Exploring genetic suppression interactions on a global scale

Leeuwen, Jolanda van; Pons, Carles; Mellor, Joseph; Yamaguchi, Takafumi N.; Friesen, Helena; Koschwanez, John H.; Ušaj, Mojca Mattiazzi; Pechlaner, Maria; Takar, Mehmet; Ušaj, Matej; VanderSluis, Benjamin; Andrusiak, Kerry; Bansal, Pritpal; Baryshnikova, Anastasia; Boone, Claire Elizabeth; Cao, Jessica; Coté, Atina G.; Gebbia, Marinella; Horecka, Gene; Horecka, Ira; Kuzmin, Elena; Legro, Nicole R.; Liang, Wendy; Lieshout, Natascha van; McNee, Margaret; Luis, Bryan-Joseph San; Shaeri, Fatemeh; Shuteriqi, Ermira; Sun, Song; Lü, Yang; Youn, Ji‐Young; Yuen, Michael Wai-Keong; Costanzo, Michael; Gingras, Anne‐Claude; Aloy, Patrick; Oostenbrink, Chris; Murray, Andrew W.; Graham, Todd R.; Myers, Chad L.; Andrews, Brenda; Roth, Frederick P.; Boone, Charles

doi:10.1126/science.aag0839

Cited by 171 publications

(254 citation statements)

References 60 publications

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“…The yeast polyubiquitin gene, UBI4, is not required for vegetative growth but is needed for stress response and for sporulation (28). Experiments looking for genes regulating fitness adaptability identified loss-of-function mutations in UBR1, an E3 ubiquitin ligase involved in N-end rule degradation (29), and genes involved in protein degradation suppress growth defects associated with mutational burdens presumably by stabilizing hypomorphic proteins (30). The role for ubiquitin may be as a pleiotropic regulator and UBI4 hypomorphic alleles produce spontaneous phenotypic variants in hyphal development and morphogenesis in candida (31).…”

Section: Discussionmentioning

confidence: 99%

Recurrent ubiquitin B silencing in gynecological cancers establishes dependence on ubiquitin C

Kedves¹,

Gleim²,

Liang³

et al. 2017

Journal of Clinical Investigation

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Section: Discussionmentioning

confidence: 99%

Recurrent ubiquitin B silencing in gynecological cancers establishes dependence on ubiquitin C

Kedves¹,

Gleim²,

Liang³

et al. 2017

Journal of Clinical Investigation

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“…Past studies, including recent work using the approaches mentioned above, have described a number of mechanisms that can lead to genetic suppression [12, 17, 35, 46]. These mechanisms include:…”

Section: Functional Mechanisms That Cause Genetic Suppressionmentioning

confidence: 99%

“…Both intragenic and intergenic suppressors may directly alter the levels of a mutated gene’s cognate mRNA or protein [12, 17, 35, 46]. Changing dosage in this way may compensate for the reduced activity of a gene product due to the destabilizing effect of an initial mutation.…”

Section: Functional Mechanisms That Cause Genetic Suppressionmentioning

confidence: 99%

“…Among the types of genetic interactions that can occur [12–14], suppression represents an extreme case in which one or more genetic changes at other sites in the genome (i.e., ‘suppressors’) reverse a mutation’s deleterious effects [15, 16]. Identifying these suppressors can provide valuable insights into the functional mechanisms by which mutations jointly affect phenotype [16–18].…”

Section: Introductionmentioning

confidence: 99%

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

2017

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Summary Many mutations have deleterious phenotypic effects that can be alleviated by suppressor mutations elsewhere in the genome. High-throughput approaches have facilitated the large-scale identification of these suppressors and have helped shed light on core functional mechanisms that give rise to suppression. Following reports that suppression occurs naturally within species, it is important to determine how our understanding of this phenomenon based on lab experiments extends to genetically diverse natural populations. Although suppression is typically mediated by individual genetic changes in lab experiments, recent studies have shown that suppression in natural populations can involve combinations of genetic variants. This difference in complexity suggests that sets of variants can exhibit similar functional effects to individual suppressors found in lab experiments. In this review, we discuss how characterizing the way in which these variants jointly lead to suppression could provide important insights into the genotype-phenotype map that are relevant to evolution and health.

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“…In yeast, large-scale studies have begun to define gene interaction networks. 98,99 In mice and humans, a combination of empirical evidence and literature review has begun to define the circuitry of networks associated with disease. 100,101 In many species, modifier genes are readily identified for both simple and complex traits.…”

mentioning

confidence: 99%

From Peas to Disease: Modifier Genes, Network Resilience, and the Genetics of Health

Riordan

Nadeau

2017

The American Journal of Human Genetics

126

107

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Phenotypes are rarely consistent across genetic backgrounds and environments, but instead vary in many ways depending on allelic variants, unlinked genes, epigenetic factors, and environmental exposures. In the extreme, individuals carrying the same causal DNA sequence variant but on different backgrounds can be classified as having distinct conditions. Similarly, some individuals that carry disease alleles are nevertheless healthy despite affected family members in the same environment. These genetic background effects often result from the action of so-called ''modifier genes'' that modulate the phenotypic manifestation of target genes in an epistatic manner. While complicating the prospects for gene discovery and the feasibility of mechanistic studies, such effects are opportunities to gain a deeper understanding of gene interaction networks that provide organismal form and function as well as resilience to perturbation. Here, we review the principles of modifier genetics and assess progress in studies of modifier genes and their targets in both simple and complex traits. We propose that modifier effects emerge from gene interaction networks whose structure and function vary with genetic background and argue that these effects can be exploited as safe and effective ways to prevent, stabilize, and reverse disease and dysfunction.

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Exploring genetic suppression interactions on a global scale

Cited by 171 publications

References 60 publications

Recurrent ubiquitin B silencing in gynecological cancers establishes dependence on ubiquitin C

Recurrent ubiquitin B silencing in gynecological cancers establishes dependence on ubiquitin C

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

From Peas to Disease: Modifier Genes, Network Resilience, and the Genetics of Health

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