dynamic of activation. Current Protocols in Microbiology 59 (1), e123 (2020)

Fijarczyk A, Hénault M, Marsit S, Charron G, Fischborn T, Nicole-Labrie L, & Landry CR. The genome sequence of the Jean-Talon strain, an archeological tetraploid beer yeast from Québec. G3: Genes, Genomes, Genetics 10 (9), 3087-3097 (2020)

Horianopoulos L, Gluck-Thaler E, Benoit Gelber I , Cowen LE, Geddes-McAlister J, Landry CR, Schwartz IS, Scott JA, Sellam A, Sheppard DC, Spribille T, Subramaniam R,Walker AK, Harris SD, Shapiro RS & AC. Gerstein. The Canadian Fungal Research Network: current challenges and future opportunities  Canadian Journal of Microbiology. 67(1): 13-22. (2020)

Després PC, Dubé AK, Seki M, Yachie N, Landry CR. Perturbing proteomes at single residue resolution using base editing. Nature Communications 11 (1), 1-13 (2020)

Hallin J, Cisneros AF, Hénault M, Fijarczyk A, Dandage R, Bautista C, & Landry CR.  Similarities in biological processes can be used to bridge ecology and molecular biology. Evolutionary Applications 13 (6), 1335-1350 (2020)

Hessenauer P*, Fijarczyk A*, Martin H, Prunier J, Charron G, Chapuis J, Bernier L, Tanguay P, Hamelin RC & Landry CR. Hybridization and introgression drive genome evolution of Dutch elm disease pathogens. Nat Ecol Evol 4 (4), 626-638 (2020)

Bleuven C, Nguyen GQ, Després PC, Filteau M, Landry CR. Competition experiments in a soil microcosm reveal the impact of genetic and biotic factors on yeast natural populations. The ISME Journal 14 (6), 1410-1421 (2020)

Cooke, S.J., V.M. Nguyen, D. Anastakis, S.D. Scott, M.R. Turetsky, A. Amirfazli, A. Hearn, C.E. Milton, L. Loewen,  E.E. Smith,  D.R. Norris, K.L. Lavoie, A. Aiken, D. Ansari, A.N. Antle, M. Babel, J. Bailey, D.M. Bernstein, R. Birnbaum, C. Bourassa, A. Calcagno, A. Campana, B. Chen, K. Collins, C.E. Connelly, M. Denov, B. Dupont, E. George, I. Gregory-Eaves, S. High, J.M. Hill, P.L. Jackson, N. Jette, M. Jurdjevic, A. Kothari, P. Khairy, S.A. Lamoureux, K. Ladner, C.R. Landry, F. Légaré, N. Lehoux, C. Leuprecht, A.R. Lieverse,  A. Luczak, M.L. Mallory,  E. Manning, A. Mazalek, S.J. Murray, L.L. Newman, V. Oosterveld, P. Potvin,  S. Reimer-Kirkham, J. Rowsell, D. Stacey, S.L. Tighe, D.J. Vocadlo, A.E. Wilson and A. Woolford. 2020. Diverse perspectives on interdisciplinarity from Members of the College of the Royal Society of Canada. FACETS. 5(1): 138-165 (202)

Hallin J & CR Landry. Regulation plays a multifaceted role in the retention of gene duplicates. PLOS Biology https://doi.org/10.1371/journal.pbio.3000519

Dandage R. & Landry CR. Paralog dependency indirectly affects the robustness of human cells. Molecular Systems Biology 15:e8871 (2019)

Charron G, Marsit S, Henault M, Martin H & CR Landry. Spontaneous whole-genome duplication restores fertility in interspecific hybrids. Nature Communications 10: 4126 (2019)

Marchant A^*, Cisneros AF^*, Dubé AK, Gagnon-Arsenault I, Ascencio D,  Jain HA, Aubé S, Eberlein C, Evans-Yamamoto D, Yachie N & CR Landry. The role of structural pleiotropy and regulatory evolution in the retention of heteromers of paralogs. eLife 2019;8:e46754 (2019)

Nielly-Thibault L & CR Landry, Differences between the de novo proteome and its non-functional precursor can result from neutral constraints on its birth process, not necessarily from natural selection alone. Genetics  10.1534/genetics.119.302187 (2019)

Dandage R, Després PC, Yachie N & CR Landry, beditor: A computational workflow for designing libraries of guide RNAs for CRISPR base editing. Genetics 212(2):377-385 (2019)

Durand E, Gagnon-Arsenault I, Hallin I, Nielly-Thibault L, Namy O & CR Landry, The high turnover of ribosome-associated transcripts from de novo ORFs produces gene-like characteristics available for de novo gene emergence in wild yeast populations. Genome Research 29(6):932-943 (2019)

Eberlein C, Hénault M, Fijarczyk A, Charron G, Bouvier M, Kohn L, Anderson J, Landry CR. Hybridization is a recurrent evolutionary stimulus in wild yeast speciation. Nature Communications 10, Article number: 923 (2019)

Bleuven C, Dubé AK, N’guyen GQ, Gagnon-Arsenault I, Martin H & Landry CR,
A collection of barcoded natural isolates of Saccharomyces paradoxus to study microbial evolutionary ecology. MicrobiologyOpen accepted  https://doi.org/10.1002/mbo3.773 (2018)

N’guyen GQ, Martin N, Jain M, Lagace L, Landry CR & Filteau M, A systems biology approach to explore the impact of maple tree dormancy release on sap variation and maple syrup quality. Scientific Reports, 8:14658 (2018)

Despres PC, Dube AK, Nielly-Thibault L, Yachie N & Landry CR, Double Selection Enhances the Efficiency of Target-AID and Cas9-Based Genome Editing in Yeast. G3 8:3163-3171 (2018)

Dionne U, Chartier FJM, de los Santos YL, Lavoie N, Bernard DN,  Banerjee SL, Otis F, Jacquet K, Tremblay MG, Jain M, Bourassa S, Gish GD, Gagné JP, Poirier GG, Laprise P, Voyer N, Landry CR, Doucet N & Bisson N, Direct phosphorylation of SRC Homology 3 domains by tyrosine kinase receptors disassembles ligand-induced signalling networks. Molecular Cell 70:1-13 (2018)

Wolters JF, Charron G, Gaspary A, Landry CR, Fiumera AC & Fiumera HI, Mitochondrial recombination reveals mito-mito epistasis in yeast. Genetics 209:307-319 (2018)

Chrétien AE, Gagnon-Arsenault I, Dubé AK, Barbeau X, Després PC, Lamothe C, Dion-Côté AM, Lagüe P & Landry CR, Extended linkers improve the detection of protein-protein interactions (PPIs) by dihydrofolate reductase protein-fragment complementation assay (DHFR PCA) in living cells. Molecular & Cellular Proteomics 17:373-383 (2018)

Hénault M*, Eberlein C*, Charron G, Durand E, Nielly-Thibault L, Martin H & Landry CR, Yeast population genomics goes wild: the case of Saccharomyces paradoxus. In: Polz M, Rajora OP (eds) Population genomics: microorganisms. Springer (2017)

Samandi S, Roy AV, Delcourt V, Lucier JF, Gagnon J, Beaudoin MC, Vanderperre B, Breton MA, Motard J, Jacques JF, Brunelle M, Gagnon-Arsenault I, Fournier I, Ouangraoua A, Hunting DJ, Cohen AA, Landry CR, Scott MS & Roucou X, Deep transcriptome annotation enables the discovery and functional characterization of cryptic small proteins. eLife 6:e27860 (2017)

Landry CR & Diss G, Molecular dependency impacts on the compensating ability of paralogs: a response to Veitia. Trends in Genetics 33:657-658 (2017)

Leducq JB*, Henault M*, Charron G, Nielly-Thibault L, Terrat Y, Fiumera HL, Shapiro BJ & Landry CR, Mitochondrial recombination and introgression during speciation by hybridization. Molecular Biology and Evolution 34:1947-1959 (2017)

Eberlein C, Nielly-Thibault L, Maaroufi H, Dubé AK, Leducq JB, Charron G & Landry CR, The rapid evolution of an ohnolog contributes to the ecological specialization of incipient yeast species. Molecular Biology and Evolution 34:2173-2186 (2017)

Charron G & Landry CR, No evidence for extrinsic post-zygotic isolation in a wild Saccharomyces yeast system. Biology Letters 13:20170197 (2017)

Marsit S, Leducq JB, Durand E, Marchant A, Filteau M & Landry CR, Evolutionary biology through the lens of budding yeast comparative genomics. Nature Reviews Genetics 18:581-598 (2017)

Peris D, Moriarty RV, Alexander WG, Baker EC, Sylvester K, Sardi M, Langdon QK, Libkind D, Wang QM, Bai FY, Leducq JB, Charron G, Landry CR, Sampaio JP, Gonçalves P, Hyma KE, Fay JC, Sato TK & Hittinger CT, Hybridization and adaptive evolution of diverse Saccharomyces species for cellulosic biofuel production. Biotechnology for Biofuels 10:78 (2017)

Diss G, Gagnon-Arsenault I, Dion-Coté AM, Vignaud H, Ascencio DI, Berger CM & Landry CR, Gene duplication can impart fragility, not robustness, in the yeast protein interaction network. Science 355:630-634 (2017)

Hébert FO, Grambauer S, Barber I, Landry CR & Aubin-Horth N, Major host transitions are modulated through transcriptome-wide reprogramming events in Schistocephalus solidus, a threespine stickleback parasite. Molecular Ecology 26:1118–1130 (2017)

Xia W, Nielly-Thibault L, Charron G, Landry CR, Kasimer D, Anderson JB & Kohn LM, Population genomics reveals structure at the individual, host-tree scale and persistence of genotypic variants of the undomesticated yeast Saccharomyces paradoxus in a natural woodland. Molecular Ecology 26:995–1007 (2017)

Hénault M & CR Landry. When nuclear-encoded proteins and mitochondrial RNAs do not get along, species split apart. EMBO Reports 18:8–10 (2017)

Caron D, Byrne DP, Thebault P, Soulet D, Landry CR, Eyers PA & Elowe S, Mitotic phosphotyrosine network analysis reveals that tyrosine phosphorylation regulates Polo-like kinase 1 (PLK1). Science Signaling 9:rs14 (2016)

Filteau M, Charron G & Landry CR, Identification of the fitness determinants of budding yeast on a natural substrate. The ISME Journal 11:959–971 (2016)

Bleuven C & Landry CR, Molecular and cellular bases of adaptation to a changing environment in microorganisms. Proceedings of the Royal Society B 283:20161458 (2016)

Peris D, Langdon QK, Moriarty RV, Sylvester K, Bontrager M, Charron G, Leducq JB, Landry CR, Libkind D & Hittinger CT, Complex ancestries of lager-brewing hybrids were shaped by standing variation in the wild yeast Saccharomyces eubayanus. PLoS Genetics 12:e1006155 (2016)

Hébert FO, Grambauer S, Barber I, Landry CR & Aubin-Horth N, Transcriptome sequences spanning key developmental states as a resource for the study of the cestode Schistocephalus solidus, a threespine stickleback parasite. GigaScience 5:24 (2016)

Leducq JB*, Nielly-Thibault L*, Charron G*, Eberlein C, Verta JP, Samani P, Sylvester K, Hittinger CT, Bell G & Landry CR, Speciation driven by hybridization and chromosomal plasticity in a wild yeast. Nature Microbiology 1:15003 (2016)

Landry CR, Analysis of biological systems. Invited book review for The Quarterly Review of Biology (2016)

Verta JP, Landry CR & Mackay J, Dissection of expression-quantitative trait locus and allele specificity using a haploid/diploid plant system – insights into compensatory evolution of transcriptional regulation within populations. New Phytologist 211:159–171 (2016)

Barbosa R, Almeida P, Safar SVB, Santos RO, Morais PB, Nielly-Thibault L, Leducq JB, Landry CR, Gonçalves P, Rosa CA & Sampaio JP, Evidence of natural hybridization in Brazilian wild lineages of Saccharomyces cerevisiae. Genome Biology and Evolution 18:317–329 (2016)

Filteau M, Hamel V & Landry CR,  La levure à vin – Modèle d’étude des gènes et des maladies humaines dans un contexte personnalisé. Médecine/Sciences 32:332–334 (2016)

Michnick SW, Landry CR, Levy ED, Diss G, Ear PH, Kowarzyk J, Malleshaiah MK, Messier V & Tchekanda E, Protein-fragment complementation assays for large-scale analysis, functional dissection, and spatiotemporal dynamic studies of protein-protein interactions in living cells. Cold Spring Harbor Protocol (2016)

Michnick SW, Levy ED, Landry CR, Kowarzyk J & Messier V, The dihydrofolate reductase protein-fragment complementation assay: a survival-selection assay for large-scale analysis of protein-protein interactions. Cold Spring Harbor Protocol (2016)

Diss G & Landry CR, Combining the dihydrofolate reductase protein-fragment complementation assay with gene deletions to establish genotype-to-phenotype maps of protein complexes and interaction networks. Cold Spring Harbor Protocol (2016)

Filteau M, Hamel V, Pouliot MC, Gagnon-Arsenault I, Dubé AK & Landry CR, Evolutionary rescue by compensatory mutations is constrained by genomic and environmental backgrounds. Molecular Systems Biology 11:832 (2015)

Filteau M, Vignaud H, Rochette S, Diss G, Chrétien AE, Berger CM & Landry CR, Multi-scale perturbations of protein interactomes reveal their mechanisms of regulation, robustness and insights into genotype-phenotype maps. Briefings in Functional Genomics 15:130–137 (2015)

Eberlein C, Leducq JB & Landry CR, The genomics of wild yeast populations sheds lights on the domestication of man’s best (micro) friend. Molecular Ecology 24:5309-5311 (2015)

Nigg M, Laroche J, Landry CR & Bernier L, RNAseq analysis highlights specific transcriptome signatures of yeast and mycelial growth phases in the Dutch elm disease fungus Ophiostoma novo-ulmi. G3: Genes|Genomes|Genetics 5:2487-2495 (2015)

Torres-Quiroz F, Filteau M & Landry CR, Feedback regulation between autophagy and PKA. Autophagy 11:1181-1183 (2015)

Freel KC, Charron G, Leducq JB, Landry CR & Schacherer J, Lachancea quebecensis sp. nov., a yeast species consistently isolated from the tree bark in the Canadian province of Quebec. International Journal of Systematic and Evolutionary Microbiology 65:3392-3399 (2015)

Filteau M, Diss G, Torres-Quiroz F, Dubé AK, Schraffl A, Bachmann VA, Gagnon-Arsenault I, Chrétien AE, Steunou AL, Dionne U, Côté J, Bisson N, Stefan E & Landry CR, Systematic identification of signal integration by protein kinase A. PNAS 112:4501-4506 (2015)

Hebert FO, Phelps L, Samonte I, Panchal M, Grambauer S, Barber I, Kalbe M, Landry CR & Aubin-Horth N, Identification of candidate mimicry proteins involved in parasite-driven phenotypic changes. Parasites & Vectors 8:225 (2015)

Landry CR, Zhong X, Nielly-Thibault L & Roucou X, Found in translation: functions and evolution of a recently discovered alternative proteome. Current Opinion in Structural Biology 32:74–80 (2015)

Boutchueng-Djidjou M, Collard-Simard G, Fortier S, Hébert SS, Kelly I, Landry CR & Faure RL, The last enzyme of the de novo purine synthesis pathway 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC) plays a central role in insulin signalling and the Golgi/endosomes protein network. Molecular and Cellular Proteomics 14:1079-1092 (2015)

Stockwell SR, Landry CR & Rifkin SA, The yeast galactose network as a quantitative model for cellular memory. Molecular BioSystems 11:28-37 (2015)

Samani P, Low-Decarie E, McKelvey K, Bell T, Burt A, Koufopanou V, Landry CR & Bell G, Metabolic variation in natural populations of wild yeast. Ecology and Evolution 5:722-732 (2015)

Rochette S*, Diss G*, Filteau M, Leducq JB, Dubé AK & Landry CR, Genome-wide protein-protein interaction screening by Protein-fragment Complementation Assay (PCA) in living cells. Journal of Visualized Experiments 97:e52255 (2015)

Nguyen Ba AN, Strome B, Hua JJ, Desmond J, Gagnon-Arsenault I, Weiss EL, Landry CR & Moses AM, Detecting functional divergence after gene duplication through evolutionary changes in posttranslational regulatory sequences. PLoS Computational Biology 12:e1003977 (2014)

Charron G*, Leducq JB* & Landry CR, Chromosomal variation segregates within incipient species and correlates with reproductive isolation. Molecular Ecology 23:4362-4372 (2014)

Landry CR, Freschi L, Zarin T & Moses AM, Turnover of protein phosphorylation evolving under stabilizing selection. Frontiers in Genetics 5:245 (2014)

Goldman A, Roy J, Bodenmiller B, Wanka S, Landry CR, Aebersold R & Cyert MS, The calcineurin signaling network evolves via conserved kinase-phosphatase modules that transcend substrate identity.  Molecular Cell 55:422-435 (2014)

Leducq JB*, Charron G*, Samani P, Dubé AK, Sylvester K, James B, Almeida P, Sampaio JP, Hittinger CT, Bell G & Landry CR, Local climatic adaptation in a widespread microorganism. Proceedings of the Royal Society B 281:20132472 (2014)

Freschi L, Osseni M & Landry CR, Functional divergence and evolutionary turnover in mammalian phosphoproteomes. PLoS Genetics 10:e1004062 (2014)

Landry CR & Aubin-Horth N, Recent advances in ecological genomics: from phenotypic plasticity to convergent and adaptive evolution and speciation. In: Landry C, Aubin-Horth N (eds) Ecological Genomics. Advances in Experimental Medicine and Biology, 781. Springer, Dordrecht (2014)

Rochette S, Gagnon-Arsenault I, Diss G & Landry CR, Modulation of the yeast protein interactome in response to DNA damage. Journal of Proteomics 100:25-36 (2014)

Diss G, Ascencio D, DeLuna A & Landry CR, Molecular mechanisms of paralogous compensation and the robustness of cellular networks. Journal of Experimental Zoology Part B: Molecular and Developmental Evolution 322:488-499 (2014)

Charron G, Leducq JB, Bertin C, Dubé AK & Landry CR, Exploring the northern limit of the distribution of Saccharomyces cerevisiae and Saccharomyces paradoxus in North America. FEMS Yeast Research 14:281-288 (2014)

Landry CR*, Levy ED*, Abd Rabbo D, Tarassov K & Michnick SW, Extracting insight from noisy cellular networks. Cell 155:983–989 (2013)

Diss G, Dubé AK, Boutin J, Gagnon-Arsenault I & Landry CR, A systematic approach for the genetic dissection of protein complexes in living cells. Cell Reports 3:2155–2167 (2013)
See also Nature Methods 10:821 (2013)

Diss G, Filteau M, Freschi L, Leducq JB, Rochette S, Torres-Quiroz F & Landry CR, Integrative avenues for exploring the dynamics and evolution of protein interaction networks. Current Opinion in Biotechnology 24:775-783 (2013)

Verta JP, Landry CR & Mackay JJ, Are long-lived trees poised for evolutionary change? Single locus effects in the evolution of gene expression networks in spruce. Molecular Ecology 22:23692379 (2013)

Gagnon-Arsenault I, Marois Blanchet FC, Rochette S, Diss G, Dubé AK & Landry CR, Transcriptional divergence plays a role in the rewiring of protein interaction networks after gene duplication. Journal of Proteomics 81:112-125 (2013)

Freschi L, Torres-Quiroz F, Dubé AK & Landry CR, qPCA: a scalable assay to measure the perturbation of protein-protein interactions in living cells. Molecular BioSystems 9:36-43 (2013)

Leducq JB, Charron G, Diss G, Gagnon-Arsenault I, Dubé AK & Landry CR, Evidence for the robustness of protein complexes to inter-species hybridization. PLoS Genetics 8:e1003161 (2012)

Goyette G*, Boulais J*, Carruthers NJ, Landry CR, Jutras I, Duclos S, Dermine JF, Michnick SW, LaBoissière S, Lajoie G, Barreiro L, Thibault P & Desjardins M, Proteomic characterization of phagosomal membrane microdomains during phagolysosome biogenesis and evolution. Molecular & Cellular Proteomics 11:1365-1377 (2012)

Pavey SA, Bernatchez L, Aubin-Horth N & Landry CR, What is needed for next-generation ecological and evolutionary genomics? Trends in Ecology and Evolution 27:673-678 (2012)

Landry CR & Rifkin SA, The genotype-phenotype maps of systems biology and quantitative genetics: distinct and complementary. In: Soyer O (eds) Evolutionary Systems Biology. Advances in Experimental Medicine and Biology, 751. Springer, New York (2012)

Diss G, Freschi L & Landry CR, Where do phosphosites come from and where do they go after gene duplication? International Journal of Evolutionary Biology 2012:843167 (2012)

Levy ED, Michnick SW & Landry CR, Protein abundance is key to distinguish promiscuous from functional phosphorylation based on evolutionary information. Philosophical Transactions of The Royal Society B Biological Sciences 367:2594-606 (2012)

Lee S, Thebault P, Freschi L, Beaufils S, Blundell TL, Landry CR, Bolanos-Garcia VM & Elowe S, Characterization of spindle checkpoint kinase Mps1 reveals a domain with functional and structural similarities to tetratricopeptide repeat motifs of the Bub1 and BubR1 checkpoint kinases. The Journal of Biological Chemistry 287:5988-6001 (2012)

Landry CR, A cellular roadmap for the plant kingdom. Science 333:532-533 (2011)

Freschi L, Courcelles M, Thibault P, Michnick SW & Landry CR, Phosphorylation network rewiring by gene duplication. Molecular Systems Biology 7:504 (2011)

Michnick SW, Ear PH, Landry C, Malleshaiah MK & Messier V, Protein-fragment complementation assays for large-scale analysis, functional dissection and dynamic studies of protein-protein interactions in living cells. In: Luttrell L, Ferguson S (eds) Signal transduction protocols. Methods in Molecular Biology 756. Humana Press, Totowa NJ (2011)

2010

Landry CR & Rifkin SA, Chromatin regulators shape the genotype-phenotype map. Molecular Systems Biology 6:434 (2010)

Boulais J, Trost M, Landry CR, Dieckmann R, Levy ED, Soldati T, Michnick SW, Thibault P & Desjardins M, Molecular characterization of the evolution of phagosomes. Molecular Systems Biology 6:423 (2010)

Landry CR & Aubin-Horth N, Gene network architecture as a canvas for the interpretation of ecological genomics investigations. Molecular Ecology 19:5084-5085 (2010)

Moses AM & Landry CR, Moving from transcriptional to phospho-evolution: generalizing regulatory evolution? Trends in Genetics 26:462-467 (2010)

Di Poi C, Diss G & Freschi L, Biodiversity matters in a changing world. Biology Letters 7:4-6 (2010) **Student initiative**

Levy ED*, Landry CR* & Michnick SW, Signaling through cooperation. Science 328:983-984 (2010)

Michnick SW, Ear PH, Landry CR, Malleshaiah MK & Messier V, A toolkit of protein-fragment complementation assays for studying and dissecting large-scale and dynamic protein-protein interactions in living cells. In: Weissman J, Guthrie C, Fink G (eds.) Guide to yeast genetics: functional genomics, proteomics and other systems analysis. Methods in Enzymology 470. Elsevier Press, New York USA (2010)

Fontanillas P, Landry CR, Wittkopp PJ, Russ C, Gruber JD, Nusbaum C & Hartl DL, Key considerations for measuring allelic expression on a genomic scale using high-throughput sequencing. Molecular Ecology 19:212–227 (2010)

 

2009

Landry CR*, Levy ED* & Michnick SW, Weak functional constraints on phosphoproteomes. Trends in Genetics 25:193-197 (2009)

Levy ED*, Landry CR* & Michnick SW, How perfect can protein interactomes be? Science Signalling 2:pe11 (2009)

Landry CR, Systems biology spins off a new model for the study of canalization. Trends in Ecology and Evolution 24:63-66 (2009)

 

2008

Cheung V, Chua G, Batada NN, Landry CR, Michnick SW, Hughes TR & Winston F, Chromatin- and transcription-related factors repress transcription from within coding regions throughout the Saccharomyces cerevisiae genome. PloS Biology 6:e277 (2008)

Tarassov K*, Messier V*, Landry CR*, Radinovic S*, Serna Molina MM, Shames I, Malitskaya Y, Vogel J, Bussey H & Michnick SW, An in vivo map of the yeast protein interactome. Science 320:1465-1479 (2008)

Lynch M, Sung W, Morris K, Coffey N, Landry CR, Dopman EB, Dickinson WJ, Okamoto K, Kulkarni S, Hartl DL & Thomas WK, A Genome-wide view of the spectrum of spontaneous mutations in yeast. Proceedings of the National Academy of Sciences of the United States of America 105:9272-9277 (2008)

Brown KM, Landry CR, Hartl DL & Cavalieri D, Cascading transcriptional effects of a naturally occurring frameshift mutation in Saccharomyces cerevisiae. Molecular Ecology 17:2985-2997 (2008)

 

2007

Stefan E, Aquin S, Berger N, Landry CR, Nyfeler B, Bouvier M & Michnick SW, Quantification of dynamic protein complexes using Renilla luciferase-fragment complementation applied to protein kinase A activities in vivo. Proceedings of the National Academy of Sciences of the United States of America 104:16916-16921 (2007)

Landry CR*, Lemos B*, Rifkin SA, Dickinson WJ & Hartl DL, Genetic properties influencing the evolvability of gene expression. Science 317:118-121 (2007)

Landry CR, Castillo-Davis CI, Ogura A, Liu JS & Hartl DL, Systems-level analysis and evolution of the Drosophila phototransduction cascade. Proceedings of the National Academy of Sciences of the United States of America 104:3283-3288 (2007)

Landry CR & Aubin-Horth N, Ecological annotation of genes and genomes through ecological genomics. Molecular Ecology 16:4419-4421 (2007)

Landry CR, Hartl DL & Ranz JM, Genome clashes in hybrids: insights from gene expression. Heredity 99:483-493 (2007)

Lemos B, Landry CR, Fontanillas P, Renn SP, Kulathinal R, Brown KM & Hartl DL, Evolution of Genomic Expression. In Pagel M, Pomiankowski A (eds) Evolutionary genomics and proteomics. Sinauer Associates, Sunderland, MA (2007)

Salathia N, Lee HN, Sangster TA, Morneau K, Landry CR, Schellenberg K, Behere AS, Gunderson KL, Cavalieri D, Jander G & Queitsch C, Indel array: an affordable alternative for genotyping. Plant Journal 51:727-737 (2007)

 

2006

Landry CR, Townsend JP, Hartl DL & Cavalieri D, Ecological and evolutionary genomics of Saccharomyces cerevisiae. Molecular Ecology 15:575-591 (2006)

Landry CR, Oh J, Hartl DL & Cavalieri D, Genome-wide scan reveals that genetic variation for transcriptional plasticity in yeast is biased towards multi-copy and dispensable genes. Gene 366:343-351 (2006)

 

2005

Landry CR, Wittkopp PJ, Taubes CH, Ranz JM, Clark AG & Hartl DL, Compensatory cis-trans evolution and the dysregulation of gene expression in interspecific hybrids of Drosophila. Genetics 171:1813-1822 (2005)

Giuntini E, Mengoni A, De Filippo C, Cavalieri D, Aubin-Horth N, Landry CR, Becker A & Bazzicalupo M, Large-scale genetic variation of the symbiosis-required megaplasmid pSymA revealed by comparative genomic analysis of Sinorhizobium meliloti natural strains. BMC Genomics 6: 158 (2005)

Aubin-Horth N, Landry CR, Letcher BH & Hofmann HA, Alternative life-histories shape brain gene expression profiles in males of the same population. Proceedings of the Royal Society B 272:1655-1662 (2005)

 

2003

Landry C, Geyer LB, Arakaki Y, Uehara T & Palumbi SR, Recent speciation in the Indo-West Pacific: rapid evolution of gamete recognition and sperm morphology in cryptic species of sea urchin. Proceedings of the Royal Society B 270:1839-1847 (2003)

Bernatchez L & Landry C, MHC studies in nonmodel vertebrates: what have we learned about natural selection in 15 years? Journal of Evolutionary Biology 16:363-377 (2003)

 

2001

Landry C & Bernatchez L, Comparative analysis of population structure across environments and geographic scales at major histocompatibility complex and microsatellite Atlantic salmon (Salmo salar). Molecular Ecology 10:2525-2540 (2001)

Landry C, Garant D, Duchesne P & Bernatchez L, “Good genes as heterozygosity”: the major histocompatibility complex and mate choice in Atlantic salmon (Salmo salar). Proceedings of the Royal Society B 268:1279-1285 (2001)