The impact of the genetic background on gene deletion phenotypes in<i>Saccharomyces cerevisiae</i>

Busby, Bede P.; Viéitez, Cristina; Dunham, Alistair S.; Typas, Athanasios; Beltrão, Pedro

doi:10.1101/487439

Cited by 8 publications

(8 citation statements)

References 54 publications

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“…In yeast, for example, 80% of gene knock-outs are silent in the sense that they produce no phenotypic effect when the yeast is well-nourished (Hillenmeyer et al, 2008). That result has been broadly confirmed by Galardini et al (2018) who have shown the extent to which the effect of a gene deletion depends on the genetic background. They conclude that “interpretation of the impact of genetic variants on the phenotypes of individuals would likely need detailed gene-phenotype information in more genetic backgrounds than that of a model individual.” We would add that the phenotype background must also be relevant.…”

Section: Main Sectionssupporting

confidence: 55%

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Biological Relativity Requires Circular Causality but Not Symmetry of Causation: So, Where, What and When Are the Boundaries?

et al. 2019

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Since the Principle of Biological Relativity was formulated and developed there have been many implementations in a wide range of biological fields. The purpose of this article is to assess the status of the applications of the principle and to clarify some misunderstandings. The principle requires circular causality between levels of organization. But the forms of causality are also necessarily different. They contribute in asymmetric ways. Upward causation can be represented by the differential or similar equations describing the mechanics of lower level processes. Downward causation is then best represented as determining initial and boundary conditions. The questions tackled in this article are: (1) where and when do these boundaries exist? and (2) how do they convey the influences between levels? We show that not all boundary conditions arise from higher-level organization. It is important to distinguish those that do from those that don’t. Both forms play functional roles in organisms, particularly in their responses to novel challenges. The forms of causation also change according to the levels concerned. These principles are illustrated with specific examples.

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Section: Main Sectionssupporting

confidence: 55%

“…The boundary between regulatory networks and DNA is necessarily a two-way boundary. The regulatory networks can filter genetic changes, acting as what we have characterized as a “cloud” at the boundary (Noble and Noble, 2017; Galardini et al, 2018).…”

Section: Main Sectionsmentioning

confidence: 99%

Biological Relativity Requires Circular Causality but Not Symmetry of Causation: So, Where, What and When Are the Boundaries?

et al. 2019

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“…Genetic background is known to play a significant role in the effect of a mutation. A large study in Saccharomyces cerevisiae recently found that 16% to 42% of deletion phenotypes changed between pairs of strains, depending on the environment (39). To fully probe the influence of the variants and genes that we identified in our screen, these variants need to be studied in the ST93 background.…”

Section: Discussionmentioning

confidence: 99%

Identification of Pathogen Genomic Differences That Impact Human Immune Response and Disease during Cryptococcus neoformans Infection

Gerstein

Jackson

McDonald

et al. 2019

mBio

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Patient outcomes during infection are due to a complex interplay between the quality of medical care, host immunity factors, and the infecting pathogen’s characteristics. To probe the influence of pathogen genotype on human survival, immune response, and other parameters of disease, we examined Cryptococcus neoformans isolates collected during the Cryptococcal Optimal Antiretroviral Therapy (ART) Timing (COAT) Trial in Uganda. We measured human participants’ survival, meningitis disease parameters, immunologic phenotypes, and pathogen in vitro growth characteristics. We compared those clinical data to whole-genome sequences from 38 C. neoformans isolates of the most frequently observed sequence type (ST), ST93, in our Ugandan participant population and to sequences from an additional 18 strains of 9 other sequence types representing the known genetic diversity within the Ugandan Cryptococcus clinical isolates. We focused our analyses on 652 polymorphisms that were variable among the ST93 genomes, were not in centromeres or extreme telomeres, and were predicted to have a fitness effect. Logistic regression and principal component analysis identified 40 candidate Cryptococcus genes and 3 hypothetical RNAs associated with human survival, immunologic response, or clinical parameters. We infected mice with 17 available KN99α gene deletion strains for these candidate genes and found that 35% (6/17) directly influenced murine survival. Four of the six gene deletions that impacted murine survival were novel. Such bedside-to-bench translational research identifies important candidate genes for future studies on virulence-associated traits in human Cryptococcus infections. IMPORTANCE Even with the best available care, mortality rates in cryptococcal meningitis range from 20% to 60%. Disease is often due to infection by the fungus Cryptococcus neoformans and involves a complex interaction between the human host and the fungal pathogen. Although previous studies have suggested genetic differences in the pathogen impact human disease, it has proven quite difficult to identify the specific C. neoformans genes that impact the outcome of the human infection. Here, we take advantage of a Ugandan patient cohort infected with closely related C. neoformans strains to examine the role of pathogen genetic variants on several human disease characteristics. Using a pathogen whole-genome sequencing approach, we showed that 40 C. neoformans genes are associated with human disease. Surprisingly, many of these genes are specific to Cryptococcus and have unknown functions. We also show deletion of some of these genes alters disease in a mouse model of infection, confirming their role in disease. These findings are particularly important because they are the first to identify C. neoformans genes associated with human cryptococcal meningitis and lay the foundation for future studies that may lead to new treatment strategies aimed at reducing patient mortality.

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“…One of the limitations of those collections is that they rely solely on the genetic backgrounds of lab strains and as we discuss in this review; strains used in industrial process are not derivatives of lab strains. Recently, a study demonstrated this point by showing a high degree of genetic background dependency by analysing ~4,000 gene knockouts in four different strains background of the same species (Galardini et al, ).…”

Section: Leveraging Genome‐scale Diversity For Host Optimizationmentioning

confidence: 98%

The renaissance of yeasts as microbial factories in the modern age of biomanufacturing

Payen

Thompson

2019

Yeast

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Yeasts are essential for many processes, including the production of some of our most beloved foods and beverages. Less is known to the public about the far‐reaching impacts of yeasts on other products such as biofuels, pharmaceuticals, and industrial products. By leveraging and combining newly discovered yeast genetic diversity with now affordable and efficient genetic engineering and synthetic biology tools, academic and industrial yeast labs have designed yeast cell factories for a wide range of novel applications such as the production of medicines, components of human breast milk, heme for meat substitutes, bioplastics, and other biomaterials. This review covers the newest technologies developed for yeast research including synthetic biology and their use in the engineering of yeast cell factories for emerging applications.

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The impact of the genetic background on gene deletion phenotypes inSaccharomyces cerevisiae

Cited by 8 publications

References 54 publications

Biological Relativity Requires Circular Causality but Not Symmetry of Causation: So, Where, What and When Are the Boundaries?

Biological Relativity Requires Circular Causality but Not Symmetry of Causation: So, Where, What and When Are the Boundaries?

Identification of Pathogen Genomic Differences That Impact Human Immune Response and Disease during Cryptococcus neoformans Infection

The renaissance of yeasts as microbial factories in the modern age of biomanufacturing

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