@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{rollmann_zwarts_edwards_yamamoto_callaerts_norga_mackay_anholt_2008, title={Pleiotropic effects of Drosophila neuralized on complex behaviors and brain structure}, volume={179}, ISSN={["1943-2631"]}, DOI={10.1534/genetics.108.088435}, abstractNote={Understanding how genotypic variation influences variation in brain structures and behavioral phenotypes represents a central challenge in behavioral genetics. In Drosophila melanogaster, the neuralized (neur) gene plays a key role in development of the nervous system. Different P-element insertional mutations of neur allow the development of viable and fertile adults with profoundly altered behavioral phenotypes that depend on the exact location of the inserted P element. The neur mutants exhibit reduced responsiveness to noxious olfactory and mechanosensory stimulation and increased aggression when limited food is presented after a period of food deprivation. These behavioral phenotypes are correlated with distinct structural changes in integrative centers in the brain, the mushroom bodies, and the ellipsoid body of the central complex. Transcriptional profiling of neur mutants revealed considerable overlap among ensembles of coregulated genes in the different mutants, but also distinct allele-specific differences. The diverse phenotypic effects arising from nearby P-element insertions in neur provide a new appreciation of the concept of allelic effects on phenotype, in which the wild type and null mutant are at the extreme ends of a continuum of pleiotropic allelic effects.}, number={3}, journal={GENETICS}, author={Rollmann, Stephanie A. and Zwarts, Liesbeth and Edwards, Alexis C. and Yamamoto, Akihiko and Callaerts, Patrick and Norga, Koenraad and Mackay, Trudy F. C. and Anholt, Robert R. H.}, year={2008}, month={Jul}, pages={1327–1336} }
 @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={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} }
 @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={Abstract Understanding 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{harbison_yamamoto_fanara_norga_mackay_2004, title={Quantitative trait loci affecting starvation resistance in Drosophila melanogaster}, volume={166}, ISSN={["1943-2631"]}, DOI={10.1534/genetics.166.4.1807}, abstractNote={The ability to withstand periods of scarce food resources is an important fitness trait.Starvation resistance is a quantitative trait controlled by multiple interacting genes and exhibits considerable genetic variation in natural populations.This genetic variation could be maintained in the face of strong selection due to a trade-off in resource allocation between reproductive activity and individual survival.Knowledge of the genes affecting starvation tolerance and the subset of genes that affect variation in starvation resistance in natural populations would enable us to evaluate this hypothesis from a quantitative genetic perspective.We screened 933 co-isogenic P-element insertion lines to identify candidate genes affecting starvation tolerance.A total of 383 P-element insertions induced highly significant and often sex-specific mutational variance in starvation resistance.We also used deficiency complementation mapping followed by complementation to mutations to identify 12 genes contributing to variation in starvation resistance between two wild-type strains.The genes we identified are involved in oogenesis, metabolism, and feeding behaviors, indicating a possible link to reproduction and survival.However, we also found genes with cell fate specification and cell proliferation phenotypes, which implies that resource allocation during development and at the cellular level may also influence the phenotypic response to starvation.I N nature, animals must often cope with periods of spermatogenesis gene fer-15 and the phosphatidylinosi- suboptimal food resources.Yeast, bacteria, and nemtol-3-kinase catalytic subunit gene age-1 also has increased atodes have a distinctive response when nutrients are starvation tolerance (Munoz and Riddle 2003).In conunavailable: they alter their morphology, become quiestrast, mutant alleles of the transcriptional regulator dafcent, and suspend reproductive activity, which enables 16 reduce starvation tolerance, even when coupled with them to survive until food resources become more plena daf-2 mutation (Munoz and Riddle 2003).tiful (Kolter et al. 1993;Thomas 1993;Kenyon 1996; Drosophila also experience periods of famine in na-Guarente et al. 1998;Hengge-Aronis 2000).Increasedture, yet the suite of genes affecting their physiological expression of the disaccharide trehalose occurs in reand behavioral responses to famine remains largely unsponse to starvation in yeast (Klionsky and Emr 2000).known.Starvation resistance is a typical quantitative trait Moreover, yeast degrade proteins and organelles in an that displays considerable genetic variation in natural attempt to scavenge nutrients during starvation (Windpopulations (Service and Rose 1985;}, number={4}, journal={GENETICS}, author={Harbison, ST and Yamamoto, AH and Fanara, JJ and Norga, KK and Mackay, TFC}, year={2004}, month={Apr}, pages={1807–1823} }
 @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{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{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{jordan_carbone_yamamoto_morgan_mackay, title={Quantitative genomics of locomotor behavior in Drosophila melanogaster}, volume={8}, number={8}, journal={Genome Biology}, author={Jordan, K. W. and Carbone, M. A. and Yamamoto, A. and Morgan, T. J. and Mackay, T. F.} }