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| Open AccessTwo mitochondrial DNA polymorphisms modulate cardiolipin binding and lead to synthetic lethality
Chiang et al. map a genetic interaction in animal mitochondrial DNA by recombination. This reveals how polymorphisms in two complex IV subunits jointly affect cardiolipin binding to impact complex stability, organismal fitness and disease expression.
- Ason C. Y. Chiang
- , Jan Ježek
- & Hansong Ma
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Article
| 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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Article
| 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 AccessStrong protective effect of the APOL1 p.N264K variant against G2-associated focal segmental glomerulosclerosis and kidney disease
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
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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 AccessDominance vs epistasis: the biophysical origins and plasticity of genetic interactions within and between alleles
The authors examine how mutations combine to alter phenotypes in biophysical models of proteins and conclude that non-additive interactions (epistasis and dominance) are frequent, context-dependent and so challenging to predict in even the simplest of biological systems.
- Xuan Xie
- , Xia Sun
- & Xianghua Li
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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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Article
| 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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Article
| 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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Article
| Open AccessVariance-quantitative trait loci enable systematic discovery of gene-environment interactions for cardiometabolic serum biomarkers
Understanding how our genes interact with the environment is critical to improving health. Using a large-scale discovery pipeline, here the authors investigate synergies between genetic variants and a broad range of environmental factors impacting cardiometabolic health.
- Kenneth E. Westerman
- , Timothy D. Majarian
- & Joanne B. Cole
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Article
| Open AccessA natural timeless polymorphism allowing circadian clock synchronization in “white nights”
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
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Article
| 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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Article
| Open AccessDiscovery of putative tumor suppressors from CRISPR screens reveals rewired lipid metabolism in acute myeloid leukemia cells
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
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Article
| Open AccessNetwork analysis reveals rare disease signatures across multiple levels of biological organization
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
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Article
| 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 AccessUbiB proteins regulate cellular CoQ distribution in Saccharomyces cerevisiae
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
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Article
| Open AccessCryptic genetic variation in a heat shock protein modifies the outcome of a mutation affecting epidermal stem cell development in C. elegans
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
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Article
| Open AccessFUT2–ABO epistasis increases the risk of early childhood asthma and Streptococcus pneumoniae respiratory illnesses
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
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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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| 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 AccessHigh-performance CRISPR-Cas12a genome editing for combinatorial genetic screening
Reliable, multiplexed gene editing to uncover synergies between targets remains challenging. Here, the authors engineer AsCas12a and the crRNA to improve double knockout for synthetic sick/lethal interaction genetic screening.
- Rodrigo A. Gier
- , Krista A. Budinich
- & Junwei Shi
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Article
| Open AccessIntegration of multiple biological contexts reveals principles of synthetic lethality that affect reproducibility
Defining robust, penetrant synthetic lethal targets for cancer therapeutics is a challenge. Here, the authors demonstrate how pathway, genetic and cellular context dictates dependence on cancer targets.
- Angel A. Ku
- , Hsien-Ming Hu
- & Sourav Bandyopadhyay
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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 AccessUsing regulatory variants to detect gene–gene interactions identifies networks of genes linked to cell immortalisation
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
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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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Article
| Open AccessA fln-2 mutation affects lethal pathology and lifespan in C. elegans
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
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| Open AccessDiscovering genetic interactions bridging pathways in genome-wide association studies
Genetic interactions may contribute to phenotypic traits but are challenging to decipher. Here, the authors develop BridGE, a computational approach for identifying pathways connected by genetic interactions from GWAS data.
- Gang Fang
- , Wen Wang
- & Chad L. Myers
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Article
| 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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Article
| 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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Article
| Open AccessSystematic analysis reveals the prevalence and principles of bypassable gene essentiality
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
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Article
| 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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Article
| Open AccessOptimized libraries for CRISPR-Cas9 genetic screens with multiple modalities
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
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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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Article
| Open AccessIdentification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk
The chromosome 15q25.1 locus is a leading susceptibility region for lung cancer. Here, the authors interrogate three GWAS cohorts with 42,901 individuals to investigate potential pathological pathways such as gated channel activity and neuroactive ligand receptor interaction in lung cancer etiology.
- Xuemei Ji
- , Yohan Bossé
- & Christopher I. Amos
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Article
| Open AccessMap of synthetic rescue interactions for the Fanconi anemia DNA repair pathway identifies USP48
Fanconi anemia is a rare disease caused by defective DNA interstrand crosslink repair. Here the authors observe that USP48 deficiencies reduce chromosomal instability in FA-defective cells, suggesting it might be a potential therapeutic target.
- Georgia Velimezi
- , Lydia Robinson-Garcia
- & Joanna I. Loizou
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Article
| Open AccessSimilarity in viral and host promoters couples viral reactivation with host cell migration
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
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Article
| 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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Article
| Open AccessMultiple novel gene-by-environment interactions modify the effect of FTO variants on body mass index
Common variants in the fat mass and obesity associated (FTO) gene are linked to body mass index (BMI). Using the latest UK Biobank data, this study shows novel gene x environment interactions between FTOand lifestyle factors, including frequency of alcohol consumption, sleep, and added dietary salt.
- Alexander I. Young
- , Fabian Wauthier
- & Peter Donnelly
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Article
| Open AccessThe severity of hereditary porphyria is modulated by the porphyrin exporter and Lan antigen ABCB6
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
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Article
| Open AccessInternal guide RNA interactions interfere with Cas9-mediated cleavage
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
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Article
| Open AccessDiverse genetic architectures lead to the same cryptic phenotype in a yeast cross
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
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Article
| Open AccessGenetic interactions contribute less than additive effects to quantitative trait variation in yeast
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
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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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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