Research Article

Exploring genetic suppression interactions on a global scale

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Science  04 Nov 2016:
Vol. 354, Issue 6312, aag0839
DOI: 10.1126/science.aag0839

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A global genetic suppression network

The genetic background of an organism can influence the overall effects of new genetic variants. Some mutations can amplify a deleterious phenotype, whereas others can suppress it. Starting with a literature survey and expanding into a genomewide assay, van Leeuwen et al. generated a large-scale suppression network in yeast. The data set reveals a set of general properties that can be used to predict suppression interactions. Furthermore, the study provides a template for extending suppression studies to other genes or to more complex organisms.

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Structured Abstract

INTRODUCTION

Genetic suppression occurs when the phenotypic defects caused by a mutated gene are rescued by a mutation in another gene.

These genetic interactions can connect genes that work within the same pathway or biological process, providing new mechanistic insights into cellular function, or they can correct defects in gene expression or protein production. More generally, suppression interactions may play an important role in the genetics underlying human diseases, such as the diverse penetrance of Mendelian disease variants. Our ability to interpret personal genome sequences remains limited, in part, because we lack an understanding of how sequence variants interact in nonadditive ways to generate profound phenotypes, including genetic suppression.

RATIONALE

Genetic interactions, in which mutations in two different genes combine to generate an unexpected phenotype, may underlie a significant component of trait heritability. Although genetic interactions that compromise fitness, such as synthetic lethality, have been mapped extensively, suppression interactions have not been explored systematically. To understand the general principles of genetic suppression and to examine the extent to which these interactions reflect cellular function, we harnessed the powerful genetics of the budding yeast Saccharomyces cerevisiae to assemble aglobal network of genetic suppression interactions.

RESULTS

By analyzing hundreds of published papers, we assembled a network of genetic suppression interactions involving ~1300 different yeast genes and ~1800 unique interactions. Through automated genetic mapping and whole-genome sequencing, we also isolated an unbiased, experimental set of ~200 spontaneous suppressor mutations that correct the fitness defects of deletion or hypomorphic mutant alleles. Integrating these results yielded a global suppression network.

The majority of suppression interactions identified novel gene-gene connections, thus providing new information about the functional wiring diagram of a cell. Most suppression pairs connected functionally related genes, including genes encoding members of the same pathway or complex. The functional enrichments observed for suppression gene pairs were several times as high as those found for other types of genetic interactions; this highlighted their discovery potential for assigning gene function. Our systematic suppression analysis also identified a prevalent allele-specific mechanism of suppression, whereby growth defects of hypomorphic alleles can be overcome by mutations that compromise either protein or mRNA degradation machineries.

From whole-genome sequencing of suppressor strains, we also identified additional secondary mutations, the vast majority of which appeared to be random passenger mutations. However, a small subset of genes was enriched for secondary mutations, several of which did not affect growth rate but rather appeared to delay the onset of the stationary phase. This delay suggests that they are selected for under laboratory growth conditions because they increase cell abundance within a propagating population.

CONCLUSION

A global network of genetic suppression interactions highlights the major potential for systematic studies of suppression to map cellular function. Our findings allowed us to formulate and quantify the general mechanisms of genetic suppression, which has the potential to guide the identification of modifier genes affecting the penetrance of genetic traits, including human disease.

Global analysis of genetic suppression.

Genetic suppression interactions occur when the detrimental effects of a primary mutation can be overcome by a secondary mutation. Both literature-curated and experimentally derived suppression interactions were collected and yielded a genetic suppression network. This global network was enriched for functional relationships and defined distinct mechanistic classes of genetic suppression.

Abstract

Genetic suppression occurs when the phenotypic defects caused by a mutation in a particular gene are rescued by a mutation in a second gene. To explore the principles of genetic suppression, we examined both literature-curated and unbiased experimental data, involving systematic genetic mapping and whole-genome sequencing, to generate a large-scale suppression network among yeast genes. Most suppression pairs identified novel relationships among functionally related genes, providing new insights into the functional wiring diagram of the cell. In addition to suppressor mutations, we identified frequent secondary mutations,in a subset of genes, that likely cause a delay in the onset of stationary phase, which appears to promote their enrichment within a propagating population. These findings allow us to formulate and quantify general mechanisms of genetic suppression.

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