Genetic interaction articles within Nature Communications

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  • Article
    | Open Access

    Reynolds and colleagues examine a biochemically-mediated epistatic interaction between metabolic enzymes involved in folate metabolism and show that biochemical coupling shapes the range of enzyme activities sufficient to rescue cell growth.

    • Thuy N. Nguyen
    • , Christine Ingle
    •  & Kimberly A. Reynolds

  • Article
    | Open Access

    Here, the authors perform statistical analyses to demonstrate that epistasis is highly pervasive in adaptive evolutionary trajectories of enzymes. Using epistatic data, they expose higher-order rewiring of intramolecular amino acid networks.

    • Karol Buda
    • , Charlotte M. Miton
    •  & Nobuhiko Tokuriki

  • Article
    | Open Access

    Global epistasis can be used to reconstruct fitness landscapes and infer adaptive trajectories. Here, the authors investigate how environmental variation impacts patterns of global epistasis, finding that global epistasis in the malaria parasite P. falciparum can be modulated by drug concentration in the environment.

    • Juan Diaz-Colunga
    • , Alvaro Sanchez
    •  & C. Brandon Ogbunugafor

  • Article
    | Open Access

    African Americans have an elevated risk of developing chronic kidney disease, yet only a fraction of those with high-risk genotypes develop the disease. Here, the authors show that a missense variant in APOL1 has a strong protective effect when co-inherited with the high-risk G2 allele of APOL1, with important implications for clinical practice and translational research.

    • Yask Gupta
    • , David J. Friedman
    •  & Simone Sanna-Cherchi

  • Article
    | Open Access

    Alterations in oncogenes and tumor suppressor genes are a hallmark of cancer, yet how they interact remains poorly understood. Here, the authors describe a quantitative functional cancer genomics platform in genetically engineered mice, and uncover complex interactions between tumor suppressors and KRAS, BRAF, and EGFR oncogenes across more than 100 different lung tumor genotypes.

    • Lily M. Blair
    • , Joseph M. Juan
    •  & Ian P. Winters

  • Article
    | Open Access

    Fitness landscapes largely shape the dynamics of evolution, but it is unclear how they shift upon ecological diversification. By engineering genome-wide knockout libraries of a nascent bacterial community, Ascensao et al. show how ecological and epistatic patterns combine to shape adaptive landscapes.

    • Joao A. Ascensao
    • , Kelly M. Wetmore
    •  & Oskar Hallatschek

  • Article
    | Open Access

    The bacterium E. coli has around 300 transcriptional factors, but the functions of many of them, and the interactions between their respective regulatory networks, are unclear. Here, the authors study genetic interactions among all transcription factor genes in E. coli, revealing condition-dependent interactions and roles for uncharacterized transcription factors.

    • Alla Gagarinova
    • , Ali Hosseinnia
    •  & Mohan Babu

  • Article
    | Open Access

    The genus Drosophila originate in subSaharan Africa and spread North up to the polar circle where they experience long days in the summer or even constant light. Here, the authors show that a form of the TIMELESS protein enables flies to synchronise their behavioural activity to long summer days

    • Angelique Lamaze
    • , Chenghao Chen
    •  & Ralf Stanewsky

  • Article
    | Open Access

    Heritable traits can be affected by additive, dominance, and epistatic effects at genetic loci. Here, the authors use chromosomally-encoded barcodes to perform linkage mapping in diploid cross progeny in budding yeast, finding that epistasis in diploids frequently modifies both additivity and dominance.

    • Takeshi Matsui
    • , Martin N. Mullis
    •  & Ian M. Ehrenreich

  • Article
    | Open Access

    CRISPR-based knockout screens in cancer cells have suggested the existence of proliferation suppressor genes (PSG). Here, the authors develop an approach to systematically identify them, and reveal a PSG module involved in fatty acid synthesis and tumour suppression in acute myeloid leukemia cell lines.

    • W. Frank Lenoir
    • , Micaela Morgado
    •  & Traver Hart

  • Article
    | Open Access

    Despite the clear causal relationship between genotype and phenotype in rare diseases, identifying the pathobiological mechanisms at various levels of biological organization remains a practical and conceptual challenge. Here, the authors introduce a network approach for evaluating the impact of rare gene defects across biological scales.

    • Pisanu Buphamalai
    • , Tomislav Kokotovic
    •  & Jörg Menche

  • Article
    | Open Access

    Studying the contribution of pairs of genes to complex traits has been challenging. Here, the authors combine exome and genotype data with RNAi to screen for genetic interactions between 30 genes identified in lipid GWAS to hint at pairs whose joint modulation may improve lipid-lowering therapies.

    • Magdalena Zimoń
    • , Yunfeng Huang
    •  & Heiko Runz

  • Article
    | Open Access

    Coenzyme Q (CoQ) is a lipid made in the inner mitochondrial membrane with antioxidant roles throughout the cell, but regulation of its cellular distribution is unclear. Here the authors identify two proteins that have reciprocal CoQ trafficking functions to help coordinate CoQ localization in yeast.

    • Zachary A. Kemmerer
    • , Kyle P. Robinson
    •  & David J. Pagliarini

  • Article
    | Open Access

    How the genetic background modifies the expression of mutations is a key question that is addressed in this study in the context of seam cell development in Caenorhabditis elegans isolates. One amino acid deletion in a conserved heat shock protein is sufficient to shape phenotype expressivity upon mutation of a GATA transcription factor.

    • Sneha L. Koneru
    • , Mark Hintze
    •  & Michalis Barkoulas

  • Article
    | Open Access

    Genetic variants discovered through genome-wide association studies for asthma together account for a small portion of the heritability. Here, the authors identify a possible epistatic relationship between coding variants in FUT2 and ABO, especially pronounced in severe and early onset asthma.

    • Tarunveer S. Ahluwalia
    • , Anders U. Eliasen
    •  & Klaus Bønnelykke

  • Article
    | Open Access

    In quantitative genetics, it is widely assumed that mutations combine additively or epistasis can be predicted with statistical or mechanistic models. Here, the authors use the phage lambda repressor model to show how biophysical ambiguity and non-monotonic functions confound phenotypic prediction.

    • Xianghua Li
    •  & Ben Lehner

  • Article
    | Open Access

    Phosphatidylinositol 3-kinase catalyzes the reaction from PI(4,5)P2 to PI(3,4,5)P3 and is encoded by the age-1 gene known to regulate lifespan. Here the researchers found that the metabolite myo-inositol, which can be converted to PI(3,4,5)P3 extends worm lifespan and alleviates worm as well as mouse health decline during aging.

    • Dawei Shi
    • , Xian Xia
    •  & Jing-Dong J. Han

  • Article
    | Open Access

    High-throughput combinatorial mutagenesis assays are useful to screen the function of many different sequences but they are not exhaustive. Here, Zhou and McCandlish develop a method to impute such missing genotype-phenotype data based on inferring the least epistatic sequence-function relationship.

    • Juannan Zhou
    •  & David M. McCandlish

  • Article
    | Open Access

    For most human genes nearby regulatory variants explain only a small proportion of their expression variation between individuals. Here the authors show how the impact of a gene’s set of nearby regulatory variant is often linked to the expression levels of distal genes, providing insights into gene networks.

    • D. Wragg
    • , Q. Liu
    •  & J. G. D. Prendergast

  • Article
    | Open Access

    A difference in the survival of respiratory chain complex III deficient Bcs1lp.S78G mice was observed between two congenic mouse strains. Here the authors show how in one of the strains the combined effects of a spontaneously arising non-pathogenic variant and the disease-causing Bcs1lp.S78G mutation exacerbate CIII deficiency and disease progression.

    • Janne Purhonen
    • , Vladislav Grigorjev
    •  & Jukka Kallijärvi

  • Article
    | Open Access

    C. elegans is a commonly used model organism in the study of ageing, and differences in genetic background can result in varying strain longevity. Here the authors demonstrate that a background mutation in fln-2 affects life-limiting pharyngeal infection and that in the mutant background the beneficial effect of sir-2.1 over-expression is suppressed.

    • Yuan Zhao
    • , Hongyuan Wang
    •  & David Gems

  • Article
    | Open Access

    Epistasis underlies the complexity of genotype-phenotype maps. Here, the authors analyze 8,192 mutants that link two phenotypically distinct variants of the Entacmaea quadricolor fluorescent protein, and show the existence, but also the sparsity, of high-order epistatic interactions.

    • Frank J. Poelwijk
    • , Michael Socolich
    •  & Rama Ranganathan

  • Article
    | Open Access

    Non-additive genetic interactions are plastic and can complicate genetic prediction. Here, using deep mutagenesis of the lambda repressor, Li et al. reveal that changes in gene expression can alter the strength and direction of genetic interactions between mutations in many genes and develop mathematical models for predicting them.

    • Xianghua Li
    • , Jasna Lalić
    •  & Ben Lehner

  • Article
    | Open Access

    Studying how genetic variants in different genes interact and their combinatorial output is experimentally and analytically challenging. Here, the authors quantify the effects of more than 5000 mutation pairs in the yeast GAL regulatory system, finding that many combinations can be predicted with statistical models.

    • Aaron M. New
    •  & Ben Lehner

  • Article
    | Open Access

    An essential gene may become non-essential when another gene is mutated. Here, the authors investigate this type of digenic interaction, termed ‘bypass of essentiality’, in the fission yeast Schizosaccharomyces pombe, and show that bypassable essential genes are common and share certain features.

    • Jun Li
    • , Hai-Tao Wang
    •  & Li-Lin Du

  • Article
    | Open Access

    Autophagic activity decreases with age via unknown mechanisms. Here the authors show that expression of the negative autophagy regulator Rubicon increases with age, that its genetic ablation improves lifespan and ameliorates a number of age-associated phenotypes in invertebrates and in mouse models.

    • Shuhei Nakamura
    • , Masaki Oba
    •  & Tamotsu Yoshimori

  • Article
    | Open Access

    Genome-wide libraries for CRISPR knockout, interference, and activation have allowed the systemic interrogation of gene function. Here, the authors evaluate the Brunello CRISPRko library and introduce Dolcetto and Calabrese for CRISPRi and CRISPRa, respectively.

    • Kendall R. Sanson
    • , Ruth E. Hanna
    •  & John G. Doench

  • Article
    | Open Access

    Mutations often show distinct phenotypic effects across different genetic backgrounds. Here the authors describe the genetic basis of these so-called background effects using data on genotype and growth in 10 environments from 1411 segregants from a cross of two strains of budding yeast.

    • Martin N. Mullis
    • , Takeshi Matsui
    •  & Ian M. Ehrenreich

  • Article
    | Open Access

    The coevolution of viruses and host cells can be mapped with interactomics. Here the authors identify coupling of human and viral promoters, and show that HIV-reactivation from dormancy is coincident with migration of HIV-infected cells owing to coupling of human CXCR4 and HIV LTR promoters.

    • Kathrin Bohn-Wippert
    • , Erin N. Tevonian
    •  & Roy D. Dar

  • Article
    | Open Access

    Dissecting the architecture of complex trait is challenging. Here, Hallin, Märtens et al. devises Phased Outbred Lines (POLs) in order to accurately decompose growth trait variation in diploid yeast across different environments.

    • Johan Hallin
    • , Kaspar Märtens
    •  & Gianni Liti

  • Article
    | Open Access

    Accumulation of intermediates of haem biosynthesis, porphyrins, is harmful and usually inherited, but it is unclear how the same mutation may make some individuals more ill than others. Here, the authors show that a porphyrin transporter ABCB6 is a modulator of porphyria, and that patients with functionally defective ABCB6 show more severe symptoms.

    • Yu Fukuda
    • , Pak Leng Cheong
    •  & John D. Schuetz

  • Article
    | Open Access

    While the CRISPR-Cas9 system has revolutionised molecular biology, it is still a mystery why not every guide RNA elicits target DNA cleavage. Here the authors show that genomic context and internal gRNA interactions can inhibit cleavage.

    • Summer B. Thyme
    • , Laila Akhmetova
    •  & Alexander F. Schier

  • Article
    | Open Access

    Cryptic genetic variants may not individually show discernible phenotypic effects, but collectively, these polymorphisms can lead to unexpected, genetically complex traits that might be relevant to evolution and disease. Here, the authors use large yeast populations to comprehensively dissect the genetic bases of 17 independent occurrences of a phenotype that arises due to combinations of epistatically interacting cryptic variants.

    • Matthew B. Taylor
    • , Joann Phan
    •  & Ian M. Ehrenreich

  • Article
    | Open Access

    This study uses a large number of crosses between a common lab strain and vineyard-isolated strain of yeast, and estimates the phenotypic variance for various quantitative traits. Using this data set, the authors show additive quantitative trait loci (QTL) and QTL–QTL interactions to be on average 43% and 9%, respectively.

    • Joshua S. Bloom
    • , Iulia Kotenko
    •  & Leonid Kruglyak

  • Article
    | Open Access

    Ankylosing spondylitis is a common, highly inheritable inflammatory arthritis with poorly understood biology. Here Brown, Cortes and colleagues use fine mapping of the major histocompatibility complex and identify novel associations, and identify other HLA alleles that like HLA-B27 interact with ERAP1 variants to influence disease risk.

    • Adrian Cortes
    • , Sara L. Pulit
    •  & Matthew A. Brown

  • Article |

    Cancer can result from mutations in more than one gene and these multiple mutated genes are often functionally dependent on each other; this interaction is known as epistasis. Here, the authors use a combinatorial RNAi screen to identify epistatic genes that are mutated in breast cancer and reveal large numbers of previously unreported gene interactions.

    • Xiaoyue Wang
    • , Audrey Q. Fu
    •  & Kevin P. White

  • Article |

    Mutations are the source of genetic variation, yet the mechanisms determining the distribution of mutations are unclear. Here, Jones et al.show that gene interactions allow natural selection to shape the distribution of mutations, suggesting that mutations can be a biased source of genetic variation.

    • Adam G. Jones
    • , Reinhard Bürger
    •  & Stevan J. Arnold

  • Article |

    It is unclear how interactions between individual genomes affect behaviour and survival in social organisms. Here, Teseo et al. show that genomic interactions between larvae and nursing adults of the clonal ant Cerapachys biroidetermine the proportion of individuals involved in reproduction or cooperation.

    • Serafino Teseo
    • , Nicolas Châline
    •  & Daniel J.C. Kronauer

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