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| Open AccessRegulatory mechanism of cold-inducible diapause in Caenorhabditis elegans
Dormancy is induced by a cold environment. Here, the authors found that C. elegans undergoes diapause at low temperatures, namely cold-inducible diapause (CID). CID can be induced by the hsf-1 mutation and is regulated by neural pathways and longevity genes.
- Makoto Horikawa
- , Masamitsu Fukuyama
- & Masaki Mizunuma
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| Open AccessThe genetic landscape of a metabolic interaction
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
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| Open AccessPervasive epistasis exposes intramolecular networks in adaptive enzyme evolution
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
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| Open AccessEnvironmental modulation of global epistasis in a drug resistance fitness landscape
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
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Article
| Open AccessOncogenic context shapes the fitness landscape of tumor suppression
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
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Article
| Open AccessFast kernel-based association testing of non-linear genetic effects for biobank-scale data
We have developed FastKAST, a highly-scalable algorithm to identify non-linear genetic effects on complex traits in large datasets. Applied to 300K UK Biobank individuals, we successfully detected significant non-linear effects across 53 traits.
- Boyang Fu
- , Ali Pazokitoroudi
- & Sriram Sankararaman
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| Open AccessQuantifying the local adaptive landscape of a nascent bacterial community
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
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| Open AccessAuxotrophic and prototrophic conditional genetic networks reveal the rewiring of transcription factors in Escherichia coli
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
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| Open AccessTransposon insertional mutagenesis of diverse yeast strains suggests coordinated gene essentiality polymorphisms
Epistasis can lead to different phenotypic consequences from the same mutation. Here the authors carry out a genome-wide analysis of conditionally essential genes in yeast, finding that gene essentiality changes tend to occur concordantly among components of the same protein complex or metabolic pathway.
- Piaopiao Chen
- , Agnès H. Michel
- & Jianzhi Zhang
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| Open AccessThe interplay of additivity, dominance, and epistasis on fitness in a diploid yeast cross
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
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| Open AccessPairwise effects between lipid GWAS genes modulate lipid plasma levels and cellular uptake
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
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Article
| Open AccessBiophysical ambiguities prevent accurate genetic prediction
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
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Article
| Open AccessThe precursor of PI(3,4,5)P3 alleviates aging by activating daf-18(Pten) and independent of daf-16
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
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Article
| Open AccessMinimum epistasis interpolation for sequence-function relationships
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
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Article
| Open AccessA spontaneous mitonuclear epistasis converging on Rieske Fe-S protein exacerbates complex III deficiency in mice
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
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| Open AccessLearning the pattern of epistasis linking genotype and phenotype in a protein
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
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| Open AccessChanges in gene expression predictably shift and switch genetic interactions
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
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| Open AccessHarmonious genetic combinations rewire regulatory networks and flip gene essentiality
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
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| Open AccessSuppression of autophagic activity by Rubicon is a signature of aging
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
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| Open AccessThe complex underpinnings of genetic background effects
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
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| Open AccessPowerful decomposition of complex traits in a diploid model
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
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| Open Access1,25D3 prevents CD8+Tc2 skewing and asthma development through VDR binding changes to the Cyp11a1 promoter
Type 2 CD8+ T cells (Tc2) play a role in the development of experimental asthma. Here the authors show that 1,25D3, the active form of vitamin D3, can prevent conversion of CD8+T cells to a Tc2 phenotype, reducing asthma susceptibility.
- Michaela Schedel
- , Yi Jia
- & Erwin W. Gelfand
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| Open AccessComprehensive survey of condition-specific reproductive isolation reveals genetic incompatibility in yeast
Chromosomal rearrangements may hamper intraspecific hybrid fertility. Here the authors show that environment-specific genetic incompatibility segregates readily within intermating populations and leads to intrinsic reproductive isolation within a yeast species.
- Jing Hou
- , Anne Friedrich
- & Joseph Schacherer
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Article
| Open AccessMajor histocompatibility complex associations of ankylosing spondylitis are complex and involve further epistasis with ERAP1
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
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Article
| Open AccessInteractome analysis identifies a new paralogue of XRCC4 in non-homologous end joining DNA repair pathway
DNA double-strand breaks (DSBs), a highly deleterious form of DNA damage, are associated with multiple types of broken ends. Here, the authors identify a XRCC4-like factor that functions in the non-homologous end-joining DNA repair pathway to repair DSBs with complex broken ends.
- Mengtan Xing
- , Mingrui Yang
- & Dongyi Xu
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Article
| Open AccessEmergence of terpene cyclization in Artemisia annua
Terpene cyclases are ring-forming enzymes found in many biosynthetic pathways, but the evolutionary origins of the cyclization mechanism is not well understood. Here, the authors use structure-guided breeding to identify an epistatic network that controls the onset of cyclization activity in Artemisia annua.
- Melissa Salmon
- , Caroline Laurendon
- & Paul E. O’Maille
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Widespread genetic epistasis among cancer genes
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
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Epistasis and natural selection shape the mutational architecture of complex traits
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
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Epistasis between adults and larvae underlies caste fate and fitness in a clonal ant
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