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1.
Res Sq ; 2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-38343805

RESUMO

Pre-Pulse Inhibition (PPI) is a neural process where suppression of a startle response is elicited by preceding the startling stimulus (Pulse) with a weak, non-startling one (Pre-Pulse). Defective PPI is widely employed as a behavioural endophenotype in humans and mammalian disorder-relevant models for neuropsychiatric disorders. We have developed a user-friendly, semi-automated, high-throughput-compatible Drosophila light-off jump response PPI paradigm, with which we demonstrate that PPI, with similar parameters measured in mammals, exists in adults of this model organism. We report that Drosophila PPI is affected by reduced expression of Dysbindin and both reduced and increased expression of Nmdar1 (N-methyl-D-aspartate receptor 1), perturbations associated with schizophrenia. Studying the biology of PPI in an organism that offers a plethora of genetic tools and a complex and well characterized connectome will greatly facilitate our efforts to gain deeper insight into the aetiology of human mental disorders, while reducing the need for mammalian models.

2.
Nat Ecol Evol ; 6(6): 763-773, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35484218

RESUMO

Deleterious mutations are generally considered to be irrelevant for morphological evolution. However, they could be compensated by conditionally beneficial mutations, thereby providing access to new adaptive paths. Here we use high-dimensional phenotyping of laboratory-evolved budding yeast lineages to demonstrate that new cellular morphologies emerge exceptionally rapidly as a by-product of gene loss and subsequent compensatory evolution. Unexpectedly, the capacities for invasive growth, multicellular aggregation and biofilm formation also spontaneously evolve in response to gene loss. These multicellular phenotypes can be achieved by diverse mutational routes and without reactivating the canonical regulatory pathways. These ecologically and clinically relevant traits originate as pleiotropic side effects of compensatory evolution and have no obvious utility in the laboratory environment. The extent of morphological diversity in the evolved lineages is comparable to that of natural yeast isolates with diverse genetic backgrounds and lifestyles. Finally, we show that both the initial gene loss and subsequent compensatory mutations contribute to new morphologies, with their synergistic effects underlying specific morphological changes. We conclude that compensatory evolution is a previously unrecognized source of morphological diversity and phenotypic novelties.


Assuntos
Saccharomycetales , Mutação , Fenótipo , Saccharomyces cerevisiae/genética , Saccharomycetales/genética
3.
J Fungi (Basel) ; 7(9)2021 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-34575784

RESUMO

Saccharomyces yeast probiotics (S. 'boulardii') have long been applied in the treatment of several gastrointestinal conditions. Despite their widespread use, they are rare opportunistic pathogens responsible for a high proportion of Saccharomyces mycosis cases. The potential virulence attributes of S. 'boulardii' as well as its interactions with the human immune system have been studied, however, no information is available on how these yeasts may change due to in-host evolution. To fill this gap, we compared the general phenotypic characteristics, cell morphology, virulence factors, epithelial and immunological interactions, and pathogenicity of four probiotic product samples, two mycosis, and eight non-mycosis samples of S. 'boulardii'. We assessed the characteristics related to major steps of yeast infections. Mycosis and non-mycosis isolates both displayed novel characters when compared to the product isolates, but in the case of most virulence factors and in pathogenicity, differences were negligible or, surprisingly, the yeasts from products showed elevated levels. No isolates inflicted considerable damage to the epithelial model or bore the hallmarks of immune evasion. Our results show that strains in probiotic products possess characteristics that enable them to act as pathogens upon permissive conditions, and their entry into the bloodstream is not due to active mechanisms but depends on the host. Survival in the host is dependent on yeast phenotypic characteristics which may change in many ways once they start evolving in the host. These facts call attention to the shortcomings of virulence phenotyping in yeast research, and the need for a more thorough assessment of probiotic use.

4.
Mol Biol Evol ; 38(3): 1137-1150, 2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33306797

RESUMO

The fitness impact of loss-of-function mutations is generally assumed to reflect the loss of specific molecular functions associated with the perturbed gene. Here, we propose that rewiring of the transcriptome upon deleterious gene inactivation is frequently nonspecific and mimics stereotypic responses to external environmental change. Consequently, transcriptional response to gene deletion could be suboptimal and incur an extra fitness cost. Analysis of the transcriptomes of ∼1,500 single-gene deletion Saccharomyces cerevisiae strains supported this scenario. First, most transcriptomic changes are not specific to the deleted gene but are rather triggered by perturbations in functionally diverse genes. Second, gene deletions that alter the expression of dosage-sensitive genes are especially harmful. Third, by elevating the expression level of downregulated genes, we could experimentally mitigate the fitness defect of gene deletions. Our work shows that rewiring of genomic expression upon gene inactivation shapes the harmful effects of mutations.


Assuntos
Regulação Fúngica da Expressão Gênica , Mutação com Perda de Função , Deleção de Genes , Saccharomyces cerevisiae , Transcriptoma
5.
Magy Seb ; 73(2): 57-60, 2020 Jun.
Artigo em Húngaro | MEDLINE | ID: mdl-32609631

RESUMO

Patients and methods: Between 1st November 2013 and 30th June 2019 we performed 112 VATS lobectomies with isolated intubation and anterior approach. In 98 cases lobectomies were performed for malignant lesions, while in 9 cases for benign changes. 78 men and 34 women were operated on. The average age was 60.5 years (42­63). In 5 cases the left upper lobes were resected, in cases 36 the left lower lobes, in 15 cases the right upper lobes, in 11 cases the mid lobes, in 44 cases the right lower lobes, and in one case pneumonectomy was performed. Results: there was no postoperative mortality. Conversion was required in three 3 patients. The average time of surgery was 150 minutes (70­215). Re-operation was needed in two cases due to bleeding and air leakage. Out of the 112 operations, primary lung cancer was demonstrated on pathology in 88 cases, while benign lesions /inflammation in 9 cases. The stages of primary lung cancer were the following: I.a:57, I.b:22, II.a:6, II.b:3 patients. Tumour subtypes were the detailed as 52 adenocarcinoma, 23 squamous cell cc., 2 small cell cc., 5 large cell cc., and 6 carcinoid. 10 patients underwent VATS lobectomy for metastatic disease. Conclusion: As a result of an adequate learning period, VATS lobectomies have become a routine surgery in our unit. Currently 65% of the thoracotomies and more than 50 percent of the lobectomies are performed by the VATS method. Our results are comparable to national as well as international data.


Assuntos
Neoplasias Pulmonares/cirurgia , Pneumonectomia/métodos , Cirurgia Torácica Vídeoassistida/métodos , Adulto , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Estudos Retrospectivos , Toracotomia , Resultado do Tratamento
6.
Mol Biol Evol ; 37(8): 2228-2240, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32191325

RESUMO

Convergent evolution is pervasive in nature, but it is poorly understood how various constraints and natural selection limit the diversity of evolvable phenotypes. Here, we analyze the transcriptome across fruiting body development to understand the independent evolution of complex multicellularity in the two largest clades of fungi-the Agarico- and Pezizomycotina. Despite >650 My of divergence between these clades, we find that very similar sets of genes have convergently been co-opted for complex multicellularity, followed by expansions of their gene families by duplications. Over 82% of shared multicellularity-related gene families were expanding in both clades, indicating a high prevalence of convergence also at the gene family level. This convergence is coupled with a rich inferred repertoire of multicellularity-related genes in the most recent common ancestor of the Agarico- and Pezizomycotina, consistent with the hypothesis that the coding capacity of ancestral fungal genomes might have promoted the repeated evolution of complex multicellularity. We interpret this repertoire as an indication of evolutionary predisposition of fungal ancestors for evolving complex multicellular fruiting bodies. Our work suggests that evolutionary convergence may happen not only when organisms are closely related or are under similar selection pressures, but also when ancestral genomic repertoires render certain evolutionary trajectories more likely than others, even across large phylogenetic distances.


Assuntos
Ascomicetos/genética , Basidiomycota/genética , Evolução Biológica , Carpóforos/genética , Regulação da Expressão Gênica no Desenvolvimento , Família Multigênica
7.
Elife ; 72018 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-29377792

RESUMO

Proteins are necessary for cellular growth. Concurrently, however, protein production has high energetic demands associated with transcription and translation. Here, we propose that activity of molecular chaperones shape protein burden, that is the fitness costs associated with expression of unneeded proteins. To test this hypothesis, we performed a genome-wide genetic interaction screen in baker's yeast. Impairment of transcription, translation, and protein folding rendered cells hypersensitive to protein burden. Specifically, deletion of specific regulators of the Hsp70-associated chaperone network increased protein burden. In agreement with expectation, temperature stress, increased mistranslation and a chemical misfolding agent all substantially enhanced protein burden. Finally, unneeded protein perturbed interactions between key components of the Hsp70-Hsp90 network involved in folding of native proteins. We conclude that specific chaperones contribute to protein burden. Our work indicates that by minimizing the damaging impact of gratuitous protein overproduction, chaperones enable tolerance to massive changes in genomic expression.


Assuntos
Metabolismo Energético , Proteínas de Choque Térmico HSP72/metabolismo , Chaperonas Moleculares/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo
8.
Mol Biol Evol ; 33(5): 1257-69, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26769030

RESUMO

Why are certain bacterial genomes so small and compact? The adaptive genome streamlining hypothesis posits that selection acts to reduce genome size because of the metabolic burden of replicating DNA. To reveal the impact of genome streamlining on cellular traits, we reduced the Escherichia coli genome by up to 20% by deleting regions which have been repeatedly subjects of horizontal transfer in nature. Unexpectedly, horizontally transferred genes not only confer utilization of specific nutrients and elevate tolerance to stresses, but also allow efficient usage of resources to build new cells, and hence influence fitness in routine and stressful environments alike. Genome reduction affected fitness not only by gene loss, but also by induction of a general stress response. Finally, we failed to find evidence that the advantage of smaller genomes would be due to a reduced metabolic burden of replicating DNA or a link with smaller cell size. We conclude that as the potential energetic benefit gained by deletion of short genomic segments is vanishingly small compared with the deleterious side effects of these deletions, selection for reduced DNA synthesis costs is unlikely to shape the evolution of small genomes.


Assuntos
Transferência Genética Horizontal , Tamanho do Genoma , Genoma Bacteriano , Evolução Biológica , Escherichia coli/genética , Evolução Molecular , Genes Bacterianos , Filogenia
9.
PLoS Biol ; 12(8): e1001935, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25157590

RESUMO

Adaptive evolution is generally assumed to progress through the accumulation of beneficial mutations. However, as deleterious mutations are common in natural populations, they generate a strong selection pressure to mitigate their detrimental effects through compensatory genetic changes. This process can potentially influence directions of adaptive evolution by enabling evolutionary routes that are otherwise inaccessible. Therefore, the extent to which compensatory mutations shape genomic evolution is of central importance. Here, we studied the capacity of the baker's yeast genome to compensate the complete loss of genes during evolution, and explored the long-term consequences of this process. We initiated laboratory evolutionary experiments with over 180 haploid baker's yeast genotypes, all of which initially displayed slow growth owing to the deletion of a single gene. Compensatory evolution following gene loss was rapid and pervasive: 68% of the genotypes reached near wild-type fitness through accumulation of adaptive mutations elsewhere in the genome. As compensatory mutations have associated fitness costs, genotypes with especially low fitnesses were more likely to be subjects of compensatory evolution. Genomic analysis revealed that as compensatory mutations were generally specific to the functional defect incurred, convergent evolution at the molecular level was extremely rare. Moreover, the majority of the gene expression changes due to gene deletion remained unrestored. Accordingly, compensatory evolution promoted genomic divergence of parallel evolving populations. However, these different evolutionary outcomes are not phenotypically equivalent, as they generated diverse growth phenotypes across environments. Taken together, these results indicate that gene loss initiates adaptive genomic changes that rapidly restores fitness, but this process has substantial pleiotropic effects on cellular physiology and evolvability upon environmental change. Our work also implies that gene content variation across species could be partly due to the action of compensatory evolution rather than the passive loss of genes.


Assuntos
Evolução Molecular , Genoma Fúngico/genética , Saccharomyces cerevisiae/genética , Adaptação Biológica/genética , Meio Ambiente , Epistasia Genética , Deleção de Genes , Regulação Fúngica da Expressão Gênica , Aptidão Genética , Pleiotropia Genética , Variação Genética , Fenótipo , Transcriptoma/genética
10.
Mol Biol Evol ; 29(10): 3153-9, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22527906

RESUMO

Although both genotypes with elevated mutation rate (mutators) and mobilization of insertion sequence (IS) elements have substantial impact on genome diversification, their potential interactions are unknown. Moreover, the evolutionary forces driving gradual accumulation of these elements are unclear: Do these elements spread in an initially transposon-free bacterial genome as they enable rapid adaptive evolution? To address these issues, we inserted an active IS1 element into a reduced Escherichia coli genome devoid of all other mobile DNA. Evolutionary laboratory experiments revealed that IS elements increase mutational supply and occasionally generate variants with especially large phenotypic effects. However, their impact on adaptive evolution is small compared with mismatch repair mutator alleles, and hence, the latter impede the spread of IS-carrying strains. Given their ubiquity in natural populations, such mutator alleles could limit early phase of IS element evolution in a new bacterial host. More generally, our work demonstrates the existence of an evolutionary conflict between mutation-promoting mechanisms.


Assuntos
Elementos de DNA Transponíveis/genética , Escherichia coli/genética , Genes Bacterianos/genética , Taxa de Mutação , Mutação/genética , Reparo de Erro de Pareamento de DNA/genética , Escherichia coli/crescimento & desenvolvimento , Evolução Molecular , Aptidão Genética , Genótipo , Interações Hospedeiro-Patógeno/genética , Mutagênese Insercional/genética , Óperon/genética
11.
Nat Genet ; 43(7): 656-62, 2011 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-21623372

RESUMO

Although experimental and theoretical efforts have been applied to globally map genetic interactions, we still do not understand how gene-gene interactions arise from the operation of biomolecular networks. To bridge the gap between empirical and computational studies, we i, quantitatively measured genetic interactions between ∼185,000 metabolic gene pairs in Saccharomyces cerevisiae, ii, superposed the data on a detailed systems biology model of metabolism and iii, introduced a machine-learning method to reconcile empirical interaction data with model predictions. We systematically investigated the relative impacts of functional modularity and metabolic flux coupling on the distribution of negative and positive genetic interactions. We also provide a mechanistic explanation for the link between the degree of genetic interaction, pleiotropy and gene dispensability. Last, we show the feasibility of automated metabolic model refinement by correcting misannotations in NAD biosynthesis and confirming them by in vivo experiments.


Assuntos
Regulação Fúngica da Expressão Gênica , Redes Reguladoras de Genes , Modelos Genéticos , Mapeamento de Interação de Proteínas , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Inteligência Artificial , Biologia Computacional , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética
12.
PLoS Biol ; 7(5): e1000115, 2009 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-19492041

RESUMO

In bacterial genomes, gene order is not random. This is most evident when looking at operons, these often encoding enzymes involved in the same metabolic pathway or proteins from the same complex. Is gene order within operons nonrandom, however, and if so why? We examine this issue using metabolic operons as a case study. Using the metabolic network of Escherichia coli, we define the temporal order of reactions. We find a pronounced trend for genes to appear in operons in the same order as they are needed in metabolism (colinearity). This is paradoxical as, at steady state, enzymes abundance should be independent of order within the operon. We consider three extensions of the steady-state model that could potentially account for colinearity: (1) increased productivity associated with higher expression levels of the most 5' genes, (2) a faster metabolic processing immediately after up-regulation, and (3) metabolic stalling owing to stochastic protein loss. We establish the validity of these hypotheses by employing deterministic and stochastic models of enzyme kinetics. The stochastic stalling hypothesis correctly and uniquely predicts that colinearity is more pronounced both for lowly expressed operons and for genes that are not physically adjacent. The alternative models fail to find any support. These results support the view that stochasticity is a pervasive problem to a cell and that gene order evolution can be driven by the selective consequences of fluctuations in protein levels.


Assuntos
Escherichia coli/metabolismo , Regulação Bacteriana da Expressão Gênica , Ordem dos Genes , Óperon , Processos Estocásticos , Escherichia coli/genética , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Genes Bacterianos/genética , Modelos Biológicos
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