Biology subjects

Shankar, V.

Publications and source records attributed to Shankar, V..

At least 19 recordsLinked to original sources

bioRxiv2026

Genetics of Cocaine Consumption and Preference in Drosophila melanogaster

Cocaine Use Disorder (CUD) poses a significant public health and socioeconomic challenge. Determining the genetic basis of predisposition for development of CUD is challenging in human populations but can be studied in Drosophila. We assessed cocaine consumption and cocaine preference of 74,875 flies from 598 sequenced, wild-derived, inbred lines from the expanded Drosophila melanogaster Genetic Reference Panel (DGRP3). We found significant genetic variation, sexual dimorphism, and genetic variation in sexual dimorphism for these traits. Whereas most lines showed cocaine avoidance, ~10% of the lines showed innate cocaine preference in at least one sex. Genome-wide association analyses for cocaine consumption, preference, and micro-environmental variance of these traits identified 2,155 polymorphisms in/near 866 genes that were enriched for Gene Ontology terms associated with neurogenesis, development, and behavior. Many of the associated genes had human orthologs with known associations with CUD and other substance use disorders as well as psychiatric and behavioral traits. We confirmed causal associations with cocaine preference for three polymorphisms with large effect sizes by assessing their effects in DGRP3 lines not included in the initial association analyses. Pairwise associations between these polymorphisms exhibited suppressing epistasis. These polymorphisms are in genes with human orthologs that fulfill essential functions in the nervous system, including the glucose transporter SLC2A8; KCNC2, a subunit of the voltage gated potassium channel; and CHRNA7, a nicotinic cholinergic receptor subunit. Thus, studies on Drosophila can provide insights into the genetic and neural mechanisms of CUD.

genetics↗

bioRxiv2026

Multiome Profiling Reveals Astrocyte and Neuroendocrine Targets of Prenatal Acoustic Programming in Zebra Finch Embryos

Climate change is driving more frequent and severe heat events, yet the developmental mechanisms by which organisms anticipate and adapt to thermal stress remain poorly understood. In zebra finches (Taeniopygia guttata), parents exposed to extreme heat emit distinctive "heat call" vocalizations during late incubation that trigger adaptive phenotypic responses in offspring, including altered growth, thermoregulation, and reproductive success. Recent transcriptomic analysis revealed that prenatal heat call exposure induces hypothalamic gene expression changes enriched in non-neuronal populations, but cellular heterogeneity has obscured which cell types are primary targets and the regulatory mechanisms underlying acoustic programming. Here, we performed single-nucleus multiome sequencing to generate a cell-type-resolved atlas of gene expression and chromatin accessibility in the late-stage embryonic zebra finch hypothalamus. We find that heat call exposure selectively remodels astrocyte regulatory landscapes, with most playback-responsive chromatin changes localized to glial populations like astrocytes, challenging neuron-centric models of developmental programming. Motif enrichment and gene regulatory network analysis showed Nuclear Factor I-C, AP-1, and Notch pathway components - canonical drivers of the gliogenic switch - coordinate this response. Chromatin co-accessibility analysis revealed extensive astrocyte-specific enhancer-promoter rewiring at developmental signaling hubs, and pseudotemporal analysis identified condition-associated shifts in developmental trajectories and astrocyte gene-expression dynamics consistent with altered gliogenic programs. In parallel, we identified sex-dimorphic regulation of transthyretin in glutamatergic neurons of the paraventricular nucleus, linking acoustic programming to thyroid-dependent neuroendocrine pathways. These findings suggest that prenatal acoustic experience engages astrocyte-selective epigenetic priming and neuroendocrine transcriptional responses that may reshape hypothalamic developmental programs under predicted thermal environments.

developmental biology↗

bioRxiv2026

The Drosophila melanogaster Genetic Reference Panel, Version 3 (DGRP3)

Drosophila melanogaster is a leading animal model for understanding basic genetic principles for biomedical research and for quantitative, population and evolutionary genetics and genomics. The D. melanogaster Genetic Reference Panel (DGRP) of [~]200 inbred strains with full genome sequences is a publicly available resource for genome wide association (GWA) studies of quantitative traits, systems genetics, and population genomic analyses. However, the small size of the DGRP limits the power to map rare variants or variants with small effect sizes. Here, we describe the DGRP Version 3 (DGRP3), consisting of full genome sequences from 1,233 inbred lines, of which 1,037 are currently extant. The DGRP3 harbors extensive genetic diversity, with 8,760,339 molecular polymorphisms including single nucleotide polymorphisms, insertions, deletions, inversions, tandem duplications and complex rearrangements. We identified 80,894 damaging variants and 4,550 genes with at least one loss-of-function haplotype. We inferred 16 mitochondrial haplotype groups, determined the microbial composition, and quantified the numbers of sensory bristles for the DGRP3 lines. We performed GWA analyses for inbreeding depression, host control of microbiome composition, and numbers of sensory bristles, identifying novel candidate variants and genes for each. The accompanying online tool (flydgrp.org) implements state-of-the-art association mapping methods and provides results for users DGRP3 data.

genomics↗

bioRxiv2026

Aging restricts maturation of CXCL13+ T follicular helper cells in human immunity

A decline in specific antibody responses is a hallmark of human aging, yet the differential contributions of B and T lymphocytes and their interactions remain unclear. CXCL13 is a critical chemokine that shapes germinal center organization, but the regulation of human-specific CXCL13+ Tfh cells during aging is not known. Using human tonsil organoids, single-cell RNA sequencing, and CRISPR perturbations, we mapped age-associated changes in T follicular helper (Tfh) cells, the cell type that provides T cell "help" to B cells in germinal centers (GCs). Tonsil organoids from older donors generated weaker influenza-specific antibody responses, which we traced to Tfh cell defects rather than B cells. Single-cell profiling revealed a selective loss of mature CXCL13 GC-Tfh cells accompanied by accumulation of Tfh precursor states. Trajectory analysis showed that aging arrests Tfh cell maturation at the early activated precursor transition, and CRISPR perturbations identified BACH2 and SOX4 as transcriptional regulators of differentiation reduced with age. These findings reveal a human-specific mechanism of immune aging with implications for strategies to restore humoral immunity.

immunology↗

bioRxiv2026

Dynamic optimization of extrachromosomal DNA copy number drives tumour evolution

Extrachromosomal DNA (ecDNA) is common in human cancers and is associated with poor clinical outcomes, yet how ecDNA-driven genetic heterogeneity is translated into functional heterogeneity remains unclear. Using single-cell multiomics sequencing and multiplexed IF-FISH, we show that asymmetric inheritance of ecDNA generates copy number heterogeneity that propagates to gene expression programs, including oncogenic signaling and cellular stress responses. Transgenerational live-cell lineage tracking directly shows that ecDNA heterogeneity arises within only a few cell divisions and modulates daughter cell division timing in a copy number-dependent manner, a property not observed for evenly inherited chromosomal amplicons. We identify an optimal middle ecDNA copy number range that maximizes proliferative fitness at baseline, while drug selection pressure induced by low-dose CHK1 inhibition selects for cells with a new optimal range at low ecDNA copy numbers. These low ecDNA copy number cells pre-exist in the population and can be generated de novo, driving copy number shifts promoting drug resistance. In vivo experiments further demonstrate that shifts toward ecDNA copy numbers that are optimal under the tumour microenvironment enhance tumourigenicity. Together, these findings establish ecDNA copy number plasticity as a central driver of tumour evolution.

cancer biology↗

bioRxiv2026

Fetal Thymic Expression Defines the Immunogenicity of Tumor Associated Antigens

Tumor associated antigens (TAAs) are promising targets for cancer immunotherapy, yet their immunogenicity varies widely and remains poorly understood. Here, we show that the immunogenic potential of TAAs is largely shaped by their expression in the thymus, likely established during fetal development. By integrating single-cell transcriptomic data across fetal and postnatal thymic epithelial cells (TECs), we find that TAA expression in fetal TECs predicts both in vitro CD8 T cell immunogenicity and the immune pressure against TAAs that occurs clinically in patients treated with immune checkpoint inhibitors. Notably, CD8 T cells recognizing TAAs highly expressed in the fetal thymus exhibit attenuated transcriptional, signaling, and metabolic responses even in the naive state, consistent with a tolerogenic imprinting imparted during thymic development and selection. Further, fetal thymic expression of TAAs can be leveraged to prioritize candidate targets for therapeutic use. These findings provide a biologic basis for the extreme variability seen in TAA immunogenicity and define guiding principles for rational antigen selection to drive the next generation of effective TAA-targeted immunotherapies.

immunology↗

bioRxiv2025

Genetic determinants that permit growth without the core septin Cdc12 in Cryptococcus neoformans

Septins are conserved cytoskeletal GTPases that regulate morphogenesis, cytokinesis, and cell-surface organization in fungi. In most model and pathogenic yeasts, including Saccharomyces cerevisiae and Candida albicans, core septin subunits such as Cdc3 and Cdc12 are essential and their loss results in lethal cytokinetic defects. In Cryptococcus neoformans, by contrast, deletion of CDC12 yields viable cells that grow normally under permissive conditions, raising the question of how this pathogen maintains cell integrity without a functional septin complex. To address this, we compared the transcriptomes of wild-type cells and a cdc12{Delta} mutant. The cdc12{Delta} strain showed a focused set of transcriptional changes, with induction of genes involved in cell wall remodeling, stress-dependent morphogenetic programs, and pathways that promote fitness under compromised cytoskeletal conditions. Genetic analysis of the most highly induced genes uncovered factors that contribute to proliferation in the absence of Cdc12, including a previously uncharacterized aspartic-type endopeptidase that becomes essential when septin function is lost. These findings outline the compensatory circuitry that permits septin-independent growth in C. neoformans and help explain why this pathogen can tolerate septin loss. This intrinsic plasticity highlights C. neoformans as a powerful comparative model for studying the evolution and function of the septin complex.

microbiology↗

bioRxiv2025

Mitochondria redistribution organizes the immunosuppressive tumor ecosystem

Hostile conditions in the tumor microenvironment restrict cellular respiration, yet mitochondrial metabolism remains indispensable for tumor growth and the activity of immunosuppressive cells. How tumor ecosystems sustain mitochondrial output has been unclear. Here, we show that cancer cells resolve this paradox by acting as hubs of intercellular mitochondrial redistribution. Using mitochondrial reporter systems, we demonstrate that cancer cells import host-derived mitochondria, integrate them into their endogenous network, and subsequently relay these hybrid organelles to neighboring immune cells. Mitochondria redistribution reprograms recipient neutrophils, macrophages, and CD4+ T cells into highly suppressive states but drives CD8+ T cell exhaustion. Within cancer cells, fusion of incoming mitochondria induces filamentous P5CS assembly, enhances biosynthetic output, and enables the refurbishment of damaged organelles into fully functional units. Disrupting mitochondrial redistribution collapses the immunosuppressive ecosystem and impairs tumor growth. Thus, cancer cells do not hoard resources but orchestrate a redistribution program that fortifies their own metabolic resilience, derails anti-tumor immunity, and sustains immunosuppressive partners. HIGHLIGHTSO_LITumor cells regulate their ecosystem by redistributing mitochondria C_LIO_LIRedistributed mitochondria expand immunosuppressive cells but exhausts CD8+ T cells C_LIO_LIMitochondria fusion within cancer cells, which precedes redistribution, optimizes metabolic output by triggering conformational changes in P5CS C_LIO_LIMitochondria fusion allows cancer cells to incorporate and refurbish seemingly incompetent host-derived mitochondria, improving efficiency in the tumor ecosystem C_LI

cancer biology↗

bioRxiv2025

Epilepsy-Associated SCN2A-L1342P Mutation Drives Network Hyperexcitability and Widespread Transcriptomic Changes in Human Cortical Organoids

ObjectiveSCN2A pathogenic mutations, such as the recurrent heterozygous Nav1.2-L1342P, are monogenic causes of epilepsy. In this human-induced pluripotent stem cell model system, we aim to investigate the molecular and cellular mechanisms underlying the SCN2A-L1342P-associated pathology. MethodsUsing a human male iPSC reference line (KOLF) carrying the Nav1.2-L1342P mutation, we generated 3D cortical organoids for functional studies. Patch clamp and multi-electrode array (MEA) recordings, immunocytochemistry, and RNA sequencing were used to characterize the disease phenotypes. ResultsNav1.2-L1342P organoid neurons displayed increased intrinsic excitability, and amplified excitatory post-synaptic currents, which are consistent with an increase in excitatory synapse formation revealed by PSD95/SYN1 immunostaining. Moreover, elevated network firing activity, as demonstrated by MEA, indicates a pronounced network hyperexcitability. Transcriptomic profiling of organoids carrying the Nav1.2-L1342P mutation further revealed significant alterations in synaptic, glutamatergic, and developmental pathways. SignificanceOur findings demonstrate that the Nav1.2-L1342P mutation drives a multifaceted disease phenotype, including network hyperexcitability and disruption of pathways related to neuronal and synaptic functions. These results advance our understanding of SCN2A-related Developmental and Epileptic Encephalopathy (DEE), laying a foundation for personalized interventions. Key PointsO_LIKey Point 1: Human neurons carrying epilepsy-causing SCN2A-L1342P display intrinsic hyperexcitability in cortical organoids. C_LIO_LIKey Point 2: Synaptic transmission is enhanced in organoids carrying the SCN2A-L1324P mutation, consistent with the presence of elevated excitatory synapses, which leads to increased network hyperexcitability. C_LIO_LIKey Point 3: Transcriptomics analysis reveals that the SCN2A-L1342P mutation causes significant differential changes in forebrain developmental genes, synaptic and glutamatergic signaling pathways, and enhances cellular senescence and apoptosis. C_LI

neuroscience↗

bioRxiv2025

Arsenic Toxicity in the Drosophila Brain at Single Cell Resolution

Arsenic is an ubiquitous environmental toxicant with harmful physiological effects, including neurotoxicity. Modulation of arsenic-induced gene expression in the brain cannot be readily studied in human subjects. However, Drosophila allows quantification of transcriptional responses to neurotoxins at single cell resolution across the entire brain in a single analysis. We exposed Drosophila melanogaster to a chronic dose of NaAsO that does not cause rapid lethality and measured survival and negative geotaxis as a proxy of sensorimotor integration. Females survive longer than males but show earlier physiological impairment in climbing ability. Single-nuclei RNA sequencing showed widespread sex-antagonistic transcriptional responses with modulation of gene expression in females biased toward neuronal cell populations and in males toward glial cells. However, differentially expressed genes implicated similar biological pathways. Evolutionary conservation of fundamental processes of the nervous system enabled us to translate arsenic-induced changes in transcript abundances from the Drosophila model to orthologous human neurogenetic networks.

genetics↗

bioRxiv2024

Altered polyadenylation site usage in SERPINA1 3'UTR in response to cellular stress affects A1AT protein expression

Alternative polyadenylation results in different 3 isoforms of messenger RNA (mRNA) transcripts. Alternative polyadenylation in the 3 untranslated region (3UTR) can alter RNA localization, stability and translational efficiency. The SERPINA1 mRNA has two distinct 3 UTR isoforms, both of which express the protease inhibitor -1-antitrypsin (A1AT). A1AT is an acute phase protein that is expressed and secreted from liver hepatocytes and upregulated during inflammation. Low levels of A1AT in the lung contributes to chronic obstructive pulmonary disease, while misfolding of A1AT in the liver contributes to liver cirrhosis. We analyzed the dynamics of alternative polyadenylation during cellular stress by treating the liver cell line HepG2 with the cytokine interleukin 6 (IL-6), ethanol or peroxide. SERPINA1 is transcriptionally upregulated after IL-6 treatment and has altered polyadenylation, resulting in an increase in long 3UTR isoforms. We find that the long 3UTR represses endogenous A1AT protein expression even with high levels of SERPINA1 mRNA. SERPINA1 expression and 3 end processing were not affected by ethanol or peroxide. IL-6-induced changes in transcriptome-wide transcriptional regulation suggest changes to the endoplasmic reticulum and in secretory protein processing. Our data suggest that inflammation influences polyA site choice for SERPINA1 transcripts, resulting in reduced A1AT protein expression.

molecular biology↗

bioRxiv2024

Improving polygenic prediction from summary data by learning patterns of effect sharing across multiple phenotypes.

Polygenic prediction of complex trait phenotypes has become important in human genetics, especially in the context of precision medicine. Recently, Morgante et al. introduced mr.mash, a flexible and computationally efficient method that models multiple phenotypes jointly and leverages sharing of effects across such phenotypes to improve prediction accuracy. However, a drawback of mr.mash is that it requires individual-level data, which are often not publicly available. In this work, we introduce mr.mash-rss, an extension of the mr.mash model that requires only summary statistics from Genome-Wide Association Studies (GWAS) and linkage disequilibrium (LD) estimates from a reference panel. By using summary data, we achieve the twin goal of increasing the applicability of the mr.mash model to data sets that are not publicly available and making it scalable to biobank-size data. Through simulations, we show that mr.mash-rss is competitive with, and often outperforms, current state-of-the-art methods for single- and multi-phenotype polygenic prediction in a variety of scenarios that differ in the pattern of effect sharing across phenotypes, the number of phenotypes, the number of causal variants, and the genomic heritability. We also present a real data analysis of 16 blood cell phenotypes in UK Biobank, showing that mr.mash-rss achieves higher prediction accuracy than competing methods for the majority of traits, especially when the data has smaller sample size. Author summaryPolygenic prediction refers to the use of an individuals genetic information (i.e., genotypes) to predict traits (i.e., phenotypes), which are often of medical relevance. It is known that some phenotypes are related and are affected by the same genotypes. When this is the case, it is possible to improve the accuracy of predictions by using methods that model multiple phenotypes jointly and account for shared effects. mr.mash is a recently developed multi-phenotype method that can learn which effects are shared and has been shown to improve prediction. However, mr.mash requires large data sets of genetic and phenotypic information collected at the individual level. Such data are often unavailable due to privacy concerns, or are difficult to work with due to the computational resources needed to analyze data of this size. Our work extends mr.mash to require only summary statistics from Genome-Wide Association Studies instead of individual-level data, which are usually publicly available. In addition, the computations using summary statistics do not depend on sample size, making the newly developed mr.mash-rss scalable to extremely large data sets. Using simulations and real data analysis, we show that our method is competitive with other methods for polygenic prediction.

genetics↗

bioRxiv2024

Oxidative Stress is a shared characteristic of ME/CFS and Long COVID

More than 65 million individuals worldwide are estimated to have Long COVID (LC), a complex multisystemic condition, wherein patients of all ages report fatigue, post-exertional malaise, and other symptoms resembling myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS). With no current treatments or reliable diagnostic markers, there is an urgent need to define the molecular underpinnings of these conditions. By studying bioenergetic characteristics of peripheral blood lymphocytes in over 16 healthy controls, 15 ME/CFS, and 15 LC, we find both ME/CFS and LC donors exhibit signs of elevated oxidative stress, relative to healthy controls, especially in the memory subset. Using a combination of flow cytometry, bulk RNA-seq analysis, mass spectrometry, and systems chemistry analysis, we also observed aberrations in ROS clearance pathways including elevated glutathione levels, decreases in mitochondrial superoxide dismutase levels, and glutathione peroxidase 4 mediated lipid oxidative damage. Critically, these changes in redox pathways show striking sex-specific trends. While females diagnosed with ME/CFS exhibit higher total ROS and mitochondrial calcium levels, males with an ME/CFS diagnosis have normal ROS levels, but larger changes in lipid oxidative damage. Further analyses show that higher ROS levels correlates with hyperproliferation of T cells in females, consistent with the known role of elevated ROS levels in the initiation of proliferation. This hyperproliferation of T cells can be attenuated by metformin, suggesting this FDA-approved drug as a possible treatment, as also suggested by a recent clinical study of LC patients. Thus, we report that both ME/CFS and LC are mechanistically related and could be diagnosed with quantitative blood cell measurements. We also suggest that effective, patient tailored drugs might be discovered using standard lymphocyte stimulation assays.

immunology↗

bioRxiv2022

Pleiotropic fitness effects of the lncRNA Uhg4 in Drosophila melanogaster

Long noncoding RNAs (lncRNAs) are a diverse class of RNAs that are critical for gene regulation, DNA repair, and splicing, and have been implicated in development, stress response, and cancer. However, the functions of many lncRNAs remain unknown. In Drosophila melanogaster, U snoRNA host gene 4 (Uhg4) encodes an antisense long noncoding RNA that is host to seven small nucleolar RNAs (snoRNAs). Uhg4 is expressed ubiquitously during development and in all adult tissues, with maximal expression in ovaries; however, it has no annotated function(s). Here, we used CRISPR-Cas9 germline gene editing to generate multiple deletions spanning the promoter region and first exon of Uhg4. Females showed arrested egg development and both males and females were sterile. In addition, Uhg4 deletion mutants showed delayed development and decreased viability, and changes in sleep and responses to stress. Whole-genome RNA sequencing of Uhg4 deletion flies and their controls identified co-regulated genes and genetic interaction networks associated with Uhg4. Gene ontology analyses highlighted a broad spectrum of biological processes, including regulation of transcription and translation, morphogenesis, and stress response. Thus, Uhg4 is a lncRNA essential for reproduction with pleiotropic effects on multiple fitness traits.

genomics↗

bioRxiv2021

Modulation of the Drosophila Transcriptome by Developmental Exposure to Alcohol

Prenatal exposure to ethanol can cause fetal alcohol spectrum disorder (FASD), a prevalent, preventable pediatric disorder. Identifying genetic risk alleles for FASD is challenging since time, dose, and frequency of exposure are often unknown, and manifestations of FASD are diverse and evident long after exposure. Drosophila melanogaster is an excellent model to study the genetic basis of the effects of developmental alcohol exposure since many individuals of the same genotype can be reared under controlled environmental conditions. We used 96 sequenced, wild-derived inbred lines from the Drosophila melanogaster Genetic Reference Panel (DGRP) to profile genome-wide transcript abundances in young adult flies that developed on ethanol-supplemented medium or standard culture medium. We found substantial genetic variation in gene expression in response to ethanol with extensive sexual dimorphism. We constructed sex-specific genetic networks associated with alcohol-dependent modulation of gene expression that include protein-coding genes, Novel Transcribed Regions (NTRs, postulated to encode long non-coding RNAs) and female-specific coordinated regulation of snoRNAs that regulate pseudouridylation of ribosomal RNA. We reared DGRP lines which showed extreme upregulation or downregulation of snoRNA expression during developmental alcohol exposure on standard or ethanol supplemented medium and demonstrated that developmental exposure to ethanol has genotype-specific effects on adult locomotor activity and sleep. There is significant and sex-specific natural genetic variation in the transcriptional response to developmental exposure to ethanol in Drosophila that comprises networks of genes affecting nervous system development and ethanol metabolism as well as networks of regulatory non-coding RNAs. Summary statementWe developed a Drosophila model for Fetal Alcohol Spectrum Disorder and found that developmental exposure to alcohol modulates expression of networks of genes affecting nervous system development and ethanol metabolism as well as networks of regulatory noncoding RNAs.

genetics↗

bioRxiv2021

Physiological and Metabolomic Consequences of Reduced Expression of the Drosophila brummer Triglyceride Lipase

Disruption of lipolysis has widespread effects on intermediary metabolism and organismal phenotypes. Defects in lipolysis can be modeled in Drosophila melanogaster through genetic manipulations of brummer (bmm), which encodes a triglyceride lipase orthologous to mammalian Adipose Triglyceride Lipase. RNAi-mediated knock-down of bmm in all tissues or metabolic specific tissues results in reduced locomotor activity, altered sleep patterns and reduced lifespan. Metabolomic analysis on flies in which bmm is downregulated reveals a marked reduction in medium chain fatty acids, long chain saturated fatty acids and long chain monounsaturated and polyunsaturated fatty acids, and an increase in diacylglycerol levels. Elevated carbohydrate metabolites and tricarboxylic acid intermediates indicate that impairment of fatty acid mobilization as an energy source may result in upregulation of compensatory carbohydrate catabolism. bmm downregulation also results in elevated levels of serotonin and dopamine neurotransmitters, possibly accounting for the impairment of locomotor activity and sleep patterns. Physiological phenotypes and metabolomic changes upon reduction of bmm expression show extensive sexual dimorphism. Altered metabolic states in the Drosophila model are relevant for understanding human metabolic disorders, since pathways of intermediary metabolism are conserved across phyla.

genetics↗

bioRxiv2021

Systems Genetics of Single Nucleotide Polymorphisms at the Drosophila Obp56h Locus

Variation in quantitative traits arises from naturally segregating alleles with environmentally sensitive effects, but how individual variants in single genes affect the genotype-phenotype map and molecular phenotypes is not understood. We used CRISPR/Cas9 germline gene editing to generate naturally occurring variants with different site classes and allele frequencies in the Drosophila melanogaster Obp56h gene in a common genetic background. Single base pair changes caused large allele-specific and sexually dimorphic effects on the mean and micro-environmental variance for multiple fitness-related traits and in the Obp56h co-regulated transcriptome. However, these alleles were not associated with quantitative traits in the Drosophila Genetic Reference Panel, suggesting that the small allelic effects observed in genome wide association studies may be an artifact of averaging variable context-dependent allelic effects over multiple genetic backgrounds. Thus, the traditional infinitesimal additive model does not reflect the underlying biology of quantitative traits.

genetics↗

bioRxiv2021

Developmental Alcohol Exposure in Drosophila: Effects on Adult Phenotypes and Gene Expression in the Brain

Fetal alcohol exposure can lead to developmental abnormalities, intellectual disability, and behavioral changes, collectively termed fetal alcohol spectrum disorder (FASD). In 2015, the Centers for Disease Control found that 1 in 10 pregnant women report alcohol use and more than 3 million women in the USA are at risk of exposing their developing baby to alcohol. Drosophila melanogaster is an excellent genetic model to study developmental effects of alcohol exposure because many individuals of the same genotype can be reared rapidly and economically under controlled environmental conditions. Flies exposed to alcohol undergo physiological and behavioral changes that resemble human alcohol-related phenotypes. Here, we show that adult flies that developed on ethanol-supplemented medium have decreased viability, reduced sensitivity to ethanol, and disrupted sleep and activity patterns. To assess the effects of exposure to alcohol during development on brain gene expression, we performed single cell RNA sequencing and resolved cell clusters with differentially expressed genes which represent distinct neuronal and glial populations. Differential gene expression showed extensive sexual dimorphism with little overlap between males and females. Gene expression differences following developmental alcohol exposure were similar to previously reported differential gene expression following cocaine consumption, suggesting that common neural substrates respond to both drugs. Genes associated with glutathione metabolism, lipid transport, glutamate and GABA metabolism, and vision feature in sexually dimorphic global multi-cluster interaction networks. Our results provide a blueprint for translational studies on alcohol-induced effects on gene expression in the brain that may contribute to or result from FASD in human populations.

genetics↗