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Sato DX, Okuyama T, Takahashi Y. Multifaceted and extensive behavioral trajectories of genomically diverse Drosophila lines. Sci Data 2025; 12:400. [PMID: 40055352 PMCID: PMC11889213 DOI: 10.1038/s41597-025-04724-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Accepted: 02/27/2025] [Indexed: 05/13/2025] Open
Abstract
Detailed tracking data is essential to understanding the intricate mechanisms behind animal behavior. Here, we present a comprehensive dataset containing behavioral movies and trajectories from over 30,000 Drosophila melanogaster individuals across 105 genetically distinct strains, including 104 wild-type strains from the Drosophila Genetic Reference Panel, along with one visually impaired mutant. These data, categorized by genetic background, sex, and social context (isolated or in groups), were collected during 15-minute sessions that included five minutes of repeated looming stimuli to elicit fear responses. Additionally, our experimental design incorporated group experiments with randomly combined pairs of strains to investigate synergistic effects of group members on behavioral dynamics. Beyond enabling detailed analyses of genetic factors underlying locomotion, fear responses, and social interactions, this dataset provides a unique opportunity to examine individual behavioral variability within genetically identical flies. By capturing a broad spectrum of behaviors across different genetic and environmental contexts, these data serve as a valuable resource for advancing our understanding of how genetics, individuality, and group interactions shape animal behavior.
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Affiliation(s)
- Daiki X Sato
- Institute for Advanced Academic Research, Chiba University, Chiba, Japan.
- Graduate School of Science, Chiba University, Chiba, Japan.
| | - Takahira Okuyama
- Graduate School of Science and Engineering, Chiba University, Chiba, Japan
| | - Yuma Takahashi
- Graduate School of Science, Chiba University, Chiba, Japan.
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Hundebøl BNRG, Rohde PD, Kristensen TN, Jensen RWM, Vosegaard T, Sørensen JG. Bugs on Drugs: Paracetamol Exposure Reveals Genotype-Specific Generational Effects on Life History Traits in Drosophila melanogaster. INSECTS 2024; 15:763. [PMID: 39452339 PMCID: PMC11509061 DOI: 10.3390/insects15100763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 09/26/2024] [Accepted: 09/26/2024] [Indexed: 10/26/2024]
Abstract
Few investigations have been made to determine whether pharmaceutical drugs cause any generational effects. These effects can be divided into intergenerational and transgenerational effects. In insects, the F1 offspring of exposed individuals are considered to show intergenerational effects (as they have been exposed as germ cells or early embryos), while the F2 generation is fully non-exposed and considered to show transgenerational effects. Here, the common over-the-counter (OTC) drug, paracetamol, is investigated for genotype-specific responses and effects across generations on three life-history traits: fecundity, longevity, and spontaneous locomotor activity levels in the model species Drosophila melanogaster. Seven isofemale D. melanogaster lines were exposed to a high and intermediate dose of paracetamol determined by a dose-response curve. NMR investigations verified the long-term presence of paracetamol in the food substrate. Phenotypic effects of paracetamol ingestion were investigated on flies exposed to the drug and in their offspring and grand-offspring. The dose-response curve indicated genotype-specific responses to paracetamol. In the following experiment, all traits investigated displayed significant effects of paracetamol ingestion for at least one of the seven isofemale lines, and we detected strong genotype-specific responses to paracetamol. Fecundity tended to increase in individuals directly exposed to the drug whereas fecundity in the F2 generation was reduced (transgenerational). Longevity generally decreased in directly exposed individuals but tended to increase in F1 offspring (intergenerational). Paracetamol effects on spontaneous locomotor activity were primarily detected as transgenerational effects and were rarely seen in directly exposed individuals. However, across lines, no clear overall trend could be determined for any trait. The generational effects and marked genotype-specific response to paracetamol warrants further investigation of both genotype-specific responses and generational effects in general.
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Affiliation(s)
| | - Palle Duun Rohde
- Department of Health Science and Technology, Aalborg University, 9220 Aalborg Ø, Denmark;
| | | | - Rune Wittendorff Mønster Jensen
- Interdisciplinary Nanoscience Center (iNANO), Aarhus University, 8000 Aarhus C, Denmark; (R.W.M.J.); (T.V.)
- Department of Chemistry, Aarhus University, 8000 Aarhus C, Denmark
| | - Thomas Vosegaard
- Interdisciplinary Nanoscience Center (iNANO), Aarhus University, 8000 Aarhus C, Denmark; (R.W.M.J.); (T.V.)
- Department of Chemistry, Aarhus University, 8000 Aarhus C, Denmark
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Qu S, Zhou X, Wang Z, Wei Y, Zhou H, Zhang X, Zhu Q, Wang Y, Yang Q, Jiang L, Ma Y, Gao Y, Kong L, Zhang L. The effects of methylphenidate and atomoxetine on Drosophila brain at single-cell resolution and potential drug repurposing for ADHD treatment. Mol Psychiatry 2024; 29:165-185. [PMID: 37957291 PMCID: PMC11078728 DOI: 10.1038/s41380-023-02314-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 10/24/2023] [Accepted: 10/30/2023] [Indexed: 11/15/2023]
Abstract
The stimulant methylphenidate (MPH) and the non-stimulant atomoxetine (ATX) are frequently used for the treatment of attention-deficit/hyperactivity disorder (ADHD); however, the function of these drugs in different types of brain cells and their effects on related genes remain largely unknown. To address these questions, we built a pipeline for the simultaneous examination of the activity behavior and transcriptional responses of Drosophila melanogaster at single-cell resolution following drug treatment. We selected the Drosophila with significantly increased locomotor activities (hyperactivity-like behavior) following the administration of each drug in comparison with the control (same food as the drug-treated groups with 5% sucrose, yeast, and blue food dye solution) using EasyFlyTracker. Subsequently, single cell RNA sequencing (scRNASEQ) was used to capture the transcriptome of 82,917 cells, unsupervised clustering analysis of which yielded 28 primary cell clusters representing the major cell types in adult Drosophila brain. Indeed, both neuronal and glial cells responded to MPH and ATX. Further analysis of differentially expressed genes (DEGs) revealed distinct transcriptional changes associated with these two drugs, such as two well-studied dopamine receptor genes (Dop2R and DopEcR) were responsive to MPH but not to ATX at their optimal doses, in addition to genes involved in dopamine metabolism pathways such as Syt1, Sytalpha, Syt7, and Ih in different cell types. More importantly, MPH also suppressed the expression of genes encoding other neurotransmitter receptors and synaptic signaling molecules in many cell types, especially those for Glu and GABA, while the responsive effects of ATX were much weaker. In addition to monoaminergic neuronal transmitters, other neurotransmitters have also shown a similar pattern with respect to a stronger effect associated with MPH than with ATX. Moreover, we identified four distinct glial cell subtypes responsive to the two drugs and detected a greater number of differentially expressed genes associated with ensheathing and astrocyte-like glia. Furthermore, our study provides a rich resource of candidate target genes, supported by drug set enrichment analysis (P = 2.10E-4; hypergeometric test), for the further exploration of drug repurposing. The whole list of candidates can be found at ADHDrug ( http://adhdrug.cibr.ac.cn/ ). In conclusion, we propose a fast and cost-efficient pipeline to explore the underlying molecular mechanisms of ADHD drug treatment in Drosophila brain at single-cell resolution, which may further facilitate drug repurposing applications.
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Affiliation(s)
- Susu Qu
- Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
- Chinese Institute for Brain Research, Beijing, China.
| | - Xiangyu Zhou
- Chinese Institute for Brain Research, Beijing, China
| | - Zhicheng Wang
- Chinese Institute for Brain Research, Beijing, China
| | - Yi Wei
- Chinese Institute for Brain Research, Beijing, China
| | - Han Zhou
- Chinese Institute for Brain Research, Beijing, China
| | | | - Qingjie Zhu
- Chinese Institute for Brain Research, Beijing, China
| | - Yanmin Wang
- Chinese Institute for Brain Research, Beijing, China
| | - Quanjun Yang
- Department of Pharmacy, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Likun Jiang
- Department of Computer Science, Xiamen University, Xiamen, China
| | - Yuan Ma
- Chinese Institute for Brain Research, Beijing, China
| | - Yuan Gao
- Chinese Institute for Brain Research, Beijing, China
| | - Lei Kong
- Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China
| | - Li Zhang
- Chinese Institute for Brain Research, Beijing, China.
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Cabana-Domínguez J, Antón-Galindo E, Fernàndez-Castillo N, Singgih EL, O'Leary A, Norton WH, Strekalova T, Schenck A, Reif A, Lesch KP, Slattery D, Cormand B. The translational genetics of ADHD and related phenotypes in model organisms. Neurosci Biobehav Rev 2023; 144:104949. [PMID: 36368527 DOI: 10.1016/j.neubiorev.2022.104949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 11/02/2022] [Accepted: 11/05/2022] [Indexed: 11/10/2022]
Abstract
Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent neurodevelopmental disorder resulting from the interaction between genetic and environmental risk factors. It is well known that ADHD co-occurs frequently with other psychiatric disorders due, in part, to shared genetics factors. Although many studies have contributed to delineate the genetic landscape of psychiatric disorders, their specific molecular underpinnings are still not fully understood. The use of animal models can help us to understand the role of specific genes and environmental stimuli-induced epigenetic modifications in the pathogenesis of ADHD and its comorbidities. The aim of this review is to provide an overview on the functional work performed in rodents, zebrafish and fruit fly and highlight the generated insights into the biology of ADHD, with a special focus on genetics and epigenetics. We also describe the behavioral tests that are available to study ADHD-relevant phenotypes and comorbid traits in these models. Furthermore, we have searched for new models to study ADHD and its comorbidities, which can be useful to test potential pharmacological treatments.
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Affiliation(s)
- Judit Cabana-Domínguez
- Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Catalonia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Spain; Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Catalonia, Spain; Institut de Recerca Sant Joan de Déu (IR-SJD), Esplugues de Llobregat, Catalonia, Spain.
| | - Ester Antón-Galindo
- Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Catalonia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Spain; Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Catalonia, Spain; Institut de Recerca Sant Joan de Déu (IR-SJD), Esplugues de Llobregat, Catalonia, Spain
| | - Noèlia Fernàndez-Castillo
- Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Catalonia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Spain; Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Catalonia, Spain; Institut de Recerca Sant Joan de Déu (IR-SJD), Esplugues de Llobregat, Catalonia, Spain
| | - Euginia L Singgih
- Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Aet O'Leary
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University, Frankfurt, Germany; Division of Neuropsychopharmacology, Department of Psychology, University of Tartu, Tartu, Estonia
| | - William Hg Norton
- Department of Genetics and Genome Biology, University of Leicester, Leicester, UK
| | - Tatyana Strekalova
- Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, Germany, and Department of Neuropsychology and Psychiatry, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Maastricht, the Netherlands
| | - Annette Schenck
- Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Andreas Reif
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University, Frankfurt, Germany
| | - Klaus-Peter Lesch
- Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, Germany, and Department of Neuropsychology and Psychiatry, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Maastricht, the Netherlands
| | - David Slattery
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University, Frankfurt, Germany
| | - Bru Cormand
- Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Catalonia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Spain; Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Catalonia, Spain; Institut de Recerca Sant Joan de Déu (IR-SJD), Esplugues de Llobregat, Catalonia, Spain.
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Qu S, Zhu Q, Zhou H, Gao Y, Wei Y, Ma Y, Wang Z, Sun X, Zhang L, Yang Q, Kong L, Zhang L. EasyFlyTracker: A Simple Video Tracking Python Package for Analyzing Adult Drosophila Locomotor and Sleep Activity to Facilitate Revealing the Effect of Psychiatric Drugs. Front Behav Neurosci 2022; 15:809665. [PMID: 35221942 PMCID: PMC8868375 DOI: 10.3389/fnbeh.2021.809665] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 12/17/2021] [Indexed: 12/13/2022] Open
Abstract
The mechanism of psychiatric drugs (stimulant and non-stimulant) is still unclear. Precision medication of psychiatric disorders faces challenges in pharmacogenetics and pharmacodynamics research due to difficulties in recruiting human subjects because of possibility of substance abuse and relatively small sample sizes. Drosophila is a powerful animal model for large-scale studies of drug effects based on the precise quantification of behavior. However, a user-friendly system for high-throughput simultaneous tracking and analysis of drug-treated individual adult flies is still lacking. It is critical to quickly setup a working environment including both the hardware and software at a reasonable cost. Thus, we have developed EasyFlyTracker, an open-source Python package that can track single fruit fly in each arena and analyze Drosophila locomotor and sleep activity based on video recording to facilitate revealing the psychiatric drug effects. The current version does not support multiple fruit fly tracking. Compared with existing software, EasyFlyTracker has the advantages of low cost, easy setup and scaling, rich statistics of movement trajectories, and compatibility with different video recording systems. Also, it accepts multiple video formats such as common MP4 and AVI formats. EasyFlyTracker provides a cross-platform and user-friendly interface combining command line and graphic configurations, which allows users to intuitively understand the process of tracking and downstream analyses and automatically generates multiple files, especially plots. Users can install EasyFlyTracker, go through tutorials, and give feedback on http://easyflytracker.cibr.ac.cn. Moreover, we tested EasyFlyTracker in a study of Drosophila melanogaster on the hyperactivity-like behavior effects of two psychiatric drugs, methylphenidate and atomoxetine, which are two commonly used drugs treating attention-deficit/hyperactivity disorder (ADHD) in human. This software has the potential to accelerate basic research on drug effect studies with fruit flies.
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Affiliation(s)
- Susu Qu
- Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
- Chinese Institute for Brain Research, Beijing, China
- *Correspondence: Susu Qu,
| | - Qingjie Zhu
- Chinese Institute for Brain Research, Beijing, China
| | - Han Zhou
- Chinese Institute for Brain Research, Beijing, China
| | - Yuan Gao
- Chinese Institute for Brain Research, Beijing, China
| | - Yi Wei
- Chinese Institute for Brain Research, Beijing, China
| | - Yuan Ma
- Chinese Institute for Brain Research, Beijing, China
| | - Zhicheng Wang
- Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
- Chinese Institute for Brain Research, Beijing, China
| | - Xueting Sun
- Chinese Institute for Brain Research, Beijing, China
| | - Lei Zhang
- Chinese Institute for Brain Research, Beijing, China
- Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Capital Medical University, Beijing, China
| | - Quanjun Yang
- Department of Pharmacy, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Lei Kong
- Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China
| | - Li Zhang
- Chinese Institute for Brain Research, Beijing, China
- Li Zhang,
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6
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Philyaw TJ, Rothenfluh A, Titos I. The Use of Drosophila to Understand Psychostimulant Responses. Biomedicines 2022; 10:119. [PMID: 35052798 PMCID: PMC8773124 DOI: 10.3390/biomedicines10010119] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 12/31/2021] [Accepted: 12/31/2021] [Indexed: 01/27/2023] Open
Abstract
The addictive properties of psychostimulants such as cocaine, amphetamine, methamphetamine, and methylphenidate are based on their ability to increase dopaminergic neurotransmission in the reward system. While cocaine and methamphetamine are predominately used recreationally, amphetamine and methylphenidate also work as effective therapeutics to treat symptoms of disorders including attention deficit and hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Although both the addictive properties of psychostimulant drugs and their therapeutic efficacy are influenced by genetic variation, very few genes that regulate these processes in humans have been identified. This is largely due to population heterogeneity which entails a requirement for large samples. Drosophila melanogaster exhibits similar psychostimulant responses to humans, a high degree of gene conservation, and allow performance of behavioral assays in a large population. Additionally, amphetamine and methylphenidate reduce impairments in fly models of ADHD-like behavior. Therefore, Drosophila represents an ideal translational model organism to tackle the genetic components underlying the effects of psychostimulants. Here, we break down the many assays that reliably quantify the effects of cocaine, amphetamine, methamphetamine, and methylphenidate in Drosophila. We also discuss how Drosophila is an efficient and cost-effective model organism for identifying novel candidate genes and molecular mechanisms involved in the behavioral responses to psychostimulant drugs.
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Affiliation(s)
- Travis James Philyaw
- Molecular Biology Graduate Program, University of Utah, Salt Lake City, UT 84112, USA;
| | - Adrian Rothenfluh
- Department of Psychiatry, Huntsman Mental Health Institute, University of Utah, Salt Lake City, UT 84108, USA
- Molecular Medicine Program, University of Utah, Salt Lake City, UT 84112, USA
- Department of Neurobiology, University of Utah, Salt Lake City, UT 84132, USA
- Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA
| | - Iris Titos
- Molecular Medicine Program, University of Utah, Salt Lake City, UT 84112, USA
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Hime GR, Stonehouse SLA, Pang TY. Alternative models for transgenerational epigenetic inheritance: Molecular psychiatry beyond mice and man. World J Psychiatry 2021; 11:711-735. [PMID: 34733638 PMCID: PMC8546770 DOI: 10.5498/wjp.v11.i10.711] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 07/19/2021] [Accepted: 08/25/2021] [Indexed: 02/06/2023] Open
Abstract
Mental illness remains the greatest chronic health burden globally with few in-roads having been made despite significant advances in genomic knowledge in recent decades. The field of psychiatry is constantly challenged to bring new approaches and tools to address and treat the needs of vulnerable individuals and subpopulations, and that has to be supported by a continuous growth in knowledge. The majority of neuropsychiatric symptoms reflect complex gene-environment interactions, with epigenetics bridging the gap between genetic susceptibility and environmental stressors that trigger disease onset and drive the advancement of symptoms. It has more recently been demonstrated in preclinical models that epigenetics underpins the transgenerational inheritance of stress-related behavioural phenotypes in both paternal and maternal lineages, providing further supporting evidence for heritability in humans. However, unbiased prospective studies of this nature are practically impossible to conduct in humans so preclinical models remain our best option for researching the molecular pathophysiologies underlying many neuropsychiatric conditions. While rodents will remain the dominant model system for preclinical studies (especially for addressing complex behavioural phenotypes), there is scope to expand current research of the molecular and epigenetic pathologies by using invertebrate models. Here, we will discuss the utility and advantages of two alternative model organisms-Caenorhabditis elegans and Drosophila melanogaster-and summarise the compelling insights of the epigenetic regulation of transgenerational inheritance that are potentially relevant to human psychiatry.
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Affiliation(s)
- Gary R Hime
- Department of Anatomy and Physiology, The University of Melbourne, Parkville 3010, VIC, Australia
| | - Sophie LA Stonehouse
- Mental Health Theme, The Florey Institute of Neuroscience and Mental Health, Parkville 3052, VIC, Australia
| | - Terence Y Pang
- Department of Anatomy and Physiology, The University of Melbourne, Parkville 3010, VIC, Australia
- Mental Health Theme, The Florey Institute of Neuroscience and Mental Health, Parkville 3052, VIC, Australia
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Genotype and Trait Specific Responses to Rapamycin Intake in Drosophila melanogaster. INSECTS 2021; 12:insects12050474. [PMID: 34065203 PMCID: PMC8161023 DOI: 10.3390/insects12050474] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 05/17/2021] [Accepted: 05/19/2021] [Indexed: 12/11/2022]
Abstract
Simple Summary Rapamycin is commonly used as an immunosuppressant, but also as an anti-aging medicine. Despite its widespread use, results suggest that there is large variability in drug efficiency among patients, and limited knowledge exists about potential side-effects. In the present study, we investigated the effects of rapamycin using the common fruit fly as model organism. Six genetically distinct lines were exposed to rapamycin, and the phenotypic consequence on fecundity, longevity and heat stress tolerance was quantified. Flies exposed to rapamycin had increased longevity and heat stress tolerance, however a side effect in the form of decreased fecundity was also observed. Our data clearly show that the costs and benefits of rapamycin treatment is strongly genotype dependent. These observations are important as they imply that a ‘one size fits all’ approach when it comes to rapamycin treatment is not advisable. Future studies should address the underlying genetic component that drive the drug response variability. Abstract Rapamycin is a powerful inhibitor of the TOR (Target of Rapamycin) pathway, which is an evolutionarily conserved protein kinase, that plays a central role in plants and animals. Rapamycin is used globally as an immunosuppressant and as an anti-aging medicine. Despite widespread use, treatment efficiency varies considerably across patients, and little is known about potential side effects. Here we seek to investigate the effects of rapamycin by using Drosophila melanogaster as model system. Six isogenic D. melanogaster lines were assessed for their fecundity, male longevity and male heat stress tolerance with or without rapamycin treatment. The results showed increased longevity and heat stress tolerance for male flies treated with rapamycin. Conversely, the fecundity of rapamycin-exposed individuals was lower than for flies from the non-treated group, suggesting unwanted side effects of the drug in D. melanogaster. We found strong evidence for genotype-by-treatment interactions suggesting that a ‘one size fits all’ approach when it comes to treatment with rapamycin is not recommendable. The beneficial responses to rapamycin exposure for stress tolerance and longevity are in agreement with previous findings, however, the unexpected effects on reproduction are worrying and need further investigation and question common believes that rapamycin constitutes a harmless drug.
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Rohde PD, Kristensen TN, Sarup P, Muñoz J, Malmendal A. Prediction of complex phenotypes using the Drosophila melanogaster metabolome. Heredity (Edinb) 2021; 126:717-732. [PMID: 33510469 PMCID: PMC8102504 DOI: 10.1038/s41437-021-00404-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 01/04/2021] [Accepted: 01/04/2021] [Indexed: 01/30/2023] Open
Abstract
Understanding the genotype-phenotype map and how variation at different levels of biological organization is associated are central topics in modern biology. Fast developments in sequencing technologies and other molecular omic tools enable researchers to obtain detailed information on variation at DNA level and on intermediate endophenotypes, such as RNA, proteins and metabolites. This can facilitate our understanding of the link between genotypes and molecular and functional organismal phenotypes. Here, we use the Drosophila melanogaster Genetic Reference Panel and nuclear magnetic resonance (NMR) metabolomics to investigate the ability of the metabolome to predict organismal phenotypes. We performed NMR metabolomics on four replicate pools of male flies from each of 170 different isogenic lines. Our results show that metabolite profiles are variable among the investigated lines and that this variation is highly heritable. Second, we identify genes associated with metabolome variation. Third, using the metabolome gave better prediction accuracies than genomic information for four of five quantitative traits analyzed. Our comprehensive characterization of population-scale diversity of metabolomes and its genetic basis illustrates that metabolites have large potential as predictors of organismal phenotypes. This finding is of great importance, e.g., in human medicine, evolutionary biology and animal and plant breeding.
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Affiliation(s)
- Palle Duun Rohde
- Department of Chemistry and Bioscience, Aalborg University, Aalborg, Denmark.
| | - Torsten Nygaard Kristensen
- Department of Chemistry and Bioscience, Aalborg University, Aalborg, Denmark
- Department of Animal Science, Aarhus University, Tjele, Denmark
| | - Pernille Sarup
- Department of Molecular Biology and Genetics, Aarhus University, Tjele, Denmark
- Nordic Seed A/S, Odder, Denmark
| | - Joaquin Muñoz
- Department of Chemistry and Bioscience, Aalborg University, Aalborg, Denmark
| | - Anders Malmendal
- Department of Science and Environment, Roskilde University, Roskilde, Denmark.
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10
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Affiliation(s)
- Palle Duun Rohde
- Department of Molecular Biology & Genetics, Aarhus University, Aarhus, Denmark
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