Genetic suppression: Extending our knowledge from lab experiments to natural populations

Matsui, Takeshi; Lee, Jonathan T.; Ehrenreich, Ian M.

doi:10.1002/bies.201700023

Cited by 10 publications

(7 citation statements)

References 76 publications

(127 reference statements)

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“…Extragenic suppression interactions are extremely rich in functional information compared to other interaction types, and mostly occur between genes that have a close functional connection, such as those encoding protein or pathway members. These interactions often involve specific genetic alterations, such as allele-specific interactions, and can be used to assign function to uncharacterized genes, to order pathway components and to understand phenotypic variability in natural populations [see (Matsui et al, 2017) for review]. Mechanistically, suppression GIs can involve gain-of-function phenotypes that compensate for a missing activity in absence of the query gene, or loss-of-function phenotypes that may antagonize query gene function or eliminate toxicity associated with absence of the query gene.…”

Section: Genetic Suppression and Modifier Effectsmentioning

confidence: 99%

Global Genetic Networks and the Genotype-to-Phenotype Relationship

Costanzo

Kuzmin

Leeuwen

et al. 2019

Cell

208

147

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Genetic interactions identify combinations of genetic variants that impinge on phenotype. With whole-genome sequence information available for thousands of individuals within a species, a major outstanding issue concerns the interpretation of allelic combinations of genes underlying inherited traits. In this review, we discuss how large-scale analyses in model systems have illuminated the general principles and phenotypic impact of genetic interactions. We focus on studies in budding yeast, including the mapping of a global genetic network. We emphasize how information gained from work in yeast translates to other systems, and how a global genetic network not only annotates gene function, but also provides new insights into the genotype to phenotype relationship.

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Section: Genetic Suppression and Modifier Effectsmentioning

confidence: 99%

Global Genetic Networks and the Genotype-to-Phenotype Relationship

Costanzo

Kuzmin

Leeuwen

et al. 2019

Cell

208

147

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“…This example is a classic case of genetic suppression, and in general any cases of genetic suppression can be reframed as cases of potentiation. Thus, to find additional examples of potentiation, one could simply compile the results of genetic suppressor screens [67,68].…”

Section: Potentiation In a Robust Sensory-organ Specification Networkmentioning

confidence: 99%

Decanalizing thinking on genetic canalization

Geiler-Samerotte

Sartori

Siegal

2019

Seminars in Cell & Developmental Biology

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The concept of genetic canalization has had an abiding influence on views of complex-trait evolution. A genetically canalized system has evolved to become less sensitive to the effects of mutation. When a gene product that supports canalization is compromised, the phenotypic impacts of a mutation should be more pronounced. This expected increase in mutational effects not only has important consequences for evolution, but has also motivated strategies to treat disease. However, recent studies demonstrate that, when putative agents of genetic canalization are impaired, systems do not behave as expected. Here, we review the evidence that is used to infer whether particular gene products are agents of genetic canalization. Then we explain how such inferences often succumb to a converse error. We go on to show that several candidate agents of genetic canalization increase the phenotypic impacts of some mutations while decreasing the phenotypic impacts of others. These observations suggest that whether a gene product acts as a 'buffer' (lessening mutational effects) or a 'potentiator' (increasing mutational effects) is not a fixed property of the gene product but instead differs for the different mutations with which it interacts. To investigate features of genetic interactions that might predispose them toward buffering versus potentiation, we explore simulated gene-regulatory networks. Similarly to putative agents of genetic canalization, the gene products in simulated networks also modify the phenotypic effects of mutations in other genes without a strong overall tendency towards lessening or increasing these effects. In sum, these observations call into question whether complex traits have evolved to become less sensitive (i.e., are canalized) to genetic change, and the degree to which trends exist that predict how one genetic change might alter another's impact. We conclude by discussing approaches to address these and other open questions that are brought into focus by re-thinking genetic canalization.

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“…Linkage‐based analyses of large panels of individuals have indeed identified second and higher‐order modifier effects (Chandler et al, 2014; Taylor & Ehrenreich, 2015; Mullis et al, 2018; Hou et al, 2019; Sanchez et al, 2019), but few modifiers are usually characterised in depth beyond mapping the loci in such designs. The relevance of established broad suppression mechanisms for natural populations thus remains unclear (Matsui et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Natural variants suppress mutations in hundreds of essential genes

Parts

Batté

Lopes

et al. 2021

Molecular Systems Biology

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The consequence of a mutation can be influenced by the context in which it operates. For example, loss of gene function may be tolerated in one genetic background, and lethal in another. The extent to which mutant phenotypes are malleable, the architecture of modifiers and the identities of causal genes remain largely unknown. Here, we measure the fitness effects of~1,100 temperature-sensitive alleles of yeast essential genes in the context of variation from ten different natural genetic backgrounds and map the modifiers for 19 combinations. Altogether, fitness defects for 149 of the 580 tested genes (26%) could be suppressed by genetic variation in at least one yeast strain. Suppression was generally driven by gain-of-function of a single, strong modifier gene, and involved both genes encoding complex or pathway partners suppressing specific temperature-sensitive alleles, as well as general modifiers altering the effect of many alleles. The emerging frequency of suppression and range of possible mechanisms suggest that a substantial fraction of monogenic diseases could be managed by modulating other gene products.

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Genetic suppression: Extending our knowledge from lab experiments to natural populations

Cited by 10 publications

References 76 publications

Global Genetic Networks and the Genotype-to-Phenotype Relationship

Global Genetic Networks and the Genotype-to-Phenotype Relationship

Decanalizing thinking on genetic canalization

Natural variants suppress mutations in hundreds of essential genes

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