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Systematic analysis of complex genetic interactions.

ABSTRACT: To systematically explore complex genetic interactions, we constructed ~200,000 yeast triple mutants and scored negative trigenic interactions. We selected double-mutant query genes across a broad spectrum of biological processes, spanning a range of quantitative features of the global digenic interaction network and tested for a genetic interaction with a third mutation. Trigenic interactions often occurred among functionally related genes, and essential genes were hubs on the trigenic network. Despite their functional enrichment, trigenic interactions tended to link genes in distant bioprocesses and displayed a weaker magnitude than digenic interactions. We estimate that the global trigenic interaction network is ~100 times as large as the global digenic network, highlighting the potential for complex genetic interactions to affect the biology of inheritance, including the genotype-to-phenotype relationship.

SUBMITTER: Kuzmin E

PROVIDER: S-EPMC6215713 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Systematic analysis of complex genetic interactions.

Kuzmin Elena E VanderSluis Benjamin B Wang Wen W Tan Guihong G Deshpande Raamesh R Chen Yiqun Y Usaj Matej M Balint Attila A Mattiazzi Usaj Mojca M van Leeuwen Jolanda J Koch Elizabeth N EN Pons Carles C Dagilis Andrius J AJ Pryszlak Michael M Wang Zi Yang ZY Hanchard Julia J Riggi Margot M Xu Kaicong K Heydari Hamed H San Luis Bryan-Joseph BJ Shuteriqi Ermira E Zhu Hongwei H Van Dyk Nydia N Sharifpoor Sara S Costanzo Michael M Loewith Robbie R Caudy Amy A Bolnick Daniel D Brown Grant W GW Andrews Brenda J BJ Boone Charles C Myers Chad L CL

Science (New York, N.Y.) 20180401 6386

To systematically explore complex genetic interactions, we constructed ~200,000 yeast triple mutants and scored negative trigenic interactions. We selected double-mutant query genes across a broad spectrum of biological processes, spanning a range of quantitative features of the global digenic interaction network and tested for a genetic interaction with a third mutation. Trigenic interactions often occurred among functionally related genes, and essential genes were hubs on the trigenic network. ...[more]

PMID: 29674565

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Project description:BackgroundDespite substantial improvement in the control of malaria and decreased prevalence of malnutrition over the past two decades, both conditions remain heavy burdens that cause hundreds of thousands of deaths in children in resource-poor countries every year. Better understanding of the complex interactions between malaria and malnutrition is crucial for optimally targeting interventions where both conditions co-exist. This systematic review aimed to assess the evidence of the interplay between malaria and malnutrition.MethodsDatabase searches were conducted in PubMed, Global Health and Cochrane Libraries and articles published in English, French or Spanish between Jan 1980 and Feb 2018 were accessed and screened. The methodological quality of the included studies was assessed using the Newcastle-Ottawa Scale and the risk of bias across studies was assessed using the GRADE approach. The preferred reporting items for systematic reviews and meta-analyses (PRISMA) guideline were followed.ResultsOf 2945 articles screened from databases, a total of 33 articles were identified looking at the association between malnutrition and risk of malaria and/or the impact of malnutrition in antimalarial treatment efficacy. Large methodological heterogeneity of studies precluded conducting meaningful aggregated data meta-analysis. Divergent results were reported on the effect of malnutrition on malaria risk. While no consistent association between risk of malaria and acute malnutrition was found, chronic malnutrition was relatively consistently associated with severity of malaria such as high-density parasitemia and anaemia. Furthermore, there is little information on the effect of malnutrition on therapeutic responses to artemisinin combination therapies (ACTs) and their pharmacokinetic properties in malnourished children in published literature.ConclusionsThe evidence on the effect of malnutrition on malaria risk remains inconclusive. Further analyses using individual patient data could provide an important opportunity to better understand the variability observed in publications by standardising both malaria and nutritional metrics. Our findings highlight the need to improve our understanding of the pharmacodynamics and pharmacokinetics of ACTs in malnourished children. Further clarification on malaria-malnutrition interactions would also serve as a basis for designing future trials and provide an opportunity to optimise antimalarial treatment for this large, vulnerable and neglected population.Trial registrationPROSPERO CRD42017056934 .

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Systematic analysis of complex genetic interactions.

Publications

Systematic analysis of complex genetic interactions.

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