RESUMEN
Structural variations (SVs) and gene copy number variations (gCNVs) have contributed to crop evolution, domestication, and improvement. Here, we assembled 31 high-quality genomes of genetically diverse rice accessions. Coupling with two existing assemblies, we developed pan-genome-scale genomic resources including a graph-based genome, providing access to rice genomic variations. Specifically, we discovered 171,072 SVs and 25,549 gCNVs and used an Oryza glaberrima assembly to infer the derived states of SVs in the Oryza sativa population. Our analyses of SV formation mechanisms, impacts on gene expression, and distributions among subpopulations illustrate the utility of these resources for understanding how SVs and gCNVs shaped rice environmental adaptation and domestication. Our graph-based genome enabled genome-wide association study (GWAS)-based identification of phenotype-associated genetic variations undetectable when using only SNPs and a single reference assembly. Our work provides rich population-scale resources paired with easy-to-access tools to facilitate rice breeding as well as plant functional genomics and evolutionary biology research.
Asunto(s)
Ecotipo , Variación Genética , Genoma de Planta , Oryza/genética , Adaptación Fisiológica/genética , Agricultura , Domesticación , Perfilación de la Expresión Génica , Regulación de la Expresión Génica de las Plantas , Genes de Plantas , Variación Estructural del Genoma , Anotación de Secuencia Molecular , FenotipoRESUMEN
The ability to maintain health, or recover to a healthy state after disease, is an active process involving distinct adaptation mechanisms coordinating interactions between all physiological systems of an organism. Studies over the past several decades have assumed the mechanisms of health and disease are essentially inter-changeable, focusing on the elucidation of the mechanisms of disease pathogenesis to enhance health, treat disease, and increase healthspan. Here, I propose that the evolved mechanisms of health are distinct from disease pathogenesis mechanisms and suggest that we develop an understanding of the biology of physiological health. In this Perspective, I provide a definition of, a conceptual framework for, and proposed mechanisms of physiological health to complement our understanding of disease and its treatment.
Asunto(s)
Adaptación Fisiológica/fisiología , Salud/tendencias , Fenómenos Fisiológicos/fisiología , Adaptación Fisiológica/genética , HumanosRESUMEN
Delineating ecologically meaningful populations among microbes is important for identifying their roles in environmental and host-associated microbiomes. Here, we introduce a metric of recent gene flow, which when applied to co-existing microbes, identifies congruent genetic and ecological units separated by strong gene flow discontinuities from their next of kin. We then develop a pipeline to identify genome regions within these units that show differential adaptation and allow mapping of populations onto environmental variables or host associations. Using this reverse ecology approach, we show that the human commensal bacterium Ruminococcus gnavus breaks up into sharply delineated populations that show different associations with health and disease. Defining populations by recent gene flow in this way will facilitate the analysis of bacterial and archaeal genomes using ecological and evolutionary theory developed for plants and animals, thus allowing for testing unifying principles across all biology.
Asunto(s)
Clostridiales/genética , Flujo Génico , Microbiota/genética , Adaptación Fisiológica/genética , Alelos , Colitis Ulcerosa/microbiología , Enfermedad de Crohn/microbiología , Transferencia de Gen Horizontal , Genoma Bacteriano , Humanos , Modelos Genéticos , Tasa de Mutación , Filogenia , Polimorfismo de Nucleótido Simple , Prochlorococcus/genética , Sulfolobus/genética , Vibrio/genéticaRESUMEN
Identifying the causes of similarities and differences in genetic disease prevalence among humans is central to understanding disease etiology. While present-day humans are not strongly differentiated, vast amounts of genomic data now make it possible to study subtle patterns of genetic variation. This allows us to trace our genomic history thousands of years into the past and its implications for the distribution of disease-associated variants today. Genomic analyses have shown that demographic processes shaped the distribution and frequency of disease-associated variants over time. Furthermore, local adaptation to new environmental conditions-including pathogens-has generated strong patterns of differentiation at particular loci. Researchers are also beginning to uncover the genetic architecture of complex diseases, affected by many variants of small effect. The field of population genomics thus holds great potential for providing further insights into the evolution of human disease.
Asunto(s)
Enfermedades Genéticas Congénitas/epidemiología , Enfermedades Genéticas Congénitas/etiología , Metagenómica/métodos , Adaptación Fisiológica/genética , Alelos , Evolución Molecular , Frecuencia de los Genes/genética , Flujo Genético , Variación Genética/genética , Genética de Población/métodos , Genómica/métodos , Humanos , Metagenómica/tendencias , Modelos Genéticos , FilogeniaRESUMEN
The living world is largely divided into autotrophs that convert CO2 into biomass and heterotrophs that consume organic compounds. In spite of widespread interest in renewable energy storage and more sustainable food production, the engineering of industrially relevant heterotrophic model organisms to use CO2 as their sole carbon source has so far remained an outstanding challenge. Here, we report the achievement of this transformation on laboratory timescales. We constructed and evolved Escherichia coli to produce all its biomass carbon from CO2. Reducing power and energy, but not carbon, are supplied via the one-carbon molecule formate, which can be produced electrochemically. Rubisco and phosphoribulokinase were co-expressed with formate dehydrogenase to enable CO2 fixation and reduction via the Calvin-Benson-Bassham cycle. Autotrophic growth was achieved following several months of continuous laboratory evolution in a chemostat under intensifying organic carbon limitation and confirmed via isotopic labeling.
Asunto(s)
Biomasa , Dióxido de Carbono/metabolismo , Carbono/metabolismo , Escherichia coli/metabolismo , Adaptación Fisiológica/genética , Aminoácidos/metabolismo , Procesos Autotróficos/fisiología , Isótopos de Carbono , Evolución Molecular Dirigida , Escherichia coli/genética , Marcaje Isotópico , Ingeniería Metabólica , Análisis de Flujos Metabólicos , Mutación/genéticaRESUMEN
Directed evolution is a powerful approach for engineering biomolecules and understanding adaptation. However, experimental strategies for directed evolution are notoriously labor intensive and low throughput, limiting access to demanding functions, multiple functions in parallel, and the study of molecular evolution in replicate. We report OrthoRep, an orthogonal DNA polymerase-plasmid pair in yeast that stably mutates â¼100,000-fold faster than the host genome in vivo, exceeding the error threshold of genomic replication that causes single-generation extinction. User-defined genes in OrthoRep continuously and rapidly evolve through serial passaging, a highly straightforward and scalable process. Using OrthoRep, we evolved drug-resistant malarial dihydrofolate reductases (DHFRs) in 90 independent replicates. We uncovered a more complex fitness landscape than previously realized, including common adaptive trajectories constrained by epistasis, rare outcomes that avoid a frequent early adaptive mutation, and a suboptimal fitness peak that occasionally traps evolving populations. OrthoRep enables a new paradigm of routine, high-throughput evolution of biomolecular and cellular function.
Asunto(s)
Adaptación Fisiológica/genética , Genoma Fúngico , Modelos Genéticos , Tasa de Mutación , Saccharomyces cerevisiae/genética , ADN Polimerasa Dirigida por ADN/genética , ADN Polimerasa Dirigida por ADN/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismoRESUMEN
Ice-binding proteins (IBPs) are a diverse class of proteins that assist organism survival in the presence of ice in cold climates. They have different origins in many organisms, including bacteria, fungi, algae, diatoms, plants, insects, and fish. This review covers the gamut of IBP structures and functions and the common features they use to bind ice. We discuss mechanisms by which IBPs adsorb to ice and interfere with its growth, evidence for their irreversible association with ice, and methods for enhancing the activity of IBPs. The applications of IBPs in the food industry, in cryopreservation, and in other technologies are vast, and we chart out some possibilities.
Asunto(s)
Adaptación Fisiológica/genética , Proteínas Anticongelantes/química , Criopreservación/métodos , Hielo/análisis , Animales , Proteínas Anticongelantes/genética , Proteínas Anticongelantes/metabolismo , Bacterias/genética , Bacterias/metabolismo , Frío , Almacenamiento de Alimentos/métodos , Expresión Génica , Humanos , Modelos Moleculares , Plantas/genética , Plantas/metabolismo , Unión Proteica , Dominios Proteicos , Ingeniería de Proteínas , Estructura Secundaria de Proteína , Levaduras/genética , Levaduras/metabolismoRESUMEN
Adaptive evolution plays a large role in generating the phenotypic diversity observed in nature, yet current methods are impractical for characterizing the molecular basis and fitness effects of large numbers of individual adaptive mutations. Here, we used a DNA barcoding approach to generate the genotype-to-fitness map for adaptation-driving mutations from a Saccharomyces cerevisiae population experimentally evolved by serial transfer under limiting glucose. We isolated and measured the fitness of thousands of independent adaptive clones and sequenced the genomes of hundreds of clones. We found only two major classes of adaptive mutations: self-diploidization and mutations in the nutrient-responsive Ras/PKA and TOR/Sch9 pathways. Our large sample size and precision of measurement allowed us to determine that there are significant differences in fitness between mutations in different genes, between different paralogs, and even between different classes of mutations within the same gene.
Asunto(s)
Adaptación Fisiológica/genética , Evolución Molecular , Aptitud Genética/genética , Técnicas Genéticas , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Diploidia , Genoma Fúngico/genética , Genotipo , Haploidia , Mutagénesis , MutaciónRESUMEN
Humans differ in the outcome that follows exposure to life-threatening pathogens, yet the extent of population differences in immune responses and their genetic and evolutionary determinants remain undefined. Here, we characterized, using RNA sequencing, the transcriptional response of primary monocytes from Africans and Europeans to bacterial and viral stimuli-ligands activating Toll-like receptor pathways (TLR1/2, TLR4, and TLR7/8) and influenza virus-and mapped expression quantitative trait loci (eQTLs). We identify numerous cis-eQTLs that contribute to the marked differences in immune responses detected within and between populations and a strong trans-eQTL hotspot at TLR1 that decreases expression of pro-inflammatory genes in Europeans only. We find that immune-responsive regulatory variants are enriched in population-specific signals of natural selection and show that admixture with Neandertals introduced regulatory variants into European genomes, affecting preferentially responses to viral challenges. Together, our study uncovers evolutionarily important determinants of differences in host immune responsiveness between human populations.
Asunto(s)
Adaptación Fisiológica/genética , Adaptación Fisiológica/inmunología , Inmunidad Adaptativa , Hombre de Neandertal/genética , Hombre de Neandertal/inmunología , Inmunidad Adaptativa/genética , Alelos , Animales , Infecciones Bacterianas/genética , Infecciones Bacterianas/inmunología , Secuencia de Bases , Evolución Biológica , Población Negra/genética , Regulación de la Expresión Génica , Variación Genética , Humanos , Sistema Inmunológico , Sitios de Carácter Cuantitativo , ARN/genética , Selección Genética , Análisis de Secuencia de ARN , Receptores Toll-Like/genética , Transcripción Genética , Virosis/genética , Virosis/inmunología , Población Blanca/genéticaRESUMEN
Our understanding of the detailed molecular mechanisms underpinning adaptation is still poor. One example for which mechanistic understanding of regulation has converged with studies of life history variation is Arabidopsis thaliana FLOWERING LOCUS C (FLC). FLC determines the need for plants to overwinter and their ability to respond to prolonged cold in a process termed vernalization. This review highlights how molecular analysis of vernalization pathways has revealed important insight into antisense-mediated chromatin silencing mechanisms that regulate FLC. In turn, such insight has enabled molecular dissection of the diversity in vernalization across natural populations of A. thaliana. Changes in both cotranscriptional regulation and epigenetic silencing of FLC are caused by noncoding polymorphisms at FLC. The FLC locus is therefore providing important concepts for how noncoding transcription and chromatin regulation influence gene expression and how these mechanisms can vary to underpin adaptation in natural populations.
Asunto(s)
Adaptación Fisiológica/genética , Epigénesis Genética , Sitios Genéticos , Proteínas de Plantas/genética , Evolución Biológica , Flores/fisiologíaRESUMEN
Advancements in precision oncology over the past decades have led to new therapeutic interventions, but the efficacy of such treatments is generally limited by an adaptive process that fosters drug resistance1. In addition to genetic mutations2, recent research has identified a role for non-genetic plasticity in transient drug tolerance3 and the acquisition of stable resistance4,5. However, the dynamics of cell-state transitions that occur in the adaptation to cancer therapies remain unknown and require a systems-level longitudinal framework. Here we demonstrate that resistance develops through trajectories of cell-state transitions accompanied by a progressive increase in cell fitness, which we denote as the 'resistance continuum'. This cellular adaptation involves a stepwise assembly of gene expression programmes and epigenetically reinforced cell states underpinned by phenotypic plasticity, adaptation to stress and metabolic reprogramming. Our results support the notion that epithelial-to-mesenchymal transition or stemness programmes-often considered a proxy for phenotypic plasticity-enable adaptation, rather than a full resistance mechanism. Through systematic genetic perturbations, we identify the acquisition of metabolic dependencies, exposing vulnerabilities that can potentially be exploited therapeutically. The concept of the resistance continuum highlights the dynamic nature of cellular adaptation and calls for complementary therapies directed at the mechanisms underlying adaptive cell-state transitions.
Asunto(s)
Adaptación Fisiológica , Plasticidad de la Célula , Resistencia a Antineoplásicos , Neoplasias , Femenino , Humanos , Ratones , Adaptación Fisiológica/efectos de los fármacos , Adaptación Fisiológica/genética , Línea Celular Tumoral , Plasticidad de la Célula/efectos de los fármacos , Plasticidad de la Célula/genética , Reprogramación Celular/efectos de los fármacos , Reprogramación Celular/genética , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Epigénesis Genética , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica/genética , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/patología , FenotipoRESUMEN
Regulation of gene expression is central to many biological processes. Although reconstruction of regulatory circuits from genomic data alone is therefore desirable, this remains a major computational challenge. Comparative approaches that examine the conservation and divergence of circuits and their components across strains and species can help reconstruct circuits as well as provide insights into the evolution of gene regulatory processes and their adaptive contribution. In recent years, advances in genomic and computational tools have led to a wealth of methods for such analysis at the sequence, expression, pathway, module, and entire network level. Here, we review computational methods developed to study transcriptional regulatory networks using comparative genomics, from sequence to functional data. We highlight how these methods use evolutionary conservation and divergence to reliably detect regulatory components as well as estimate the extent and rate of divergence. Finally, we discuss the promise and open challenges in linking regulatory divergence to phenotypic divergence and adaptation.
Asunto(s)
Regulación de la Expresión Génica/genética , Redes Reguladoras de Genes/genética , Adaptación Fisiológica/genética , Animales , Biología Computacional/métodos , Evolución Molecular , Genoma/genética , Genómica/métodos , HumanosRESUMEN
Temperature is a variable component of the environment, and all organisms must deal with or adapt to temperature change. Acute temperature change activates cellular stress responses, resulting in refolding or removal of damaged proteins. However, how organisms adapt to long-term temperature change remains largely unexplored. Here we report that budding yeast responds to long-term high temperature challenge by switching from chaperone induction to reduction of temperature-sensitive proteins and re-localizing a portion of its proteome. Surprisingly, we also find that many proteins adopt an alternative conformation. Using Fet3p as an example, we find that the temperature-dependent conformational difference is accompanied by distinct thermostability, subcellular localization, and, importantly, cellular functions. We postulate that, in addition to the known mechanisms of adaptation, conformational plasticity allows some polypeptides to acquire new biophysical properties and functions when environmental change endures.
Asunto(s)
Adaptación Fisiológica/genética , Proteoma/genética , Estrés Fisiológico/genética , Transcriptoma/genética , Aclimatación/genética , Animales , Exposición a Riesgos Ambientales/efectos adversos , Regulación Fúngica de la Expresión Génica/genética , Calor/efectos adversos , Saccharomycetales/genéticaRESUMEN
Lamper et al. (2020) reported that eIF3d-mediated cap-dependent translation is subject to regulation by phosphorylation during chronic glucose deprivation, providing a mechanism underlying selective translation of stress genes essential for cell survival.
Asunto(s)
Factor 3 de Iniciación Eucariótica , Estrés Fisiológico , Adaptación Fisiológica/genética , Supervivencia Celular , Factor 3 de Iniciación Eucariótica/genética , Factor 3 de Iniciación Eucariótica/metabolismo , FosforilaciónRESUMEN
Small noncoding piRNAs act as sequence-specific guides to repress complementary targets in Metazoa. Prior studies in Drosophila ovaries have demonstrated the function of the piRNA pathway in transposon silencing and therefore genome defense. However, the ability of the piRNA program to respond to different transposon landscapes and the role of piRNAs in regulating host gene expression remain poorly understood. Here, we comprehensively analyzed piRNA expression and defined the repertoire of their targets in Drosophila melanogaster testes. Comparison of piRNA programs between sexes revealed sexual dimorphism in piRNA programs that parallel sex-specific transposon expression. Using a novel bioinformatic pipeline, we identified new piRNA clusters and established complex satellites as dual-strand piRNA clusters. While sharing most piRNA clusters, the two sexes employ them differentially to combat the sex-specific transposon landscape. We found two piRNA clusters that produce piRNAs antisense to four host genes in testis, including CG12717/pirate, a SUMO protease gene. piRNAs encoded on the Y chromosome silence pirate, but not its paralog, to exert sex- and paralog-specific gene regulation. Interestingly, pirate is targeted by endogenous siRNAs in a sibling species, Drosophila mauritiana, suggesting distinct but related silencing strategies invented in recent evolution to regulate a conserved protein-coding gene.
Asunto(s)
Adaptación Fisiológica/genética , Elementos Transponibles de ADN/genética , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Regulación del Desarrollo de la Expresión Génica/genética , Células Germinativas/metabolismo , ARN Interferente Pequeño/metabolismo , Animales , Femenino , Masculino , Caracteres Sexuales , Factores SexualesRESUMEN
Humans and other mammals inhabit hypoxic high-altitude locales. In many of these species, genes under positive selection include ones in the Hypoxia Inducible Factor (HIF) pathway. One is PHD2 (EGLN1), which encodes for a key oxygen sensor. Another is HIF2A (EPAS1), which encodes for a PHD2-regulated transcription factor. Recent studies have provided insights into mechanisms for these high-altitude alleles. These studies have (i) shown that selection can occur on nonconserved, unstructured regions of proteins, (ii) revealed that high altitude-associated amino acid substitutions can have differential effects on protein-protein interactions, (iii) provided evidence for convergent evolution by different molecular mechanisms, and (iv) suggested that mutations in different genes can complement one another to produce a set of adaptive phenotypes.
Asunto(s)
Adaptación Fisiológica , Altitud , Humanos , Animales , Adaptación Fisiológica/genética , Hipoxia/genética , Fenotipo , Regulación de la Expresión Génica , Prolina Dioxigenasas del Factor Inducible por Hipoxia/genética , Prolina Dioxigenasas del Factor Inducible por Hipoxia/metabolismo , Mamíferos/genéticaRESUMEN
Non-lymphoid tissues (NLTs) harbor a pool of adaptive immune cells with largely unexplored phenotype and development. We used single-cell RNA-seq to characterize 35,000 CD4+ regulatory (Treg) and memory (Tmem) T cells in mouse skin and colon, their respective draining lymph nodes (LNs) and spleen. In these tissues, we identified Treg cell subpopulations with distinct degrees of NLT phenotype. Subpopulation pseudotime ordering and gene kinetics were consistent in recruitment to skin and colon, yet the initial NLT-priming in LNs and the final stages of NLT functional adaptation reflected tissue-specific differences. Predicted kinetics were recapitulated using an in vivo melanoma-induction model, validating key regulators and receptors. Finally, we profiled human blood and NLT Treg and Tmem cells, and identified cross-mammalian conserved tissue signatures. In summary, we describe the relationship between Treg cell heterogeneity and recruitment to NLTs through the combined use of computational prediction and in vivo validation.
Asunto(s)
Adaptación Fisiológica/inmunología , Análisis de la Célula Individual/métodos , Linfocitos T Reguladores/inmunología , Transcriptoma/inmunología , Adaptación Fisiológica/genética , Animales , Línea Celular Tumoral , Movimiento Celular/genética , Movimiento Celular/inmunología , Colon/inmunología , Colon/metabolismo , Humanos , Memoria Inmunológica/genética , Memoria Inmunológica/inmunología , Tejido Linfoide/inmunología , Tejido Linfoide/metabolismo , Ratones Transgénicos , Neoplasias Experimentales/genética , Neoplasias Experimentales/inmunología , Neoplasias Experimentales/patología , Piel/inmunología , Piel/metabolismo , Bazo/inmunología , Bazo/metabolismo , Linfocitos T Reguladores/metabolismoRESUMEN
Our body has a remarkable ability to remember its past encounters with allergens, pathogens, wounds and irritants, and to react more quickly to the next experience. This accentuated sensitivity also helps us to cope with new threats. Despite maintaining a state of readiness and broadened resistance to subsequent pathogens, memories can also be maladaptive, leading to chronic inflammatory disorders and cancers. With the ever-increasing emergence of new pathogens, allergens and pollutants in our world, the urgency to unravel the molecular underpinnings of these phenomena has risen to new heights. Here we reflect on how the field of inflammatory memory has evolved, since 2007, when researchers realized that non-specific memory is contained in the nucleus and propagated at the epigenetic level. We review the flurry of recent discoveries revealing that memory is not just a privilege of the immune system but also extends to epithelia of the skin, lung, intestine and pancreas, and to neurons. Although still unfolding, epigenetic memories of inflammation have now been linked to possible brain disorders such as Alzheimer disease, and to an elevated risk of cancer. In this Review, we consider the consequences-good and bad-of these epigenetic memories and their implications for human health and disease.
Asunto(s)
Adaptación Fisiológica , Epigénesis Genética , Salud , Inflamación , Adaptación Fisiológica/genética , Enfermedad de Alzheimer/genética , Humanos , Memoria Inmunológica , Inflamación/genética , Neoplasias/genéticaRESUMEN
Genetic and epigenetic variation, together with transcriptional plasticity, contribute to intratumour heterogeneity1. The interplay of these biological processes and their respective contributions to tumour evolution remain unknown. Here we show that intratumour genetic ancestry only infrequently affects gene expression traits and subclonal evolution in colorectal cancer (CRC). Using spatially resolved paired whole-genome and transcriptome sequencing, we find that the majority of intratumour variation in gene expression is not strongly heritable but rather 'plastic'. Somatic expression quantitative trait loci analysis identified a number of putative genetic controls of expression by cis-acting coding and non-coding mutations, the majority of which were clonal within a tumour, alongside frequent structural alterations. Consistently, computational inference on the spatial patterning of tumour phylogenies finds that a considerable proportion of CRCs did not show evidence of subclonal selection, with only a subset of putative genetic drivers associated with subclone expansions. Spatial intermixing of clones is common, with some tumours growing exponentially and others only at the periphery. Together, our data suggest that most genetic intratumour variation in CRC has no major phenotypic consequence and that transcriptional plasticity is, instead, widespread within a tumour.
Asunto(s)
Adaptación Fisiológica , Neoplasias Colorrectales , Regulación Neoplásica de la Expresión Génica , Fenotipo , Humanos , Adaptación Fisiológica/genética , Células Clonales/metabolismo , Células Clonales/patología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Mutación , Secuenciación del Exoma , Transcripción GenéticaRESUMEN
Mechanistic target of rapamycin complex 1 (mTORC1) regulates cell growth and metabolism in response to multiple nutrients, including the essential amino acid leucine1. Recent work in cultured mammalian cells established the Sestrins as leucine-binding proteins that inhibit mTORC1 signalling during leucine deprivation2,3, but their role in the organismal response to dietary leucine remains elusive. Here we find that Sestrin-null flies (Sesn-/-) fail to inhibit mTORC1 or activate autophagy after acute leucine starvation and have impaired development and a shortened lifespan on a low-leucine diet. Knock-in flies expressing a leucine-binding-deficient Sestrin mutant (SesnL431E) have reduced, leucine-insensitive mTORC1 activity. Notably, we find that flies can discriminate between food with or without leucine, and preferentially feed and lay progeny on leucine-containing food. This preference depends on Sestrin and its capacity to bind leucine. Leucine regulates mTORC1 activity in glial cells, and knockdown of Sesn in these cells reduces the ability of flies to detect leucine-free food. Thus, nutrient sensing by mTORC1 is necessary for flies not only to adapt to, but also to detect, a diet deficient in an essential nutrient.