@article{yamamoto_huang_anholt_mackay_2024, title={Article The genetic basis of variation in Drosophila melanogaster mating behavior}, volume={27}, ISSN={["2589-0042"]}, DOI={10.1016/j.isci.2024.109837}, abstractNote={Mating behavior is an essential fitness trait. We used the inbred, sequenced lines of the}, number={5}, journal={ISCIENCE}, author={Yamamoto, Akihiko and Huang, Wen and Anholt, Robert R. H. and Mackay, Trudy F. C.}, year={2024}, month={May} }
 @article{yamamoto_huang_carbone_anholt_mackay_2024, title={The genetic basis of incipient sexual isolation in <i>Drosophila melanogaster</i>}, volume={291}, ISSN={["1471-2954"]}, DOI={10.1098/rspb.2024.0672}, abstractNote={Speciation is a fundamental evolutionary process but the genetic changes accompanying speciation are difficult to determine since true species do not produce viable and fertile offspring. Partially reproductively isolated incipient species are useful for assessing genetic changes that occur prior to speciation.}, number={2027}, journal={PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES}, author={Yamamoto, Akihiko and Huang, Wen and Carbone, Mary Anna and Anholt, Robert R. H. and Mackay, Trudy F. C.}, year={2024}, month={Jul} }
 @article{ozsoy_yilmaz_patlar_emecen_durmaz_magwire_zhou_huang_anholt_mackay_2021, title={Epistasis for head morphology in Drosophila melanogaster}, volume={11}, ISSN={["2160-1836"]}, DOI={10.1093/g3journal/jkab285}, abstractNote={Abstract
               Epistasis—gene–gene interaction—is common for mutations with large phenotypic effects in humans and model organisms. Epistasis impacts quantitative genetic models of speciation, response to natural and artificial selection, genetic mapping, and personalized medicine. However, the existence and magnitude of epistasis between alleles with small quantitative phenotypic effects are controversial and difficult to assess. Here, we use the Drosophila melanogaster Genetic Reference Panel of sequenced inbred lines to evaluate the magnitude of naturally occurring epistasis modifying the effects of mutations in jing and inv, two transcription factors that have subtle quantitative effects on head morphology as homozygotes. We find significant epistasis for both mutations and performed single marker genome-wide association analyses to map candidate modifier variants and loci affecting head morphology. A subset of these loci was significantly enriched for a known genetic interaction network, and mutations of the candidate epistatic modifier loci also affect head morphology.}, number={10}, journal={G3-GENES GENOMES GENETICS}, author={Ozsoy, Ergi D. and Yilmaz, Murat and Patlar, Bahar and Emecen, Guzin and Durmaz, Esra and Magwire, Michael M. and Zhou, Shanshan and Huang, Wen and Anholt, Robert R. H. and Mackay, Trudy F. C.}, year={2021}, month={Oct} }
 @article{johnstun_shankar_mokashi_sunkara_ihearahu_lyman_mackay_anholt_2021, title={Functional Diversification, Redundancy, and Epistasis among Paralogs of the Drosophila melanogaster Obp50a-d Gene Cluster}, volume={38}, ISSN={["1537-1719"]}, DOI={10.1093/molbev/msab004}, abstractNote={Abstract
               Large multigene families, such as the insect odorant-binding proteins (OBPs), are thought to arise through functional diversification after repeated gene duplications. Whereas many OBPs function in chemoreception, members of this family are also expressed in tissues outside chemosensory organs. Paralogs of the Obp50 gene cluster are expressed in metabolic and male reproductive tissues, but their functions and interrelationships remain unknown. Here, we report the genetic dissection of four members of the Obp50 cluster, which are in close physical proximity without intervening genes. We used CRISPR technology to excise the entire cluster while introducing a PhiC31 reintegration site to reinsert constructs in which different combinations of the constituent Obp genes were either intact or rendered inactive. We performed whole transcriptome sequencing and assessed sexually dimorphic changes in transcript abundances (transcriptional niches) associated with each gene-edited genotype. Using this approach, we were able to estimate redundancy, additivity, diversification, and epistasis among Obp50 paralogs. We analyzed the effects of gene editing of this cluster on organismal phenotypes and found a significant skewing of sex ratios attributable to Obp50a, and sex-specific effects on starvation stress resistance attributable to Obp50d. Thus, there is functional diversification within the Obp50 cluster with Obp50a contributing to development and Obp50d to stress resistance. The deletion–reinsertion approach we applied to the Obp50 cluster provides a general paradigm for the genetic dissection of paralogs of multigene families.}, number={5}, journal={MOLECULAR BIOLOGY AND EVOLUTION}, author={Johnstun, Joel A. and Shankar, Vijay and Mokashi, Sneha S. and Sunkara, Lakshmi T. and Ihearahu, Ugonna E. and Lyman, Roberta L. and Mackay, Trudy F. C. and Anholt, Robert R. H.}, year={2021}, month={May}, pages={2030–2044} }
 @article{baker_carbone_huang_anholt_mackay_2021, title={Genetic basis of variation in cocaine and methamphetamine consumption in outbred populations of Drosophila melanogaster}, volume={118}, ISSN={["0027-8424"]}, DOI={10.1073/pnas.2104131118}, abstractNote={Significance
          
            The use of cocaine and methamphetamine presents significant socioeconomic problems. However, identifying the genetic underpinnings that determine susceptibility to substance use is challenging in human populations. The fruit fly,
            Drosophila melanogaster
            , presents a powerful genetic model since we can control the genetic background and environment, 75% of disease-causing genes in humans have a fly counterpart, and flies—like humans—exhibit adverse effects upon cocaine and methamphetamine exposure. We showed that the genetic architecture underlying variation in voluntary cocaine and methamphetamine consumption differs between sexes and is dominated by variants in genes associated with connectivity and function of the nervous system. Results obtained from the
            Drosophila
            gene discovery model can guide studies on substance abuse susceptibility in human populations.
          }, number={23}, journal={PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA}, author={Baker, Brandon M. and Carbone, Mary Anna and Huang, Wen and Anholt, Robert R. H. and Mackay, Trudy F. C.}, year={2021}, month={Jun} }
 @article{huang_campbell_carbone_jones_unselt_anholt_mackay_2020, title={Context-dependent genetic architecture of Drosophila life span}, volume={18}, ISSN={["1545-7885"]}, DOI={10.1371/journal.pbio.3000645}, abstractNote={Understanding the genetic basis of variation in life span is a major challenge that is difficult to address in human populations. Evolutionary theory predicts that alleles affecting natural variation in life span will have properties that enable them to persist in populations at intermediate frequencies, such as late-life–specific deleterious effects, antagonistic pleiotropic effects on early and late-age fitness components, and/or sex- and environment-specific or antagonistic effects. Here, we quantified variation in life span in males and females reared in 3 thermal environments for the sequenced, inbred lines of the Drosophila melanogaster Genetic Reference Panel (DGRP) and an advanced intercross outbred population derived from a subset of DGRP lines. Quantitative genetic analyses of life span and the micro-environmental variance of life span in the DGRP revealed significant genetic variance for both traits within each sex and environment, as well as significant genotype-by-sex interaction (GSI) and genotype-by-environment interaction (GEI). Genome-wide association (GWA) mapping in both populations implicates over 2,000 candidate genes with sex- and environment-specific or antagonistic pleiotropic allelic effects. Over 1,000 of these genes are associated with variation in life span in other D. melanogaster populations. We functionally assessed the effects of 15 candidate genes using RNA interference (RNAi): all affected life span and/or micro-environmental variance of life span in at least one sex and environment and exhibited sex-and environment-specific effects. Our results implicate novel candidate genes affecting life span and suggest that variation for life span may be maintained by variable allelic effects in heterogeneous environments.}, number={3}, journal={PLOS BIOLOGY}, author={Huang, Wen and Campbell, Terry and Carbone, Mary Anna and Jones, W. Elizabeth and Unselt, Desiree and Anholt, Robert R. H. and Mackay, Trudy F. C.}, year={2020}, month={Mar} }
 @article{everett_huang_zhou_carbone_lyman_arya_geisz_ma_morgante_st armour_et al._2020, title={Gene expression networks in the Drosophila Genetic Reference Panel}, volume={30}, ISSN={["1549-5469"]}, DOI={10.1101/gr.257592.119}, abstractNote={A major challenge in modern biology is to understand how naturally occurring variation in DNA sequences affects complex organismal traits through networks of intermediate molecular phenotypes. This question is best addressed in a genetic mapping population in which all molecular polymorphisms are known and for which molecular endophenotypes and complex traits are assessed on the same genotypes. Here, we performed deep RNA sequencing of 200 Drosophila Genetic Reference Panel inbred lines with complete genome sequences and for which phenotypes of many quantitative traits have been evaluated. We mapped expression quantitative trait loci for annotated genes, novel transcribed regions, transposable elements, and microbial species. We identified host variants that affect expression of transposable elements, independent of their copy number, as well as microbiome composition. We constructed sex-specific expression quantitative trait locus regulatory networks. These networks are enriched for novel transcribed regions and target genes in heterochromatin and euchromatic regions of reduced recombination, as well as genes regulating transposable element expression. This study provides new insights regarding the role of natural genetic variation in regulating gene expression and generates testable hypotheses for future functional analyses.}, number={3}, journal={GENOME RESEARCH}, author={Everett, Logan J. and Huang, Wen and Zhou, Shanshan and Carbone, Mary Anna and Lyman, Richard F. and Arya, Gunjan H. and Geisz, Matthew S. and Ma, Junwu and Morgante, Fabio and St Armour, Genevieve and et al.}, year={2020}, month={Mar}, pages={485–496} }
 @article{huang_carbone_lyman_anholt_mackay_2020, title={Genotype by environment interaction for gene expression in Drosophila melanogaster}, volume={11}, ISSN={["2041-1723"]}, DOI={10.1038/s41467-020-19131-y}, abstractNote={AbstractThe genetics of phenotypic responses to changing environments remains elusive. Using whole-genome quantitative gene expression as a model, here we study how the genetic architecture of regulatory variation in gene expression changed in a population of fully sequenced inbred Drosophila melanogaster strains when flies developed in different environments (25 °C and 18 °C). We find a substantial fraction of the transcriptome exhibited genotype by environment interaction, implicating environmentally plastic genetic architecture of gene expression. Genetic variance in expression increases at 18 °C relative to 25 °C for most genes that have a change in genetic variance. Although the majority of expression quantitative trait loci (eQTLs) for the gene expression traits in the two environments are shared and have similar effects, analysis of the environment-specific eQTLs reveals enrichment of binding sites for two transcription factors. Finally, although genotype by environment interaction in gene expression could potentially disrupt genetic networks, the co-expression networks are highly conserved across environments. Genes with higher network connectivity are under stronger stabilizing selection, suggesting that stabilizing selection on expression plays an important role in promoting network robustness.}, number={1}, journal={NATURE COMMUNICATIONS}, author={Huang, Wen and Carbone, Mary Anna and Lyman, Richard F. and Anholt, Robert R. H. and Mackay, Trudy F. C.}, year={2020}, month={Oct} }
 @article{highfill_baker_stevens_anholt_mackay_2019, title={Genetics of cocaine and methamphetamine consumption and preference in Drosophila melanogaster}, volume={15}, ISSN={["1553-7404"]}, DOI={10.1371/journal.pgen.1007834}, abstractNote={Illicit use of psychostimulants, such as cocaine and methamphetamine, constitutes a significant public health problem. Whereas neural mechanisms that mediate the effects of these drugs are well-characterized, genetic factors that account for individual variation in susceptibility to substance abuse and addiction remain largely unknown. Drosophila melanogaster can serve as a translational model for studies on substance abuse, since flies have a dopamine transporter that can bind cocaine and methamphetamine, and exposure to these compounds elicits effects similar to those observed in people, suggesting conserved evolutionary mechanisms underlying drug responses. Here, we used the D. melanogaster Genetic Reference Panel to investigate the genetic basis for variation in psychostimulant drug consumption, to determine whether similar or distinct genetic networks underlie variation in consumption of cocaine and methamphetamine, and to assess the extent of sexual dimorphism and effect of genetic context on variation in voluntary drug consumption. Quantification of natural genetic variation in voluntary consumption, preference, and change in consumption and preference over time for cocaine and methamphetamine uncovered significant genetic variation for all traits, including sex-, exposure- and drug-specific genetic variation. Genome wide association analyses identified both shared and drug-specific candidate genes, which could be integrated in genetic interaction networks. We assessed the effects of ubiquitous RNA interference (RNAi) on consumption behaviors for 34 candidate genes: all affected at least one behavior. Finally, we utilized RNAi knockdown in the nervous system to implicate dopaminergic neurons and the mushroom bodies as part of the neural circuitry underlying experience-dependent development of drug preference.}, number={5}, journal={PLOS GENETICS}, author={Highfill, Chad A. and Baker, Brandon M. and Stevens, Stephenie D. and Anholt, Robert R. H. and Mackay, Trudy F. C.}, year={2019}, month={May} }
 @article{zhou_morgante_geisz_ma_anholt_mackay_2020, title={Systems genetics of the Drosophila metabolome}, volume={30}, ISSN={["1549-5469"]}, DOI={10.1101/gr.243030.118}, abstractNote={How effects of DNA sequence variants are transmitted through intermediate endophenotypes to modulate organismal traits remains a central question in quantitative genetics. This problem can be addressed through a systems approach in a population in which genetic polymorphisms, gene expression traits, metabolites, and complex phenotypes can be evaluated on the same genotypes. Here, we focused on the metabolome, which represents the most proximal link between genetic variation and organismal phenotype, and quantified metabolite levels in 40 lines of the Drosophila melanogaster Genetic Reference Panel. We identified sex-specific modules of genetically correlated metabolites and constructed networks that integrate DNA sequence variation and variation in gene expression with variation in metabolites and organismal traits, including starvation stress resistance and male aggression. Finally, we asked to what extent SNPs and metabolites can predict trait phenotypes and generated trait- and sex-specific prediction models that provide novel insights about the metabolomic underpinnings of complex phenotypes.}, number={3}, journal={GENOME RESEARCH}, author={Zhou, Shanshan and Morgante, Fabio and Geisz, Matthew S. and Ma, Junwu and Anholt, Robert R. H. and Mackay, Trudy F. C.}, year={2020}, month={Mar}, pages={392–405} }
 @article{garcia_carbone_mackay_anholt_2017, title={Regulation of Drosophila Lifespan by bellwether Promoter Alleles}, volume={7}, ISSN={2045-2322}, url={http://dx.doi.org/10.1038/S41598-017-04530-X}, DOI={10.1038/S41598-017-04530-X}, abstractNote={AbstractLongevity varies among individuals, but how natural genetic variation contributes to variation in lifespan is poorly understood. Drosophila melanogaster presents an advantageous model system to explore the genetic underpinnings of longevity, since its generation time is brief and both the genetic background and rearing environment can be precisely controlled. The bellwether (blw) gene encodes the α subunit of mitochondrial ATP synthase. Since metabolic rate may influence lifespan, we investigated whether alternative haplotypes in the blw promoter affect lifespan when expressed in a co-isogenic background. We amplified 521 bp upstream promoter sequences containing alternative haplotypes and assessed promoter activity both in vitro and in vivo using a luciferase reporter system. The AG haplotype showed significantly greater expression of luciferase than the GT haplotype. We then overexpressed a blw cDNA construct driven by either the AG or GT haplotype promoter in transgenic flies and showed that the AG haplotype also results in greater blw cDNA expression and a significant decrease in lifespan relative to the GT promoter haplotype, in male flies only. Thus, our results show that naturally occurring regulatory variants of blw affect lifespan in a sex-specific manner.}, number={1}, journal={Scientific Reports}, publisher={Springer Nature}, author={Garcia, Júlia Frankenberg and Carbone, Mary Anna and Mackay, Trudy F. C. and Anholt, Robert R. H.}, year={2017}, month={Jun} }
 @article{anholt_mackay_2018, title={The road less traveled: from genotype to phenotype in flies and humans}, volume={29}, ISSN={0938-8990 1432-1777}, url={http://dx.doi.org/10.1007/S00335-017-9722-7}, DOI={10.1007/S00335-017-9722-7}, abstractNote={Understanding how genomic variation gives rise to phenotypic variation is essential for elucidating mechanisms of adaptive evolution, plant and animal breeding, and precision medicine. However, identifying causal links between DNA sequence variants and variation in phenotypes is challenging in human populations, due to large blocks of linkage disequilibrium in the genome and heterogeneous developmental histories, lifestyles, and social and physical environments. Drosophila melanogaster presents a powerful genetic model, since linkage disequilibrium decays rapidly, facilitating assignment of causality to polymorphisms associated with phenotypic variation, and large numbers of individuals can be reared under defined environmental conditions, economically, and without regulatory restrictions. The D. melanogaster Genetic Reference Panel (DGRP), a population of 205 sequenced, inbred wild-derived flies, has enabled genome-wide association studies of morphological, physiological, behavioral, and life history traits, and demonstrated that genetic architectures of complex traits are highly polygenic, sexually dimorphic, and context dependent with extensive sex-, environment-, and genetic background (epistatic) effects. These features together with a modular organization of the transcriptome illustrate a dynamic integrative genetic architecture for complex traits. The complexity of the genetic architectures for complex traits in Drosophila provides important caveats for the interpretation of genetic studies in human populations. Aspects of the genetic underpinnings of complex traits can be represented as simplified gene networks on which human orthologues can be superimposed to provide blueprints for subsequent studies on analogous traits in human populations. Fundamental principles of the genetic architectures of Drosophila complex traits are likely applicable across phyla, from the DGRP to human populations.}, number={1-2}, journal={Mammalian Genome}, publisher={Springer Science and Business Media LLC}, author={Anholt, Robert R. H. and Mackay, Trudy F. C.}, year={2018}, month={Feb}, pages={5–23} }
 @article{carbone_yamamoto_huang_lyman_meadors_yamamoto_anholt_mackay_2016, title={Genetic architecture of natural variation in visual senescence in Drosophila}, volume={113}, ISSN={0027-8424 1091-6490}, url={http://dx.doi.org/10.1073/PNAS.1613833113}, DOI={10.1073/PNAS.1613833113}, abstractNote={Significance
          
            Functional decline with age—senescence—is a major determinant of health span in an aging population, but its genetic basis remains largely unknown. In humans, visual decline often heralds the onset of senescence. We used the fruit fly,
            Drosophila melanogaster
            , to explore the genetic basis of natural variation in phototaxis, the innate tendency to move toward light, and age-dependent decline in phototaxis as a proxy for visual senescence. We found the genetic basis for visual senescence is distinct from that which determines variation in life span. Furthermore, genes shaping early development of the nervous system, in particular the visual system, also contribute to senescence at later age, demonstrating that senescence is part of a genetic continuum throughout the life span.
          }, number={43}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Carbone, Mary Anna and Yamamoto, Akihiko and Huang, Wen and Lyman, Rachel A. and Meadors, Tess Brune and Yamamoto, Ryoan and Anholt, Robert R. H. and Mackay, Trudy F. C.}, year={2016}, month={Oct}, pages={E6620–E6629} }
 @article{rand_montgomery_vorojeikina_huang_mackay_anholt_2015, title={Drosophotoxicolgy takes flight: Genomic elucidation of adverse outcome pathways of mercury toxicity in the fruit fly}, volume={238}, ISSN={0378-4274}, url={http://dx.doi.org/10.1016/J.TOXLET.2015.08.153}, DOI={10.1016/J.TOXLET.2015.08.153}, number={2}, journal={Toxicology Letters}, publisher={Elsevier BV}, author={Rand, M. and Montgomery, S. and Vorojeikina, D. and Huang, W. and MacKay, T.F. and Anholt, R.R.}, year={2015}, month={Oct}, pages={S55} }
 @article{shorter_couch_huang_carbone_peiffer_anholt_mackay_2015, title={Genetic architecture of natural variation in Drosophila melanogaster aggressive behavior}, volume={112}, ISSN={0027-8424 1091-6490}, url={http://dx.doi.org/10.1073/PNAS.1510104112}, DOI={10.1073/PNAS.1510104112}, abstractNote={Significance
          
            Aggressive behavior is evolutionarily conserved and genetically complex, but the genetic basis of natural variation in aggression is largely unknown. We performed genome-wide association analyses using the inbred, sequenced lines of the
            Drosophila
            Genetic Reference Panel (DGRP) and an advanced intercross population derived from the most and least aggressive DGRP lines. These analyses identified largely nonoverlapping genes that mapped onto a genetic interaction network inferred from an analysis of pairwise epistasis in the DGRP. We functionally validated candidate genes and genetic interactions. Epistasis for aggressive behavior causes cryptic genetic variation in the DGRP that is revealed by changing allele frequencies. This observation may apply to other fitness traits and species, with implications for evolution, applied breeding, and human genetics.
          }, number={27}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Shorter, John and Couch, Charlene and Huang, Wen and Carbone, Mary Anna and Peiffer, Jason and Anholt, Robert R. H. and Mackay, Trudy F. C.}, year={2015}, month={Jun}, pages={E3555–E3563} }
 @article{huang_carbone_magwire_peiffer_lyman_stone_anholt_mackay_2015, title={Genetic basis of transcriptome diversity in Drosophila melanogaster}, volume={112}, ISSN={0027-8424 1091-6490}, url={http://dx.doi.org/10.1073/PNAS.1519159112}, DOI={10.1073/PNAS.1519159112}, abstractNote={Significance
          
            RNA provides a link between variation at the DNA and phenotypic levels. We measured the abundances of RNA products of protein-coding genes and novel transcribed regions in a population of wild-derived inbred strains of
            Drosophila melanogaster
            whose genome sequences are also available. We exploited this unique resource to characterize the genetic basis of transcriptome diversity. We found high complexity of the genetic control of gene expression, including widespread sexual dimorphism, highly modularized expression patterns with involvement of novel RNA transcripts, and frequent epistatic interactions among expression quantitative trait loci (QTLs) which often give rise to variance expression QTLs. This study highlights the importance and general applicability of integrating expression phenotypes to understand the genetic architecture of complex quantitative phenotypes.
          }, number={44}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Huang, Wen and Carbone, Mary Anna and Magwire, Michael M. and Peiffer, Jason A. and Lyman, Richard F. and Stone, Eric A. and Anholt, Robert R. H. and Mackay, Trudy F. C.}, year={2015}, month={Oct}, pages={E6010–E6019} }
 @article{rand_montgomery_vorojeikina_huang_mackay_anholt_2015, title={Identification of conserved developmental pathways targeted by methylmercury in Drosophila melanogaster}, volume={49}, ISSN={0892-0362}, url={http://dx.doi.org/10.1016/J.NTT.2015.04.131}, DOI={10.1016/J.NTT.2015.04.131}, journal={Neurotoxicology and Teratology}, publisher={Elsevier BV}, author={Rand, Matthew D. and Montgomery, Sara and Vorojeikina, Daria and Huang, Wen and MacKay, Trudy F.C. and Anholt, Robert R.H.}, year={2015}, month={May}, pages={141} }
 @article{anholt_mackay_2015, title={Dissecting the genetic architecture of behavior in Drosophila melanogaster}, volume={2}, ISSN={2352-1546}, url={http://dx.doi.org/10.1016/J.COBEHA.2014.06.001}, DOI={10.1016/J.COBEHA.2014.06.001}, abstractNote={Variation in behaviors in natural populations arises from complex networks of multiple segregating polymorphic alleles whose expression can be modulated by the environment. Since behaviors reflect dynamic interactions between organisms and their environments, they are central targets for adaptive evolution. Drosophila melanogaster presents a powerful system for dissecting the genetic basis of behavioral phenotypes, since both the genetic background and environmental conditions can be controlled and behaviors accurately quantified. Single gene mutational analyses can identify the roles of individual genes within cellular pathways, whereas systems genetic approaches that exploit natural variation can construct genetic networks that underlie phenotypic variation. Combining these approaches with emerging technologies, such as genome editing, is likely to yield a comprehensive understanding of the neurogenetic underpinnings that orchestrate the manifestation of behaviors.}, journal={Current Opinion in Behavioral Sciences}, publisher={Elsevier BV}, author={Anholt, Robert RH and Mackay, Trudy FC}, year={2015}, month={Apr}, pages={1–7} }
 @article{morozova_mackay_anholt_2014, title={Genetics and genomics of alcohol sensitivity}, volume={289}, ISSN={1617-4615 1617-4623}, url={http://dx.doi.org/10.1007/S00438-013-0808-Y}, DOI={10.1007/S00438-013-0808-Y}, abstractNote={Alcohol abuse and alcoholism incur a heavy socioeconomic cost in many countries. Both genetic and environmental factors contribute to variation in the inebriating effects of alcohol and alcohol addiction among individuals within and across populations. From a genetics perspective, alcohol sensitivity is a quantitative trait determined by the cumulative effects of multiple segregating genes and their interactions with the environment. This review summarizes insights from model organisms as well as human populations that represent our current understanding of the genetic and genomic underpinnings that govern alcohol metabolism and the sedative and addictive effects of alcohol on the nervous system.}, number={3}, journal={Molecular Genetics and Genomics}, publisher={Springer Science and Business Media LLC}, author={Morozova, Tatiana V. and Mackay, Trudy F. C. and Anholt, Robert R. H.}, year={2014}, month={Jan}, pages={253–269} }
 @article{huang_massouras_inoue_peiffer_ramia_tarone_turlapati_zichner_zhu_lyman_et al._2014, title={Natural variation in genome architecture among 205 Drosophila melanogaster Genetic Reference Panel lines}, volume={24}, number={7}, journal={Genome Research}, author={Huang, W. and Massouras, A. and Inoue, Y. and Peiffer, J. and Ramia, M. and Tarone, A. M. and Turlapati, L. and Zichner, T. and Zhu, D. H. and Lyman, R. F. and et al.}, year={2014}, pages={1193–1208} }
 @article{zhou_mackay_anholt_2014, title={Transcriptional and epigenetic responses to mating and aging in Drosophila melanogaster}, volume={15}, ISSN={["1471-2164"]}, DOI={10.1186/1471-2164-15-927}, abstractNote={Phenotypic plasticity allows organisms to respond rapidly to changing environmental circumstances, and understanding its genomic basis can yield insights regarding the underlying genes and genetic networks affecting complex phenotypes. Female Drosophila melanogaster undergo dramatic physiological changes mediated by seminal fluid components transferred upon mating, including decreased longevity. Their physiological and behavioral effects have been well characterized, but little is known about resulting changes in regulation of gene expression or the extent to which mating-induced changes in gene expression are the same as those occurring during aging.We assessed genome-wide mRNA, microRNA, and three common histone modifications implicated in gene activation for young and aged virgin and mated female D. melanogaster in a factorial design. We identified phenotypically plastic transcripts and epigenetic modifications associated with mating and aging. We used these data to derive phenotypically plastic regulatory networks associated with mating of young flies, and aging of virgin and mated flies. Many of the mRNAs, microRNAs and epigenetic modifications associated with mating of young flies also occur with age in virgin flies, which may reflect mating-induced accelerated aging. We functionally tested the plastic regulatory networks by overexpressing environmentally sensitive microRNAs. Overexpression resulted in altered expression of ~70% of candidate target genes, and in all cases affected oviposition.Our results implicate microRNAs as mediators of phenotypic plasticity associated with mating and provide a comprehensive documentation of the genomic and epigenomic changes that accompany mating- and aging-induced physiological changes in female D. melanogaster.}, journal={BMC GENOMICS}, author={Zhou, Shanshan and Mackay, Trudy F. C. and Anholt, Robert R. H.}, year={2014}, month={Oct} }
 @misc{anholt_carbone_2013, title={A molecular mechanism for glaucoma: endoplasmic reticulum stress and the unfolded protein response}, volume={19}, ISSN={["1471-499X"]}, DOI={10.1016/j.molmed.2013.06.005}, abstractNote={Primary open angle glaucoma (POAG) is a common late-onset neurodegenerative disease. Ocular hypertension represents a major risk factor, but POAG etiology remains poorly understood. Some cases of early-onset congenital glaucoma and adult POAG are linked to mutations in myocilin, a secreted protein of poorly defined function. Transgenic overexpression of myocilin in Drosophila and experiments in mice and human populations implicate the unfolded protein response (UPR) in the pathogenesis of glaucoma. We postulate that compromised ability of the UPR to eliminate misfolded mutant or damaged proteins, including myocilin, causes endoplasmic reticulum stress, resulting in functional impairment of trabecular meshwork cells that regulate intraocular pressure. This mechanism of POAG is reminiscent of other age-dependent neurodegenerative diseases that involve accumulation of protein aggregates.}, number={10}, journal={TRENDS IN MOLECULAR MEDICINE}, author={Anholt, Robert R. H. and Carbone, Mary Anna}, year={2013}, month={Oct}, pages={586–593} }
 @article{swarup_huang_mackay_anholt_2012, title={Analysis of natural variation reveals neurogenetic networks for Drosophila olfactory behavior}, volume={110}, ISSN={0027-8424 1091-6490}, url={http://dx.doi.org/10.1073/pnas.1220168110}, DOI={10.1073/pnas.1220168110}, abstractNote={
            Understanding the relationship between genetic variation and phenotypic variation for quantitative traits is necessary for predicting responses to natural and artificial selection and disease risk in human populations, but is challenging because of large sample sizes required to detect and validate loci with small effects. Here, we used the inbred, sequenced, wild-derived lines of the
            Drosophila melanogaster
            Genetic Reference Panel (DGRP) to perform three complementary genome-wide association (GWA) studies for natural variation in olfactory behavior. The first GWA focused on single nucleotide polymorphisms (SNPs) associated with mean differences in olfactory behavior in the DGRP, the second was an extreme quantitative trait locus GWA on an outbred advanced intercross population derived from extreme DGRP lines, and the third was for SNPs affecting the variance among DGRP lines. No individual SNP in any analysis was associated with variation in olfactory behavior by using a strict threshold accounting for multiple tests, and no SNP overlapped among the analyses. However, combining the top SNPs from all three analyses revealed a statistically enriched network of genes involved in cellular signaling and neural development. We used mutational and gene expression analyses to validate both candidate genes and network connectivity at a high rate. The lack of replication between the GWA analyses, small marginal SNP effects, and convergence on common cellular networks were likely attributable to epistasis. These results suggest that fully understanding the genotype–phenotype relationship requires a paradigm shift from a focus on single SNPs to pathway associations.
          }, number={3}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Swarup, S. and Huang, W. and Mackay, T. F. C. and Anholt, R. R. H.}, year={2012}, month={Dec}, pages={1017–1022} }
 @article{huang_richards_carbone_zhu_anholt_ayroles_duncan_jordan_lawrence_magwire_et al._2012, title={Epistasis dominates the genetic architecture of Drosophila quantitative traits}, volume={109}, ISSN={0027-8424 1091-6490}, url={http://dx.doi.org/10.1073/pnas.1213423109}, DOI={10.1073/pnas.1213423109}, abstractNote={
            Epistasis—nonlinear genetic interactions between polymorphic loci—is the genetic basis of canalization and speciation, and epistatic interactions can be used to infer genetic networks affecting quantitative traits. However, the role that epistasis plays in the genetic architecture of quantitative traits is controversial. Here, we compared the genetic architecture of three
            Drosophila
            life history traits in the sequenced inbred lines of the
            Drosophila melanogaster
            Genetic Reference Panel (DGRP) and a large outbred, advanced intercross population derived from 40 DGRP lines (Flyland). We assessed allele frequency changes between pools of individuals at the extremes of the distribution for each trait in the Flyland population by deep DNA sequencing. The genetic architecture of all traits was highly polygenic in both analyses. Surprisingly, none of the SNPs associated with the traits in Flyland replicated in the DGRP and vice versa. However, the majority of these SNPs participated in at least one epistatic interaction in the DGRP. Despite apparent additive effects at largely distinct loci in the two populations, the epistatic interactions perturbed common, biologically plausible, and highly connected genetic networks. Our analysis underscores the importance of epistasis as a principal factor that determines variation for quantitative traits and provides a means to uncover genetic networks affecting these traits. Knowledge of epistatic networks will contribute to our understanding of the genetic basis of evolutionarily and clinically important traits and enhance predictive ability at an individualized level in medicine and agriculture.
          }, number={39}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Huang, W. and Richards, S. and Carbone, M. A. and Zhu, D. and Anholt, R. R. H. and Ayroles, J. F. and Duncan, L. and Jordan, K. W. and Lawrence, F. and Magwire, M. M. and et al.}, year={2012}, month={Sep}, pages={15553–15559} }
 @article{swarup_harbison_hahn_morozova_yamamoto_mackay_anholt_2012, title={Extensive epistasis for olfactory behaviour, sleep and waking activity in Drosophila melanogaster}, volume={94}, ISSN={0016-6723 1469-5073}, url={http://dx.doi.org/10.1017/S001667231200002X}, DOI={10.1017/S001667231200002X}, abstractNote={SummaryEpistasis is an important feature of the genetic architecture of quantitative traits, but the dynamics of epistatic interactions in natural populations and the relationship between epistasis and pleiotropy remain poorly understood. Here, we studied the effects of epistatic modifiers that segregate in a wild-derivedDrosophila melanogasterpopulation on the mutational effects ofP-element insertions inSemaphorin-5C(Sema-5c) andCalreticulin(Crc), pleiotropic genes that affect olfactory behaviour and startle behaviour and, in the case ofCrc, sleep phenotypes. We introducedCanton-S B(CSB) third chromosomes with or without aP-element insertion at theCrcorSema-5clocus in multiple wild-derived inbred lines of theDrosophila melanogasterGenetic Reference Panel (DGRP) and assessed the effects of epistasis on the olfactory response to benzaldehyde and, forCrc, also on sleep. In each case, we found substantial epistasis and significant variation in the magnitude of epistasis. The predominant direction of epistatic effects was to suppress the mutant phenotype. These observations support a previous study on startle behaviour using the sameD. melanogasterchromosome substitution lines, which concluded that suppressing epistasis may buffer the effects of new mutations. However, epistatic effects are not correlated among the different phenotypes. Thus, suppressing epistasis appears to be a pervasive general feature of natural populations to protect against the effects of new mutations, but different epistatic interactions modulate different phenotypes affected by mutations at the same pleiotropic gene.}, number={1}, journal={Genetics Research}, publisher={Cambridge University Press (CUP)}, author={Swarup, Shilpa and Harbison, Susan T. and Hahn, Lauren E. and Morozova, Tatiana V. and Yamamoto, Akihiko and Mackay, Trudy F. C. and Anholt, Robert R. H.}, year={2012}, month={Feb}, pages={9–20} }
 @article{zhou_campbell_stone_mackay_anholt_2012, title={Phenotypic Plasticity of the Drosophila Transcriptome}, volume={8}, ISSN={["1553-7404"]}, DOI={10.1371/journal.pgen.1002593}, abstractNote={Phenotypic plasticity is the ability of a single genotype to produce different phenotypes in response to changing environments. We assessed variation in genome-wide gene expression and four fitness-related phenotypes of an outbred Drosophila melanogaster population under 20 different physiological, social, nutritional, chemical, and physical environments; and we compared the phenotypically plastic transcripts to genetically variable transcripts in a single environment. The environmentally sensitive transcriptome consists of two transcript categories, which comprise ∼15% of expressed transcripts. Class I transcripts are genetically variable and associated with detoxification, metabolism, proteolysis, heat shock proteins, and transcriptional regulation. Class II transcripts have low genetic variance and show sexually dimorphic expression enriched for reproductive functions. Clustering analysis of Class I transcripts reveals a fragmented modular organization and distinct environmentally responsive transcriptional signatures for the four fitness-related traits. Our analysis suggests that a restricted environmentally responsive segment of the transcriptome preserves the balance between phenotypic plasticity and environmental canalization.}, number={3}, journal={PLOS GENETICS}, author={Zhou, Shanshan and Campbell, Terry G. and Stone, Eric A. and Mackay, Trudy F. C. and Anholt, Robert R. H.}, year={2012}, month={Mar} }
 @article{mackay_richards_stone_barbadilla_ayroles_zhu_casillas_han_magwire_cridland_et al._2012, title={The Drosophila melanogaster Genetic Reference Panel}, volume={482}, ISSN={0028-0836 1476-4687}, url={http://dx.doi.org/10.1038/nature10811}, DOI={10.1038/nature10811}, abstractNote={A major challenge of biology is understanding the relationship between molecular genetic variation and variation in quantitative traits, including fitness. This relationship determines our ability to predict phenotypes from genotypes and to understand how evolutionary forces shape variation within and between species. Previous efforts to dissect the genotype–phenotype map were based on incomplete genotypic information. Here, we describe the Drosophila melanogaster Genetic Reference Panel (DGRP), a community resource for analysis of population genomics and quantitative traits. The DGRP consists of fully sequenced inbred lines derived from a natural population. Population genomic analyses reveal reduced polymorphism in centromeric autosomal regions and the X chromosome, evidence for positive and negative selection, and rapid evolution of the X chromosome. Many variants in novel genes, most at low frequency, are associated with quantitative traits and explain a large fraction of the phenotypic variance. The DGRP facilitates genotype–phenotype mapping using the power of Drosophila genetics. A new resource for the analysis of population genomics and quantitative traits, the Drosophila melanogaster Genetic Reference Panel is presented. The Drosophila melanogaster Genetic Reference Panel (DGRP) is a community resource charting the molecular and phenotypic variation in 168 fully sequenced fruitfly strains derived from a single outbred natural population. The first set of analyses of DGRP data provides insights into the genomic landscape of genetic variation, positive and negative selection, and rapid evolution of the X chromosome. The results also reveal many low frequency variants in novel loci that are associated with quantitative traits, and explain a large fraction of the phenotypic variance.}, number={7384}, journal={Nature}, publisher={Springer Science and Business Media LLC}, author={Mackay, Trudy F. C. and Richards, Stephen and Stone, Eric A. and Barbadilla, Antonio and Ayroles, Julien F. and Zhu, Dianhui and Casillas, Sònia and Han, Yi and Magwire, Michael M. and Cridland, Julie M. and et al.}, year={2012}, month={Feb}, pages={173–178} }
 @article{morozova_sridhar_magwire_mackay_anholt_2012, title={The genetic basis for natural variation in alcohol sensitivity in drosophila}, volume={34}, ISSN={0892-0362}, url={http://dx.doi.org/10.1016/j.ntt.2012.05.030}, DOI={10.1016/j.ntt.2012.05.030}, number={3}, journal={Neurotoxicology and Teratology}, publisher={Elsevier BV}, author={Morozova, Tatiana and Sridhar, Sruthipriya and Magwire, Michael and Mackay, Trudy F.C. and Anholt, Robert R.H.}, year={2012}, month={May}, pages={377} }
 @article{zwarts_magwire_carbone_versteven_herteleer_anholt_callaerts_mackay_2011, title={Complex genetic architecture of Drosophila aggressive behavior}, volume={108}, ISSN={0027-8424 1091-6490}, url={http://dx.doi.org/10.1073/pnas.1113877108}, DOI={10.1073/pnas.1113877108}, abstractNote={
            Epistasis and pleiotropy feature prominently in the genetic architecture of quantitative traits but are difficult to assess in outbred populations. We performed a diallel cross among coisogenic
            Drosophila P
            -element mutations associated with hyperaggressive behavior and showed extensive epistatic and pleiotropic effects on aggression, brain morphology, and genome-wide transcript abundance in head tissues. Epistatic interactions were often of greater magnitude than homozygous effects, and the topology of epistatic networks varied among these phenotypes. The transcriptional signatures of homozygous and double heterozygous genotypes derived from the six mutations imply a large mutational target for aggressive behavior and point to evolutionarily conserved genetic mechanisms and neural signaling pathways affecting this universal fitness trait.
          }, number={41}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Zwarts, L. and Magwire, M. M. and Carbone, M. A. and Versteven, M. and Herteleer, L. and Anholt, R. R. H. and Callaerts, P. and Mackay, T. F. C.}, year={2011}, month={Sep}, pages={17070–17075} }
 @article{swarup_williams_anholt_2011, title={Functional dissection of Odorant binding protein genes in Drosophila melanogaster}, volume={10}, ISSN={["1601-183X"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-79961026622&partnerID=MN8TOARS}, DOI={10.1111/j.1601-183x.2011.00704.x}, abstractNote={Most organisms rely on olfaction for survival and reproduction. The olfactory system of Drosophila melanogaster is one of the best characterized chemosensory systems and serves as a prototype for understanding insect olfaction. Olfaction in Drosophila is mediated by multigene families of odorant receptors and odorant binding proteins (OBPs). Although molecular response profiles of odorant receptors have been well documented, the contributions of OBPs to olfactory behavior remain largely unknown. Here, we used RNAi‐mediated suppression of Obp gene expression and measurements of behavioral responses to 16 ecologically relevant odorants to systematically dissect the functions of 17 OBPs. We quantified the effectiveness of RNAi‐mediated suppression by quantitative real‐time polymerase chain reaction and used a proteomic liquid chromatography and tandem mass spectrometry procedure to show target‐specific suppression of OBPs expressed in the antennae. Flies in which expression of a specific OBP is suppressed often show altered behavioral responses to more than one, but not all, odorants, in a sex‐dependent manner. Similarly, responses to a specific odorant are frequently affected by suppression of expression of multiple, but not all, OBPs. These results show that OBPs are essential for mediating olfactory behavioral responses and suggest that OBP‐dependent odorant recognition is combinatorial.}, number={6}, journal={GENES BRAIN AND BEHAVIOR}, author={Swarup, S. and Williams, T. I. and Anholt, R. R. H.}, year={2011}, month={Aug}, pages={648–657} }
 @article{carbone_chen_hughes_weinreb_zabriskie_zhang_anholt_2011, title={Genes of the Unfolded Protein Response Pathway Harbor Risk Alleles for Primary Open Angle Glaucoma}, volume={6}, ISSN={["1932-6203"]}, DOI={10.1371/journal.pone.0020649}, abstractNote={The statistical power of genome-wide association (GWA) studies to detect risk alleles for human diseases is limited by the unfavorable ratio of SNPs to study subjects. This multiple testing problem can be surmounted with very large population sizes when common alleles of large effects give rise to disease status. However, GWA approaches fall short when many rare alleles may give rise to a common disease, or when the number of subjects that can be recruited is limited. Here, we demonstrate that this multiple testing problem can be overcome by a comparative genomics approach in which an initial genome-wide screen in a genetically amenable model organism is used to identify human orthologues that may harbor risk alleles for adult-onset primary open angle glaucoma (POAG). Glaucoma is a major cause of blindness, which affects over 60 million people worldwide. Several genes have been associated with juvenile onset glaucoma, but genetic factors that predispose to adult onset primary open angle glaucoma (POAG) remain largely unknown. Previous genome-wide analysis in a Drosophila ocular hypertension model identified transcripts with altered regulation and showed induction of the unfolded protein response (UPR) upon overexpression of transgenic human glaucoma-associated myocilin (MYOC). We selected 16 orthologous genes with 62 polymorphic markers and identified in two independent human populations two genes of the UPR that harbor POAG risk alleles, BIRC6 and PDIA5. Thus, effectiveness of the UPR in response to accumulation of misfolded or aggregated proteins may contribute to the pathogenesis of POAG and provide targets for early therapeutic intervention.}, number={5}, journal={PLOS ONE}, author={Carbone, Mary Anna and Chen, Yuhong and Hughes, Guy A. and Weinreb, Robert N. and Zabriskie, Norman A. and Zhang, Kang and Anholt, Robert R. H.}, year={2011}, month={May} }
 @article{anholt_2010, title={Making scents of behavioural genetics: lessons from Drosophila}, volume={92}, ISSN={["1469-5073"]}, DOI={10.1017/s0016672310000492}, abstractNote={SummaryThe expression of behaviours is influenced by many segregating genes. Behaviours are, therefore, complex traits. They have, however, unique characteristics that set them apart from physiological and morphological quantitative traits. First, behaviours are the ultimate expression of the nervous system. This means that understanding the genetic underpinnings of behaviours requires a neurobiological context, i.e. an understanding of the genes–brain–behaviour axis. In other words, how do ensembles of genes empower specific neural circuits to drive behaviours? Second, behaviours represent the interface between an organism and its environment. Thus, environmental effects are likely to make substantial contributions to determining behavioural outputs and genotype-by-environment interactions are expected to be prominent. It is important to differentiate between genes that contribute to the manifestation of the behavioural phenotype and genes that contribute to phenotypic variation in behaviour. The former are identified by classical mutagenesis experiments, whereas the latter can be detected through quantitative genetic approaches. Genes that contribute to phenotypic variation in behaviour harbour polymorphisms that provide the substrates for evolution. This review focuses on olfactory behaviour inDrosophilawith the goal to illustrate how fundamental insights derived from studies on chemosensation can be applied to a wide range of behavioural phenotypes.}, number={5-6}, journal={GENETICS RESEARCH}, author={Anholt, Robert R. H.}, year={2010}, pages={349–359} }
 @article{anholt_2010, title={Presentation Skills for Scientists. E. Zanders & L. MacLeod. Cambridge University Press. 2010. 80 pages. ISBN 9780521741033. Price £19.99 (paperback with DVD-ROM).}, volume={92}, ISSN={0016-6723 1469-5073}, url={http://dx.doi.org/10.1017/S0016672310000431}, DOI={10.1017/S0016672310000431}, abstractNote={On being asked to review the Elements of Evolutionary Genetics by Brian and Deborah Charlesworth, I felt a bit like a minor apostle being asked to peer review the New Testament. (I assume the New Testament was peer reviewed?) The Elements of Evolutionary Genetics is a work of biblical proportions for the age of genetics. For much of the 20th Century, evolutionary genetics was an arcane field populated by nerdy mathematically inclined biologists. However, population genetics provides the tools necessary for analysis of gene sequence data, in particular the wealth of information now available on population variation in humans and other ‘model ’ species. The human genome sequence, originally trumpeted as the ‘blueprint ’ for humanity, actually makes little sense without an understanding of how and why gene sequences vary between individuals, populations and species. In the face of the avalanche of gene sequence data, population genetics has recently begun to take centre stage in biology. In this context, the publication of this book is very timely. The Charlesworths are leaders in the field, and have covered virtually all areas of population genetic analysis, starting with the basics. Early chapters deal with the measurement of genetic variability, the action of selection and maintenance of variation. Complexity is added with succeeding chapters – such as mutation and migration, the influence of stochastic processes in finite populations and spatial structure. This gradual building from basic principles, with the simpler concepts at the beginning of each chapter leads the reader through the field. I especially enjoyed the section on ‘Testing for selection’, which outlines the multitude of methods now available for detecting the influence of natural selection in DNA sequence data – I shall certainly be recommending sections such as this for graduate and undergraduate student reading in the future. If I have any grumble, it is that inevitably in such a wide-ranging book there was not enough space for any detailed critique of the topics described. In several places, I was left wanting more. As one might expect from the authors, the book contains lots of equations. Nonetheless, the less mathematically able, such as myself, can still take a great deal from it. The text is clearly written and easy to follow, with the more complex maths set aside in text boxes. Unlike in some population genetic texts, here theory is closely intertwined with empirical examples. A nice example is the section on the evolution of sex, where case studies, especially from the complex world of plant sex, are used to highlight the theoretical ideas. So who is likely to read this book? It is described as being aimed at ‘advanced undergraduates ’, and it will certainly be a useful text for advanced courses in evolutionary genetics. However, I think the book will really come into its own at graduate level, where there is no other comparable work that covers such a broad range of topics. I guess that few will read it all the way through from start to finish, but anyone interested in evolution or population genetics should have a copy on their shelves. I certainly anticipate that I will use it as a reference book, for the definitions and principles underlying key concepts are more clearly outlined here than in any other single volume. In a fast-moving field, I anticipate that this book will be a key textbook for many years to come.}, number={4}, journal={Genetics Research}, publisher={Cambridge University Press (CUP)}, author={Anholt, Robert R. H.}, year={2010}, month={Aug}, pages={323–324} }
 @article{morozova_ayroles_jordan_duncan_carbone_lyman_stone_govindaraju_ellison_mackay_et al._2009, title={Alcohol Sensitivity in Drosophila: Translational Potential of Systems Genetics}, volume={183}, ISSN={["1943-2631"]}, DOI={10.1534/genetics.109.107490}, abstractNote={AbstractIdentification of risk alleles for human behavioral disorders through genomewide association studies (GWAS) has been hampered by a daunting multiple testing problem. This problem can be circumvented for some phenotypes by combining genomewide studies in model organisms with subsequent candidate gene association analyses in human populations. Here, we characterized genetic networks that underlie the response to ethanol exposure in Drosophila melanogaster by measuring ethanol knockdown time in 40 wild-derived inbred Drosophila lines. We associated phenotypic variation in ethanol responses with genomewide variation in gene expression and identified modules of correlated transcripts associated with a first and second exposure to ethanol vapors as well as the induction of tolerance. We validated the computational networks and assessed their robustness by transposon-mediated disruption of focal genes within modules in a laboratory inbred strain, followed by measurements of transcript abundance of connected genes within the module. Many genes within the modules have human orthologs, which provides a stepping stone for the identification of candidate genes associated with alcohol drinking behavior in human populations. We demonstrated the potential of this translational approach by identifying seven intronic single nucleotide polymorphisms of the Malic Enzyme 1 (ME1) gene that are associated with cocktail drinking in 1687 individuals of the Framingham Offspring cohort, implicating that variation in levels of cytoplasmic malic enzyme may contribute to variation in alcohol consumption.}, number={2}, journal={GENETICS}, author={Morozova, Tatiana V. and Ayroles, Julien F. and Jordan, Katherine W. and Duncan, Laura H. and Carbone, Mary Anna and Lyman, Richard E. and Stone, Eric A. and Govindaraju, Diddahally R. and Ellison, R. Curtis and Mackay, Trudy F. C. and et al.}, year={2009}, month={Oct}, pages={733–745} }
 @article{yamamoto_anholt_mackay_2009, title={Epistatic interactions attenuate mutations affecting startle behaviour in Drosophila melanogaster}, volume={91}, ISSN={0016-6723 1469-5073}, url={http://dx.doi.org/10.1017/S0016672309990279}, DOI={10.1017/S0016672309990279}, abstractNote={SummaryEpistasis is an important feature of the genetic architecture of quantitative traits. Previously, we showed that startle-induced locomotor behaviour ofDrosophila melanogaster, a critical survival trait, is highly polygenic and exhibits epistasis. Here, we characterize epistatic interactions among homozygousP-element mutations affecting startle-induced locomotion in theCanton-Sisogenic background and in 21 wild-derived inbred genetic backgrounds. We find pervasive epistasis for pairwise combinations of homozygousP-element insertional mutations as well as for mutations in wild-derived backgrounds. In all cases, the direction of the epistatic effects is to suppress the mutant phenotypes. The magnitude of the epistatic interactions in wild-derived backgrounds is highly correlated with the magnitude of the main effects of mutations, leading to phenotypic robustness of the startle response in the face of deleterious mutations. There is variation in the magnitude of epistasis among the wild-derived genetic backgrounds, indicating evolutionary potential for enhancing or suppressing effects of single mutations. These results provide a partial glimpse of the complex genetic network underlying the genetic architecture of startle behaviour and provide empirical support for the hypothesis that suppressing epistasis is the mechanism underlying genetic canalization of traits under strong stabilizing selection. Widespread suppressing epistasis will lead to underestimates of the main effects of quantitative trait loci (QTLs) in mapping experiments when not explicitly accounted for. In addition, suppressing epistasis could lead to underestimates of mutational variation for quantitative traits and overestimates of the strength of stabilizing selection, which has implications for maintenance of variation of complex traits by mutation–selection balance.}, number={6}, journal={Genetics Research}, publisher={Cambridge University Press (CUP)}, author={Yamamoto, Akihiko and Anholt, Robert R. H. and Mackay, Trudy F. C.}, year={2009}, month={Dec}, pages={373–382} }
 @article{ayroles_carbone_stone_jordan_lyman_magwire_rollmann_duncan_lawrence_anholt_et al._2009, title={Systems genetics of complex traits in Drosophila melanogaster}, volume={41}, ISSN={["1546-1718"]}, DOI={10.1038/ng.332}, abstractNote={Trudy Mackay and colleagues present a resource of 40 Drosophila melanogaster wild-derived inbred lines. The authors quantify genome-wide variation in transcript abundance for six ecologically relevant traits, characterize the transcriptome and identify transcriptional modules. Determining the genetic architecture of complex traits is challenging because phenotypic variation arises from interactions between multiple, environmentally sensitive alleles. We quantified genome-wide transcript abundance and phenotypes for six ecologically relevant traits in D. melanogaster wild-derived inbred lines. We observed 10,096 genetically variable transcripts and high heritabilities for all organismal phenotypes. The transcriptome is highly genetically intercorrelated, forming 241 transcriptional modules. Modules are enriched for transcripts in common pathways, gene ontology categories, tissue-specific expression and transcription factor binding sites. The high degree of transcriptional connectivity allows us to infer genetic networks and the function of predicted genes from annotations of other genes in the network. Regressions of organismal phenotypes on transcript abundance implicate several hundred candidate genes that form modules of biologically meaningful correlated transcripts affecting each phenotype. Overlapping transcripts in modules associated with different traits provide insight into the molecular basis of pleiotropy between complex traits.}, number={3}, journal={NATURE GENETICS}, author={Ayroles, Julien F. and Carbone, Mary Anna and Stone, Eric A. and Jordan, Katherine W. and Lyman, Richard F. and Magwire, Michael M. and Rollmann, Stephanie M. and Duncan, Laura H. and Lawrence, Faye and Anholt, Robert R. H. and et al.}, year={2009}, month={Mar}, pages={299–307} }
 @article{anholt_williams_2010, title={The Soluble Proteome of the Drosophila Antenna}, volume={35}, ISSN={1464-3553 0379-864X}, url={http://dx.doi.org/10.1093/chemse/bjp073}, DOI={10.1093/chemse/bjp073}, abstractNote={The olfactory system of Drosophila melanogaster is one of the best characterized chemosensory systems. Identification of proteins contained in the third antennal segment, the main olfactory organ, has previously relied primarily on immunohistochemistry, and although such studies and in situ hybridization studies are informative, they focus generally on one or few gene products at a time, and quantification is difficult. In addition, purification of native proteins from the antenna is challenging because it is small and encased in a hard cuticle. Here, we describe a simple method for the large-scale detection of soluble proteins from the Drosophila antenna by chromatographic separation of tryptic peptides followed by tandem mass spectrometry with femtomole detection sensitivities. Examination of the identities of these proteins indicates that they originate both from the extracellular perilymph and from the cytoplasm of disrupted cells. We identified enzymes involved with intermediary metabolism, proteins associated with regulation of gene expression, nucleic acid metabolism and protein metabolism, proteins associated with microtubular transport, 8 odorant-binding proteins, protective enzymes associated with antibacterial defense and defense against oxidative damage, cuticular proteins, and proteins of unknown function, which represented about one-third of all soluble proteins. The procedure described here opens the way for precise quantification of any target protein in the Drosophila antenna and should be readily applicable to antennae from other insects.}, number={1}, journal={Chemical Senses}, publisher={Oxford University Press (OUP)}, author={Anholt, Robert R.H. and Williams, Taufika Islam}, year={2010}, month={Jan}, pages={21–30} }
 @article{harbison_mackay_anholt_2009, title={Understanding the neurogenetics of sleep: progress from Drosophila}, volume={25}, ISSN={0168-9525}, url={http://dx.doi.org/10.1016/j.tig.2009.04.003}, DOI={10.1016/j.tig.2009.04.003}, abstractNote={Most behaviors manifest themselves through interactions with environments. Sleep, however, is characterized by immobility and reduced responsiveness. Although nearly all animals sleep, the purpose of sleep remains an enduring puzzle. Drosophila melanogaster exhibits all the behavioral characteristics of mammalian sleep, enabling the use of powerful genetic approaches to dissect conserved fundamental neurogenetic aspects of sleep. Drosophila studies over the past four years have identified novel genes and pathways modulating sleep, such as Shaker and sleepless, and candidate brain regions known to function in circadian regulation and learning and memory. Advances in systems genetics coupled with the ability to target specific brain regions enable the characterization of transcriptional networks and neural circuits contributing to phenotypic variation in sleep.}, number={6}, journal={Trends in Genetics}, publisher={Elsevier BV}, author={Harbison, Susan T. and Mackay, Trudy F.C. and Anholt, Robert R.H.}, year={2009}, month={Jun}, pages={262–269} }
 @article{yamamoto_zwarts_callaerts_norga_mackay_anholt_2008, title={Neurogenetic networks for startle-induced locomotion in Drosophila melanogaster}, volume={105}, ISSN={["0027-8424"]}, DOI={10.1073/pnas.0804889105}, abstractNote={
            Understanding how the genome empowers the nervous system to express behaviors remains a critical challenge in behavioral genetics. The startle response is an attractive behavioral model for studies on the relationship between genes, brain, and behavior, as the ability to respond rapidly to harmful changes in the environment is a universal survival trait.
            Drosophila melanogaster
            provides a powerful system in which genetic studies on individuals with controlled genetic backgrounds and reared under controlled environmental conditions can be combined with neuroanatomical studies to analyze behaviors. In a screen of 720 lines of
            D. melanogaster
            , carrying single
            P[GT1]
            transposon insertions, we found 267 lines that showed significant changes in startle-induced locomotor behavior. Excision of the transposon reversed this effect in five lines out of six tested. We infer that most of the 267 lines show mutant effects on startle-induced locomotion that are caused by the transposon insertions. We selected a subset of 15 insertions in the same genetic background in autosomal genes with strong mutant effects and crossed them to generate all 105 possible nonreciprocal double heterozygotes. These hybrids revealed an extensive network of epistatic interactions on the behavioral trait. In addition, we observed changes in neuroanatomy that were caused by these 15 mutations, individually and in their double heterozygotes. We find that behavioral and neuroanatomical phenotypes are determined by a common set of genes that are organized as partially overlapping genetic networks.
          }, number={34}, journal={PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA}, author={Yamamoto, Akihiko and Zwarts, Liesbeth and Callaerts, Patrick and Norga, Koenraad and Mackay, Trudy F. C. and Anholt, Robert R. H.}, year={2008}, month={Aug}, pages={12393–12398} }
 @article{sambandan_carbone_anholt_mackay_2008, title={Phenotypic plasticity and genotype by environment interaction for olfactory behavior in Drosophila melanogaster}, volume={179}, ISSN={["0016-6731"]}, DOI={10.1534/genetics.108.086769}, abstractNote={AbstractGenotype by environment interactions (GEI) play a major part in shaping the genetic architecture of quantitative traits and are confounding factors in genetic studies, for example, in attempts to associate genetic variation with disease susceptibility. It is generally not known what proportion of phenotypic variation is due to GEI and how many and which genes contribute to GEI. Behaviors are complex traits that mediate interactions with the environment and, thus, are ideally suited for studies of GEI. Olfactory behavior in Drosophila melanogaster presents an opportunity to systematically dissect GEI, since large numbers of genetically identical individuals can be reared under defined environmental conditions and the olfactory system of Drosophila and its behavioral response to odorants have been well characterized. We assessed variation in olfactory behavior in a population of 41 wild-derived inbred lines and asked to what extent different larval-rearing environments would influence adult olfactory behavior and whether GEI is a minor or major contributing source of phenotypic variation. We found that ∼50% of phenotypic variation in adult olfactory behavior is attributable to GEI. In contrast, transcriptional analysis revealed that only 20 genes show GEI at the level of gene expression [false discovery rate (FDR) < 0.05], some of which are associated with physiological responses to environmental chemicals. Quantitative complementation tests with piggyBac-tagged mutants for 2 of these genes (CG9664 and Transferrin 1) demonstrate that genes that show transcriptional GEI are candidate genes for olfactory behavior and that GEI at the level of gene expression is correlated with GEI at the level of phenotype.}, number={2}, journal={GENETICS}, author={Sambandan, Deepa and Carbone, Mary Anna and Anholt, Robert R. H. and Mackay, Trudy E. C.}, year={2008}, month={Jun}, pages={1079–1088} }
 @article{lavagnino_anholt_fanara_2008, title={Variation in genetic architecture of olfactory behaviour among wild-derived populations of Drosophila melanogaster}, volume={21}, ISSN={["1010-061X"]}, DOI={10.1111/j.1420-9101.2008.01546.x}, abstractNote={AbstractOdour‐guided behaviour is a quantitative trait determined by many genes that are sensitive to gene–environment interactions. Different natural populations are likely to experience different selection pressures on the genetic underpinnings of chemosensory behaviour. However, few studies have reported comparisons of the quantitative genetic basis of olfactory behaviour in geographically distinct populations. We generated isofemale lines of Drosophila melanogaster from six populations in Argentina and measured larval and adult responses to benzaldehyde. There was significant variation within populations for both larval and adult olfactory behaviour and a significant genotype × sex interaction (GSI) for adult olfactory behaviour. However, there is substantial variation in the contribution of GSI to the total phenotypic variance among populations. Estimates of evolvability are orders of magnitude higher for larvae than for adults. Our results suggest that the potential for evolutionary adaptation to the chemosensory environment is greater at the larval feeding stage than at the adult reproductive stage.}, number={4}, journal={JOURNAL OF EVOLUTIONARY BIOLOGY}, author={Lavagnino, N. J. and Anholt, R. R. H. and Fanara, J. J.}, year={2008}, month={Jul}, pages={988–996} }
 @article{mackay_anholt_2007, title={Ain't misbehavin? Genotype-environment interactions and the genetics of behavior}, volume={23}, ISSN={["1362-4555"]}, DOI={10.1016/j.tig.2007.03.013}, abstractNote={Although the multiple interacting genes affecting complex traits can readily be dissected, how much genotype-environment interactions contribute to variation in complex traits remains elusive. A recent study that quantified several behavioral phenotypes on the same mouse strains in different laboratories decades apart, shows that some behavioral differences between laboratories remain greatly replicable, whereas others are less robust over time. This report, together with studies from Drosophila, stresses the importance of understanding genotype-environment interactions.}, number={7}, journal={TRENDS IN GENETICS}, author={Mackay, Trudy F. C. and Anholt, Robert R. H.}, year={2007}, month={Jul}, pages={311–314} }
 @article{wang_lyman_shabalina_mackay_anholt_2007, title={Association of polymorphisms in odorant-binding protein genes with variation in olfactory response to benzaldehyde in Drosophila}, volume={177}, ISSN={["0016-6731"]}, DOI={10.1534/genetics.107.079731}, abstractNote={Abstract
               Adaptive evolution of animals depends on behaviors that are essential for their survival and reproduction. The olfactory system of Drosophila melanogaster has emerged as one of the best characterized olfactory systems, which in addition to a family of odorant receptors, contains an approximately equal number of odorant-binding proteins (OBPs), encoded by a multigene family of 51 genes. Despite their abundant expression, little is known about their role in chemosensation, largely due to the lack of available mutations in these genes. We capitalized on naturally occurring mutations (polymorphisms) to gain insights into their functions. We analyzed the sequences of 13 Obp genes in two chromosomal clusters in a population of wild-derived inbred lines, and asked whether polymorphisms in these genes are associated with variation in olfactory responsiveness. Four polymorphisms in 3 Obp genes exceeded the statistical permutation threshold for association with responsiveness to benzaldehyde, suggesting redundancy and/or combinatorial recognition by these OBPs of this odorant. Model predictions of alternative pre-mRNA secondary structures associated with polymorphic sites suggest that alterations in Obp mRNA structure could contribute to phenotypic variation in olfactory behavior.}, number={3}, journal={GENETICS}, author={Wang, Ping and Lyman, Richard F. and Shabalina, Svetlana A. and Mackay, Trudy F. C. and Anholt, Robert R. H.}, year={2007}, month={Nov}, pages={1655–1665} }
 @article{lee_anholt_cole_2008, title={Olfactomedin-2 mediates development of the anterior central nervous system and head structures in zebrafish}, volume={125}, ISSN={["0925-4773"]}, DOI={10.1016/j.mod.2007.09.009}, abstractNote={Olfactomedins comprise a diverse family of secreted glycoproteins, which includes noelin, tiarin, pancortin and gliomedin, implicated in development of the nervous system, and the glaucoma-associated protein myocilin. Here we show in zebrafish that olfactomedin-2 (OM2) is a developmentally regulated gene, and that knockdown of protein expression by morpholino antisense oligonucleotides leads to perturbations of nervous system development. Interference with OM2 expression results in impaired development of branchiomotor neurons, specific disruption of the late phase branchiomotor axon guidance, and affects development of the caudal pharyngeal arches, olfactory pits, eyes and optic tectum. Effects of OM2 knockdown on eye development are likely associated with Pax6 signaling in developing eyes, as Pax6.1 and Pax6.2 mRNA expression patterns are altered in the eyes of OM2 morphants. The specific absence of most cartilaginous structures in the pharyngeal arches indicates that the observed craniofacial phenotypes may be due to perturbed differentiation of cranial neural crest cells. Our studies show that this member of the olfactomedin protein family is an important regulator of development of the anterior nervous system.}, number={1-2}, journal={MECHANISMS OF DEVELOPMENT}, author={Lee, Ju-Ahng and Anholt, Robert R. H. and Cole, Gregory J.}, year={2008}, pages={167–181} }
 @article{rollmann_yamamoto_goossens_zwarts_callaerts-vegh_callaerts_norga_mackay_anholt_2007, title={The early developmental gene Semaphorin 5c contributes to olfactory behavior in adult Drosophila}, volume={176}, ISSN={["1943-2631"]}, DOI={10.1534/genetics.106.069781}, abstractNote={Abstract
               Behaviors are complex traits influenced by multiple pleiotropic genes. Understanding the mechanisms that give rise to complex behaviors requires an understanding of how variation in transcriptional regulation shapes nervous system development and how variation in brain structure influences an organism's ability to respond to its environment. To begin to address this problem, we used olfactory behavior in Drosophila melanogaster as a model and showed that a hypomorphic transposon-mediated mutation of the early developmental gene Semaphorin-5c (Sema-5c) results in aberrant behavioral responses to the repellant odorant benzaldehyde. We fine mapped this effect to the Sema-5c locus using deficiency mapping, phenotypic reversion through P-element excision, and transgenic rescue. Morphometric analysis of this Sema-5c allele reveals subtle neuroanatomical changes in the brain with a reduction in the size of the ellipsoid body. High-density oligonucleotide expression microarrays identified 50 probe sets with altered transcriptional regulation in the Sema-5c background and quantitative complementation tests identified epistatic interactions between nine of these coregulated genes and the transposon-disrupted Sema-5c gene. Our results demonstrate how hypomorphic mutation of an early developmental gene results in genomewide transcriptional consequences and alterations in brain structure accompanied by profound impairment of adult behavior.}, number={2}, journal={GENETICS}, author={Rollmann, Stephanie M. and Yamamoto, Akihiko and Goossens, Tim and Zwarts, Liesbeth and Callaerts-Vegh, Zsuzsanna and Callaerts, Patrick and Norga, Koenraad and Mackay, Trudy F. C. and Anholt, Robert R. H.}, year={2007}, month={Jun}, pages={947–956} }
 @book{anholt_2006, title={Dazzle 'em with style the art of oral scientific presentation}, publisher={Burlington, MA: Elsevier Academic Press}, author={Anholt, Robert R.H.}, year={2006} }
 @article{sambandan_yamamoto_fanara_mackay_anholt_2006, title={Dynamic genetic interactions determine odor-guided behavior in Drosophila melanogaster}, volume={174}, ISSN={["0016-6731"]}, DOI={10.1534/genetics.106.060574}, abstractNote={AbstractUnderstanding the genetic architecture of complex traits requires identification of the underlying genes and characterization of gene-by-gene and genotype-by-environment interactions. Behaviors that mediate interactions between organisms and their environment are complex traits expected to be especially sensitive to environmental conditions. Previous studies on the olfactory avoidance response of Drosophila melanogaster showed that the genetic architecture of this model behavior depends on epistatic networks of pleiotropic genes. We performed a screen of 1339 co-isogenic p[GT1]-element insertion lines to identify novel genes that contribute to odor-guided behavior and identified 55 candidate genes with known p[GT1]-element insertion sites. Characterization of the expression profiles of 10 p[GT1]-element insertion lines showed that the effects of the transposon insertions are often dependent on developmental stage and that hypomorphic mutations in developmental genes can elicit profound adult behavioral deficits. We assessed epistasis among these genes by constructing all possible double heterozygotes and measuring avoidance responses under two stimulus conditions. We observed enhancer and suppressor effects among subsets of these P-element-tagged genes, and surprisingly, epistatic interactions shifted with changes in the concentration of the olfactory stimulus. Our results show that the manifestation of epistatic networks dynamically changes with alterations in the environment.}, number={3}, journal={GENETICS}, author={Sambandan, Deepa and Yamamoto, Akihiko and Fanara, Juan-Jose and Mackay, Trudy F. C. and Anholt, Robert R. H.}, year={2006}, month={Nov}, pages={1349–1363} }
 @article{rollmann_magwire_morgan_ozsoy_yamamoto_mackay_anholt_2006, title={Pleiotropic fitness effects of the Tre1-Gr5a region in Drosophila melanogaster}, volume={38}, ISSN={["1546-1718"]}, DOI={10.1038/ng1823}, abstractNote={The abundance of transposable elements and DNA repeat sequences in mammalian genomes raises the question of whether such insertions represent passive evolutionary baggage or may influence the expression of complex traits. We addressed this question in Drosophila melanogaster, in which the effects of single transposable elements on complex traits can be assessed in genetically identical individuals reared in controlled environments. Here we demonstrate that single P-element insertions in the intergenic region between the gustatory receptor 5a (Gr5a, also known as Tre) and trapped in endoderm 1 (Tre1), which encodes an orphan receptor, exert complex pleiotropic effects on fitness traits, including selective nutrient intake, life span, and resistance to starvation and heat stress. Mutations in this region interact epistatically with downstream components of the insulin signaling pathway. Transposon-induced sex-specific and sex-antagonistic effects further accentuate the complex influences that intergenic transposable elements can contribute to quantitative trait phenotypes.}, number={7}, journal={NATURE GENETICS}, author={Rollmann, Stephanie M. and Magwire, Michael M. and Morgan, Theodore J. and Ozsoy, Ergi D. and Yamamoto, Akihiko and Mackay, Trudy F. C. and Anholt, Robert R. H.}, year={2006}, month={Jul}, pages={824–829} }
 @article{rollmann_mackay_anholt_2005, title={Pinocchio, a novel protein expressed in the antenna, contributes to olfactory behavior in Drosophila melanogaster}, volume={63}, ISSN={["0022-3034"]}, DOI={10.1002/neu.20123}, abstractNote={Most organisms depend on chemoreception for survival and reproduction. In Drosophila melanogaster multigene families of chemosensory receptors and putative odorant binding proteins have been identified. Here, we introduce an additional distinct protein, encoded by the CG4710 gene, that contributes to olfactory behavior. Previously, we identified through P[lArB]-element mutagenesis a smell impaired (smi) mutant, smi21F, with odorant-specific defects in avoidance responses. Here, we show that the smi21F mutant also exhibits reduced attractant responses to some, but not all, of a select group of odorants. Furthermore, electroantennogram amplitudes are increased in smi21F flies. Characterization of flanking sequences of the P[lArB] insertion site, complementation mapping, phenotypic reversion through P-element excision, and expression analysis implicate a predicted gene, CG4710, as the candidate smi gene. CG4710 produces two transcripts that encode proteins that contain conserved cysteines and which are reduced in the smi21F mutant. Furthermore, in situ hybridization reveals CG4710 expression in the third antennal segment. We have named this gene of previously unknown function and its product "Pinocchio (Pino)".}, number={2}, journal={JOURNAL OF NEUROBIOLOGY}, author={Rollmann, SM and Mackay, TFC and Anholt, RRH}, year={2005}, month={May}, pages={146–158} }
 @misc{anholt_2004, title={Genetic modules and networks for behavior: lessons from Drosophila}, volume={26}, ISSN={["0265-9247"]}, DOI={10.1002/bies.20131}, abstractNote={AbstractBehaviors are quantitative traits determined through actions of multiple genes and subject to genome–environment interactions. Early studies concentrated on analyzing the effects of single genes on behaviors, often generating views of simplified linear genetic pathways. The genome era has generated a profound paradigm shift enabling us to identify all the genes that contribute to expression of a behavioral phenotype, to investigate how they are organized as functional ensembles and to begin to identify polymorphisms that contribute to phenotypic variation and are targets for natural selection. Recent studies show that the genetic architecture of behavior is determined by dynamic and plastic modular networks of pleiotropic genes and that the behavioral phenotype manifests itself as an emergent property of such networks. Such networks are exquisitely sensitive to genetic background and sex effects. This review describes how Drosophila can serve as a model for uncovering fundamental principles of the genetic architecture of behavior. BioEssays 26:1299–1306, 2004. © 2004 Wiley Periodicals, Inc.}, number={12}, journal={BIOESSAYS}, author={Anholt, RRH}, year={2004}, month={Dec}, pages={1299–1306} }
 @misc{anholt_mackay_2004, title={Quantitative genetic analyses of complex behaviours in Drosophila}, volume={5}, ISSN={["1471-0056"]}, DOI={10.1038/nrg1472}, abstractNote={Behaviours are exceptionally complex quantitative traits. Sensitivity to environmental variation and genetic background, the presence of sexual dimorphism, and the widespread functional pleiotropy that is inherent in behavioural phenotypes pose daunting challenges for unravelling their underlying genetics. Drosophila melanogaster provides an attractive system for elucidating the unifying principles of the genetic architectures that drive behaviours, as genetically identical individuals can be reared rapidly in controlled environments and extensive publicly accessible genetic resources are available. Recent advances in quantitative genetic and functional genomic approaches now enable the extensive characterization of complex genetic networks that mediate behaviours in this important model organism.}, number={11}, journal={NATURE REVIEWS GENETICS}, author={Anholt, RRH and Mackay, TFC}, year={2004}, month={Nov}, pages={838–849} }
 @article{ganguly_mackay_anholt_2003, title={Scribble is essential for olfactory Behavior in Drosphila melanogaster}, volume={164}, number={4}, journal={Genetics}, author={Ganguly, I. and MacKay, T. F. C. and Anholt, R. R. H.}, year={2003}, month={Aug}, pages={1447–1457} }
 @article{anholt_dilda_chang_fanara_kulkarni_ganguly_rollmann_kamdar_mackay_2003, title={The genetic architecture of odor-guided behavior in Drosophila: epistasis and the transcriptome}, volume={35}, ISSN={["1546-1718"]}, DOI={10.1038/ng1240}, abstractNote={We combined transcriptional profiling and quantitative genetic analysis to elucidate the genetic architecture of olfactory behavior in Drosophila melanogaster. We applied whole-genome expression analysis to five coisogenic smell-impaired (smi) mutant lines and their control. We used analysis of variance to partition variation in transcript abundance between males and females and between smi genotypes and to determine the genotype-by-sex interaction. A total of 666 genes showed sexual dimorphism in transcript abundance, and 530 genes were coregulated in response to one or more smi mutations, showing considerable epistasis at the level of the transcriptome in response to single mutations. Quantitative complementation tests of mutations at these coregulated genes with the smi mutations showed that in most cases (67%) epistatic interactions for olfactory behavior mirrored epistasis at the level of transcription, thus identifying new candidate genes regulating olfactory behavior.}, number={2}, journal={NATURE GENETICS}, author={Anholt, RRH and Dilda, CL and Chang, S and Fanara, JJ and Kulkarni, NH and Ganguly, I and Rollmann, SM and Kamdar, KP and Mackay, TFC}, year={2003}, month={Oct}, pages={180–184} }
 @article{borras_morozova_heinsohn_lyman_mackay_anholt_2003, title={Transcription profiling in Drosophila eyes that overexpress the human glaucoma-associated trabecular meshwork-inducible glucocorticoid response protein/myocilin (TIGR/MYOC)}, volume={163}, number={2}, journal={Genetics}, author={Borras, T. and Morozova, T. V. and Heinsohn, S. L. and Lyman, R. F. and Mackay, T. F. C. and Anholt, R. R. H.}, year={2003}, month={Feb}, pages={637–645} }
 @article{luo_cannon_wekesa_lyman_vandenbergh_anholt_2002, title={Impaired olfactory behavior in mice deficient in the a subunit of G(0)}, volume={941}, ISSN={["0006-8993"]}, DOI={10.1016/S0006-8993(02)02566-0}, abstractNote={The ability to respond to chemical signals is essential for the survival and reproduction of most organisms. Olfactory signaling involves odorant receptor-mediated activation of G(olf), a homologue of G(s), on the dendrites of olfactory neurons. Olfactory receptor cells, however, also express Galpha(i2) and Galpha(o) on their axons, with all neurons expressing G(o) and a subset G(i2). Despite their abundance, possible contributions of G(o) and G(i2) to chemoreception remain unexplored. We investigated whether homologous recombinant mice deficient in the alpha subunit of G(o) are able to respond to odorants, whether possible olfactory impairments are dependent on genetic background, and whether formation of glomeruli in their olfactory bulbs is compromised. In an olfactory habituation/dishabituation test, G(o)-/- mice were unresponsive when exposed to odorants. Analysis of variance shows that performance of G(o)+/- mice crossed into the CD-1 background is also diminished in this test compared to their G(o)+/+ counterparts. Following food deprivation, G(o)-/- mice in the 129 Sv-ter/C57BL/6 genetic background were unable to locate a buried food pellet until they were approximately 10 weeks of age after which they performed as well as their litter mate controls. However, CD-1 G(o)-/- mice could locate a buried food pellet even when tested immediately after weaning. Despite their compromised olfactory responsiveness, histological examination did not reveal gross alterations in the olfactory bulbs of G(o)-/- mice. Thus, Galpha(o) is necessary for the expression of olfactory behavior under normal conditions and dependent on genetic background, but is not essential for the formation and maintenance of glomeruli.}, number={1-2}, journal={BRAIN RESEARCH}, author={Luo, AH and Cannon, EH and Wekesa, KS and Lyman, RF and Vandenbergh, JG and Anholt, RRH}, year={2002}, month={Jun}, pages={62–71} }
 @article{kulkarni_yamamoto_robinson_mackay_anholt_2002, title={The DSC1 channel, encoded by the smi60E locus, contributes to odor-guided behavior in Drosophila melanogaster}, volume={161}, number={4}, journal={Genetics}, author={Kulkarni, N. H. and Yamamoto, A. H. and Robinson, K. O. and Mackay, T. F. C. and Anholt, R. R. H.}, year={2002}, month={Aug}, pages={1507–1516} }
 @article{fanara_robinson_rollmann_anholt_mackay_2002, title={Vanaso is a candidate quantitative trait gene for Drosophila olfactory behavior}, volume={162}, number={3}, journal={Genetics}, author={Fanara, J. J. and Robinson, K. O. and Rollmann, S. M. and Anholt, R. R. H. and MacKay, T. F. C.}, year={2002}, month={Nov}, pages={1321–1328} }
 @article{anholt_fanara_fedorowicz_ganguly_kulkarni_mackay_rollmann_2001, title={Functional genomics of odor-guided behavior in Drosophila melanogaster}, volume={26}, ISSN={["0379-864X"]}, DOI={10.1093/chemse/26.2.215}, abstractNote={The avoidance response to repellent odorants in Drosophila melanogaster, a response essential for survival, provides an advantageous model for studies on the genetic architecture of olfactory behavior. Transposon tagging in a highly inbred strain of flies in combination with a rapid and simple statistical behavioral assay enables the identification of not only large phenotypic effects, but also small aberrations from wild-type avoidance behavior. The recent completion of the sequence of the Drosophila genome facilitates the molecular characterization of transposon-tagged genes and correlation between gene expression and behavior in smell-impaired (smi) mutant lines. Quantitative genetic analyses of a collection of smi lines in a co-isogenic background revealed an extensive network of epistatic interactions among genes that shape the olfactory avoidance response. Candidate genes for several of these transposon-tagged smi loci implicate genes that mediate odorant recognition, including a novel odorant binding protein; signal propagation, including a voltage-gated sodium channel; and a protein containing multiple leucine rich repeats and PDZ domains likely to be involved in postsynaptic organization in the olfactory pathway. Several novel genes of unknown function have also been implicated, including a novel tyrosine-regulated protein kinase. The discovery and characterization of novel gene products that have major, hitherto unappreciated effects on olfactory behavior will provide new insights in the generation and regulation of odor-guided behavior. The identification and functional characterization of proteins encoded by smi genes that form part of the olfactory subgenome and correlation of polymorphisms in these genes with variation in odor-guided behavior in natural populations will advance our understanding of the genetic architecture of chemosensory behavior.}, number={2}, journal={CHEMICAL SENSES}, author={Anholt, RRH and Fanara, JJ and Fedorowicz, GM and Ganguly, I and Kulkarni, NH and Mackay, TFC and Rollmann, SM}, year={2001}, month={Feb}, pages={215–221} }
 @article{anholt_2001, title={Olfaction in Drosophila: from receptors to behavior}, volume={26}, ISSN={["0379-864X"]}, DOI={10.1093/chemse/26.2.193}, number={2}, journal={CHEMICAL SENSES}, author={Anholt, R}, year={2001}, month={Feb}, pages={193–193} }
 @article{anholt_mackay_2001, title={The genetic architecture of odor-guided behavior in Drosophila melanogaster}, volume={31}, ISSN={["0001-8244"]}, DOI={10.1023/A:1010201723966}, abstractNote={The avoidance response to repellent odorants in Drosophila melanogaster, a response essential for survival, provides an advantageous model for studies on the genetic architecture of behavior. Transposon tagging in a highly inbred strain of flies in combination with a rapid and simple statistical behavioral assay enables the identification of not only large phenotypic effects, but also small aberrations from wild-type avoidance behavior. The recent completion of the sequence of the Drosophila genome facilitates the molecular characterization of transposon-tagged genes and correlation between gene expression and behavior in smell-impaired (smi) mutant lines. Quantitative genetic analyses of a collection of smi lines in a coisogenic background revealed an extensive network of epistatic interactions among genes that shape the olfactory avoidance response. The identification and functional characterization of proteins encoded by smi genes that form part of the olfactory subgenome and correlation of polymorphisms in these genes with variation in odor-guided behavior in natural populations will advance our understanding of the genetic architecture of chemosensory behavior.}, number={1}, journal={BEHAVIOR GENETICS}, author={Anholt, RRH and Mackay, TFC}, year={2001}, month={Jan}, pages={17–27} }
 @article{kulkarni_karavanich_atchley_anholt_2000, title={Characterization and differential expression of a human gene family of olfactomedin-related proteins}, volume={76}, ISSN={["0016-6723"]}, DOI={10.1017/S0016672300004584}, abstractNote={Olfactomedin-related proteins are secreted glycoproteins with conserved C-terminal motifs. Olfactomedin was originally identified as the major component of the mucus layer that surrounds the chemosensory dendrites of olfactory neurons. Homologues were subsequently found also in other tissues, including the brain and in species ranging from Caenorhabditis elegans to Homo sapiens. Most importantly, the TIGR/myocilin protein, expressed in the eye and associated with the pathogenesis of glaucoma, is an olfactomedin-related protein. The prevalence of olfactomedin-related proteins among species and their identification in different tissues prompted us to investigate whether a gene family exists within a species, specifically Homo sapiens. A GenBank search indeed revealed an entire human gene family of olfactomedin-related proteins with at least five members, designated hOlfA through hOlfD and the TIGR/myocilin protein. hOlfA corresponds to the rat neuronal AMZ protein. Phylogenetic analyses of 18 olfactomedin-related sequences resolved four distinct subfamilies. Among the human proteins, hOlfA and hOlfC, both expressed in brain, are most closely related. Northern blot analyses of 16 human tissues demonstrated highly specific expression patterns: hOlfA is expressed in brain, hOlfB in pancreas and prostate, hOlfC in cerebellum, hOlfD in colon, small intestine and prostate and TIGR/myocilin in heart and skeletal muscle. The link between TIGR/myocilin and ocular hypertension and the expression of several of these proteins in mucus-lined tissues suggest that they play an important role in regulating physical properties of the extracellular environment. Future studies can now assess whether other members of this gene family, like TIGR/myocilin, are also associated with human disease processes.}, number={1}, journal={GENETICAL RESEARCH}, author={Kulkarni, NH and Karavanich, CA and Atchley, WR and Anholt, RRH}, year={2000}, month={Aug}, pages={41–50} }
 @article{wekesa_anholt_1999, title={Differential expression of G proteins in the mouse olfactory system}, volume={837}, ISSN={["0006-8993"]}, DOI={10.1016/S0006-8993(99)01630-3}, abstractNote={Transmembrane signaling events at the dendrites and axons of olfactory receptor neurons mediate distinct functions. Whereas odorant recognition and chemosensory transduction occur at the dendritic membranes of olfactory neurons, signal propagation, axon sorting and target innervation are functions of their axons. The roles of G proteins in transmembrane signaling at the dendrites have been studied extensively, but axonal G proteins have not been investigated in detail. We used immunohistochemistry to visualize expression of α subunits of Go and Gi2 in the mouse olfactory system. Go is expressed ubiquitously on axons of olfactory receptor neurons throughout the olfactory neuroepithelium and in virtually all glomeruli in the main olfactory bulb. In contrast, expression of Gi2 is restricted to a sub-population of olfactory neurons, along the dorsal septum and the dorsal recess of the nasal cavity, which projects primarily to medial regions of the olfactory bulb, with the exception of glomeruli adjacent to the pathway of the vomeronasal nerve. In contrast to the overlapping expression patterns of Go and Gi2 in the main olfactory system, neurons expressing Go and those expressing Gi2 in the accessory olfactory bulb are more clearly separated, in agreement with previous studies. Vomeronasal axons terminating in glomeruli in the rostral region of the accessory olfactory bulb express Gi2, whereas those projecting to the caudal region express Go. Characterization of the expression patterns of Gi2 and Go in the olfactory projection is essential for future studies aimed at relating transmembrane signaling events to signal propagation, axon sorting and target innervation.}, number={1-2}, journal={BRAIN RESEARCH}, author={Wekesa, KS and Anholt, RRH}, year={1999}, month={Aug}, pages={117–126} }
 @article{fedorowicz_fry_anholt_mackay_1998, title={Epistatic interactions between smell-impaired loci in Drosophila melanogaster}, volume={148}, number={4}, journal={Genetics}, author={Fedorowicz, G. M. and Fry, J. D. and Anholt, R. R. H. and MacKay, T. F. C.}, year={1998}, pages={1885–1891} }
 @article{karavanich_anholt_1998, title={Molecular evolution of olfactomedin}, volume={15}, ISSN={["0737-4038"]}, DOI={10.1093/oxfordjournals.molbev.a025975}, abstractNote={Olfactomedin is a secreted polymeric glycoprotein of unknown function, originally discovered at the mucociliary surface of the amphibian olfactory neuroepithelium and subsequently found throughout the mammalian brain. As a first step toward elucidating the function of olfactomedin, its phylogenetic history was examined to identify conserved structural motifs. Such conserved motifs may have functional significance and provide targets for future mutagenesis studies aimed at establishing the function of this protein. Previous studies revealed 33% amino acid sequence identity between rat and frog olfactomedins in their carboxyl terminal segments. Further analysis, however, reveals more extensive homologies throughout the molecule. Despite significant sequence divergence, cysteines essential for homopolymer formation such as the CXC motif near the amino terminus are conserved, as is the characteristic glycosylation pattern, suggesting that these posttranslational modifications are essential for function. Furthermore, evolutionary analysis of a region of 53 amino acids of fish, frog, rat, mouse, and human olfactomedins indicates that an ancestral olfactomedin gene arose before the evolution of terrestrial vertebrates and evolved independently in teleost, amphibian, and mammalian lineages. Indeed, a distant olfactomedin homolog was identified in Caenorhabditis elegans. Although the amino acid sequence of this invertebrate protein is longer and highly divergent compared with its vertebrate homologs, the protein from C. elegans shows remarkable similarities in terms of conserved motifs and posttranslational modification sites. Six universally conserved motifs were identified, and five of these are clustered in the carboxyl terminal half of the protein. Sequence comparisons indicate that evolution of the N-terminal half of the molecule involved extensive insertions and deletions; the C-terminal segment evolved mostly through point mutations, at least during vertebrate evolution. The widespread occurrence of olfactomedin among vertebrates and invertebrates underscores the notion that this protein has a function of universal importance. Furthermore, extensive modification of its N-terminal half and the acquisition of a C-terminal SDEL endoplasmic-reticulum-targeting sequence may have enabled olfactomedin to adopt new functions in the mammalian central nervous system.}, number={6}, journal={MOLECULAR BIOLOGY AND EVOLUTION}, author={Karavanich, CA and Anholt, RRH}, year={1998}, month={Jun}, pages={718–726} }
 @inbook{karavanich_anholt_1998, title={Olf evolution of olfactomedin: Structural constraints and conservation of primary sequence motifs}, volume={855}, booktitle={Olfaction and taste XII: An international symposium}, publisher={New York, NY: New York Academy of Sciences}, author={Karavanich, C. A. and Anholt, R. R. H.}, year={1998}, pages={294–300} }
 @article{wekesa_anholt_1997, title={Pheromone regulated production of inositol-(1, 4, 5)trisphosphate in the mammalian vomeronasal organ}, volume={138}, ISSN={["0013-7227"]}, DOI={10.1210/en.138.8.3497}, number={8}, journal={ENDOCRINOLOGY}, author={Wekesa, KS and Anholt, RRH}, year={1997}, month={Aug}, pages={3497–3504} }
 @book{anholt_1994, title={Dazzle 'em with style the art of oral scientific presentation}, publisher={New York: WH Freeman and Co.}, author={Anholt, Robert R.H.}, year={1994} }
 @article{zhou_luoma_armour_thakkar_mackay_anholt, title={A drosophila model for toxicogenomics: Genetic variation in susceptibility to heavy metal exposure}, volume={13}, number={7}, journal={PLoS Genetics}, author={Zhou, S. S. and Luoma, S. E. and Armour, G. E. S. and Thakkar, E. and Mackay, T. F. C. and Anholt, R. R. H.} }
 @article{swarup_huang_mackay_anholt, title={Analysis of natural variation reveals neurogenetic networks for Drosophila olfactory behavior}, volume={110}, number={3}, journal={Proceedings of the National Academy of Sciences of the United States of America}, author={Swarup, S. and Huang, W. and Mackay, T. F. C. and Anholt, R. R. H.}, pages={1017–1022} }
 @article{zwarts_magwire_carbone_versteven_herteleer_anholt_callaerts_mackay, title={Complex genetic architecture of Drosophila aggressive behavior}, volume={108}, number={41}, journal={Proceedings of the National Academy of Sciences of the United States of America}, author={Zwarts, L. and Magwire, M. M. and Carbone, M. A. and Versteven, M. and Herteleer, L. and Anholt, R. R. H. and Callaerts, P. and Mackay, T. F. C.}, pages={17070–17075} }
 @article{huang_richards_carbone_zhu_anholt_ayroles_duncan_jordan_lawrence_magwire_et al., title={Epistasis dominates the genetic architecture of Drosophila quantitative traits}, volume={109}, number={39}, journal={Proceedings of the National Academy of Sciences of the United States of America}, author={Huang, W. and Richards, S. and Carbone, M. A. and Zhu, D. H. and Anholt, R. R. H. and Ayroles, J. F. and Duncan, L. and Jordan, K. W. and Lawrence, F. and Magwire, M. M. and et al.}, pages={15553–15559} }
 @article{yamamoto_anholt_mackay, title={Epistatic interactions attenuate mutations affecting startle behaviour in Drosophila melanogaster}, volume={91}, number={6}, journal={Genetical Research}, author={Yamamoto, A. and Anholt, R. R. H. and Mackay, T. F. C.}, pages={373–382} }
 @article{dembeck_boroczky_huang_schal_anholt_mackay, title={Genetic architecture of natural variation in cuticular hydrocarbon composition in Drosophila melanogaster}, volume={4}, journal={Elife}, author={Dembeck, L. M. and Boroczky, K. and Huang, W. and Schal, C. and Anholt, R. R. H. and Mackay, T. F. C.} }
 @article{carbone_yamamoto_huang_lyman_meadors_yamamoto_anholt_mackay, title={Genetic architecture of natural variation in visual senescence in Drosophila}, volume={113}, number={43}, journal={Proceedings of the National Academy of Sciences of the United States of America}, author={Carbone, M. A. and Yamamoto, A. and Huang, W. and Lyman, R. A. and Meadors, T. B. and Yamamoto, R. and Anholt, R. R. H. and Mackay, T. F. C.}, pages={E6620–6629} }
 @article{huang_carbone_magwire_peiffer_lyman_stone_anholt_mackay, title={Genetic basis of transcriptome diversity in Drosophila melanogaster}, volume={112}, number={44}, journal={Proceedings of the National Academy of Sciences of the United States of America}, author={Huang, W. and Carbone, M. A. and Magwire, M. M. and Peiffer, J. A. and Lyman, R. F. and Stone, E. A. and Anholt, R. R. H. and Mackay, T. F. C.}, pages={E6010–6019} }
 @misc{morozova_mackay_anholt, title={Genetics and genomics of alcohol sensitivity}, volume={289}, number={3}, journal={Molecular Genetics and Genomics}, author={Morozova, T. V. and Mackay, T. F. C. and Anholt, R. R. H.}, pages={253–269} }
 @article{fochler_morozova_davis_gearhart_huang_mackay_anholt, title={Genetics of alcohol consumption in Drosophila melanogaster}, volume={16}, number={7}, journal={Genes Brain and Behavior}, author={Fochler, S. and Morozova, T. V. and Davis, M. R. and Gearhart, A. W. and Huang, W. and Mackay, T. F. C. and Anholt, R. R. H.}, pages={675–685} }
 @article{weber_khan_magwire_tabor_mackay_anholt, title={Genome-wide association analysis of oxidative stress resistance in Drosophila melanogaster}, volume={7}, number={4}, journal={PLoS One}, author={Weber, A. L. and Khan, G. F. and Magwire, M. M. and Tabor, C. L. and Mackay, T. F. C. and Anholt, R. R. H.} }
 @article{montgomery_vorojeikina_huang_mackay_anholt_rand, title={Genome-wide association analysis of tolerance to methylmercury toxicity in Drosophila implicates myogenic and neuromuscular developmental pathways}, volume={9}, number={10}, journal={PLoS One}, author={Montgomery, S. L. and Vorojeikina, D. and Huang, W. and Mackay, T. F. C. and Anholt, R. R. H. and Rand, M. D.} }
 @article{jordan_craver_magwire_cubilla_mackay_anholt, title={Genome-wide association for sensitivity to chronic oxidative stress in Drosophila melanogaster}, volume={7}, number={6}, journal={PLoS One}, author={Jordan, K. W. and Craver, K. L. and Magwire, M. M. and Cubilla, C. E. and Mackay, T. F. C. and Anholt, R. R. H.} }
 @article{wang_lyman_mackay_anholt, title={Natural variation in odorant recognition among odorant-binding proteins in Drosophila melanogaster}, volume={184}, number={3}, journal={Genetics}, author={Wang, P. and Lyman, R. F. and Mackay, T. F. C. and Anholt, R. R. H.}, pages={759–767} }
 @article{arya_weber_wang_magwire_negron_mackay_anholt, title={Natural variation, functional pleiotropy and transcriptional contexts of odorant binding protein genes in Drosophila melanogaster}, volume={186}, number={4}, journal={Genetics}, author={Arya, G. H. and Weber, A. L. and Wang, P. and Magwire, M. M. and Negron, Y. L. S. and Mackay, T. F. C. and Anholt, R. R. H.}, pages={1475–623} }
 @article{shorter_dembeck_everett_morozova_arya_turlapati_st armour_schal_mackay_anholt, title={Obp56h modulates mating behavior in Drosophila melanogaster}, volume={6}, number={10}, journal={G3-Genes Genomes Genetics}, author={Shorter, J. R. and Dembeck, L. M. and Everett, L. J. and Morozova, T. V. and Arya, G. H. and Turlapati, L. and St Armour, G. E. and Schal, C. and Mackay, T. F. C. and Anholt, R. R. H.}, pages={3335–3342} }
 @article{rollmann_wang_date_west_mackay_anholt, title={Odorant receptor polymorphisms and natural variation in olfactory behavior in Drosophila melanogaster}, volume={186}, number={2}, journal={Genetics}, author={Rollmann, S. M. and Wang, P. and Date, P. and West, S. A. and Mackay, T. F. C. and Anholt, R. R. H.}, pages={687–364} }
 @misc{mackay_anholt, title={Of flies and man: Drosophila as a model for human complex traits}, volume={7}, journal={Annual Review of Genomics and Human Genetics}, author={Mackay, T. E. C. and Anholt, R. R. H.}, pages={339–367} }
 @article{carbone_ayroles_yamamoto_morozova_west_magwire_mackay_anholt, title={Overexpression of myocilin in the Drosophila eye activates the unfolded protein response: Implications for glaucoma}, volume={4}, number={1}, journal={PLoS One}, author={Carbone, M. A. and Ayroles, J. F. and Yamamoto, A. and Morozova, T. V. and West, S. A. and Magwire, M. M. and Mackay, T. F. C. and Anholt, R. R. H.} }
 @article{morozova_anholt_mackay, title={Phenotypic and transcriptional response to selection for alcohol sensitivity in Drosophila melanogaster}, volume={8}, number={10}, journal={Genome Biology}, author={Morozova, T. V. and Anholt, R. R. and MacKay, T. F.} }
 @article{zhou_stone_mackay_anholt, title={Plasticity of the chemoreceptor repertoire in Drosophila melanogaster}, volume={5}, number={10}, journal={PLoS Genetics}, author={Zhou, S. S. and Stone, E. A. and Mackay, T. F. C. and Anholt, R. R. H.} }
 @article{morozova_huang_pray_whitham_anholt_mackay, title={Polymorphisms in early neurodevelopmental genes affect natural variation in alcohol sensitivity in adult drosophila}, volume={16}, journal={BMC Genomics}, author={Morozova, T. V. and Huang, W. and Pray, V. A. and Whitham, T. and Anholt, R. R. H. and Mackay, T. F. C.} }
 @article{ganguly_mackay_anholt, title={Scribble is essential for olfactory behavior in Drosophila melanogaster}, volume={164}, number={4}, journal={Genetics}, author={Ganguly, I. and MacKay, T. F. C. and Anholt, R. R. H.}, pages={1447–1457} }
 @article{arya_magwire_huang_serrano-negron_mackay_anholt, title={The genetic basis for variation in olfactory behavior in Drosophila melanogaster}, volume={40}, number={4}, journal={Chemical Senses}, author={Arya, G. H. and Magwire, M. M. and Huang, W. and Serrano-Negron, Y. L. and Mackay, T. F. C. and Anholt, R. R. H.}, pages={233–243} }
 @article{zhou_morozova_hussain_luoma_mccoy_yamamoto_mackay_anholt, title={The genetic basis for variation in sensitivity to lead toxicity in Drosophila melanogaster}, volume={124}, number={7}, journal={Environmental Health Perspectives}, author={Zhou, S. S. and Morozova, T. V. and Hussain, Y. N. and Luoma, S. E. and McCoy, L. and Yamamoto, A. and Mackay, T. F. C. and Anholt, R. R. H.}, pages={1062–1070} }
 @misc{morozova_goldman_mackay_anholt, title={The genetic basis of alcoholism: Multiple phenotypes, many genes, complex networks}, volume={13}, number={2}, journal={Genome Biology}, author={Morozova, T. V. and Goldman, D. and Mackay, T. F. C. and Anholt, R. R. H.} }
 @article{anholt_mackay, title={The road less traveled: from genotype to phenotype in flies and humans}, volume={29}, number={1-2}, journal={Mammalian Genome}, author={Anholt, R. R. H. and Mackay, T. F. C.}, pages={5–23} }
 @article{morozova_mackay_anholt, title={Transcriptional networks for alcohol sensitivity in drosophila melanogaster}, volume={187}, number={4}, journal={Genetics}, author={Morozova, T. V. and Mackay, T. F. C. and Anholt, R. R. H.}, pages={1193–345} }
 @article{morozova_anholt_mackay, title={Transcriptional response to alcohol exposure in Drosophila melanogaster}, volume={7}, number={10}, journal={Genome Biology}, author={Morozova, T. V. and Anholt, R. R. H. and MacKay, T. F. C.} }
 @article{zhou_mackay_anholt, title={Tuning the chemosensory window A fly's perspective}, volume={4}, number={3}, journal={Fly}, author={Zhou, S. S. and Mackay, T. F. C. and Anholt, R. R. H.}, pages={230–235} }
 @misc{harbison_mackay_anholt, title={Understanding the neurogenetics of sleep: Progress from Drosophila}, volume={25}, number={6}, journal={Trends in Genetics}, author={Harbison, S. T. and Mackay, T. F. C. and Anholt, R. R. H.}, pages={262–269} }