@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{molo_white_cornish_gell_baars_singh_carbone_isakeit_wise_woloshuk_et al._2022, title={Asymmetrical lineage introgression and recombination in populations of Aspergillus flavus: Implications for biological control}, volume={17}, ISSN={["1932-6203"]}, url={https://doi.org/10.1371/journal.pone.0276556}, DOI={10.1371/journal.pone.0276556}, abstractNote={Aspergillus flavusis an agriculturally important fungus that causes ear rot of maize and produces aflatoxins, of which B1is the most carcinogenic naturally-produced compound. In the US, the management of aflatoxins includes the deployment of biological control agents that comprise two nonaflatoxigenicA.flavusstrains, either Afla-Guard (member of lineage IB) or AF36 (lineage IC). We used genotyping-by-sequencing to examine the influence of both biocontrol agents on native populations ofA.flavusin cornfields in Texas, North Carolina, Arkansas, and Indiana. This study examined up to 27,529 single-nucleotide polymorphisms (SNPs) in a total of 815A.flavusisolates, and 353 genome-wide haplotypes sampled before biocontrol application, three months after biocontrol application, and up to three years after initial application. Here, we report that the two distinctA.flavusevolutionary lineages IB and IC differ significantly in their frequency distributions across states. We provide evidence of increased unidirectional gene flow from lineage IB into IC, inferred to be due to the applied Afla-Guard biocontrol strain. Genetic exchange and recombination of biocontrol strains with native strains was detected in as little as three months after biocontrol application and up to one and three years later. There was limited inter-lineage migration in the untreated fields. These findings suggest that biocontrol products that include strains from lineage IB offer the greatest potential for sustained reductions in aflatoxin levels over several years. This knowledge has important implications for developing new biocontrol strategies.}, number={10}, journal={PLOS ONE}, author={Molo, Megan S. and White, James B. and Cornish, Vicki and Gell, Richard M. and Baars, Oliver and Singh, Rakhi and Carbone, Mary Anna and Isakeit, Thomas and Wise, Kiersten A. and Woloshuk, Charles P. and et al.}, editor={Nierman, William C.Editor}, year={2022}, month={Oct} }
 @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{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{tallo_duncan_yamamoto_slaydon_arya_turlapati_mackay_carbone_2021, title={Heat shock proteins and small nucleolar RNAs are dysregulated in a Drosophila model for feline hypertrophic cardiomyopathy}, volume={11}, ISSN={["2160-1836"]}, DOI={10.1093/g3journal/jkaa014}, abstractNote={Abstract
               In cats, mutations in myosin binding protein C (encoded by the MYBPC3 gene) have been associated with hypertrophic cardiomyopathy (HCM). However, the molecular mechanisms linking these mutations to HCM remain unknown. Here, we establish Drosophila melanogaster as a model to understand this connection by generating flies harboring MYBPC3 missense mutations (A31P and R820W) associated with feline HCM. The A31P and R820W flies displayed cardiovascular defects in their heart rates and exercise endurance. We used RNA-seq to determine which processes are misregulated in the presence of mutant MYBPC3 alleles. Transcriptome analysis revealed significant downregulation of genes encoding small nucleolar RNA (snoRNAs) in exercised female flies harboring the mutant alleles compared to flies that harbor the wild-type allele. Other processes that were affected included the unfolded protein response and immune/defense responses. These data show that mutant MYBPC3 proteins have widespread effects on the transcriptome of co-regulated genes. Transcriptionally differentially expressed genes are also candidate genes for future evaluation as genetic modifiers of HCM as well as candidate genes for genotype by exercise environment interaction effects on the manifestation of HCM; in cats as well as humans.}, number={1}, journal={G3-GENES GENOMES GENETICS}, author={Tallo, Christian A. and Duncan, Laura H. and Yamamoto, Akihiko H. and Slaydon, Joshua D. and Arya, Gunjan H. and Turlapati, Lavanya and Mackay, Trudy F. C. and Carbone, Mary A.}, year={2021}, month={Jan} }
 @article{gabrawy_campbell_carbone_morozova_arya_turlapati_walston_starz-gaiano_everett_mackay_et al._2019, title={Lisinopril Preserves Physical Resilience and Extends Life Span in a Genotype-Specific Manner in Drosophila melanogaster}, volume={74}, ISSN={["1758-535X"]}, DOI={10.1093/gerona/glz152}, abstractNote={Abstract
               Physical resiliency declines with age and comorbid conditions. In humans, angiotensin-converting enzyme (ACE) has been associated with attenuation of the decline in physical performance with age. ACE-inhibitor compounds, commonly prescribed for hypertension, often have beneficial effects on physical performance however the generality of these effects are unclear. Here, we tested the effects of the ACE-inhibitor Lisinopril on life span, and age-specific speed, endurance, and strength using three genotypes of the Drosophila melanogaster Genetic Reference Panel. We show that age-related decline in physical performance and survivorship varies with genetic background. Lisinopril treatment increased mean life span in all Drosophila Genetic Reference Panel lines, but its effects on life span, speed, endurance, and strength depended on genotype. We show that genotypes with increased physical performance on Lisinopril treatment experienced reduced age-related protein aggregation in muscle. Knockdown of skeletal muscle-specific Ance, the Drosophila ortholog of ACE, abolished the effects of Lisinopril on life span, implying a role for skeletal muscle Ance in survivorship. Using transcriptome profiling, we identified genes involved in stress response that showed expression changes associated with genotype and age-dependent responsiveness to Lisinopril. Our results demonstrate that Ance is involved in physical decline and demonstrate genetic variation in phenotypic responses to an ACE inhibitor.}, number={12}, journal={JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES}, author={Gabrawy, Mariann M. and Campbell, Sarah and Carbone, Mary Anna and Morozova, Tatiana V and Arya, Gunjan H. and Turlapati, Lavanya B. and Walston, Jeremy D. and Starz-Gaiano, Michelle and Everett, Logan and Mackay, Trudy F. C. and et al.}, year={2019}, month={Dec}, pages={1844–1852} }
 @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{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{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{dembeck_huang_carbone_mackay_2015, title={Genetic basis of natural variation in body pigmentation in Drosophila melanogaster}, volume={9}, ISSN={1933-6934 1933-6942}, url={http://dx.doi.org/10.1080/19336934.2015.1102807}, DOI={10.1080/19336934.2015.1102807}, abstractNote={Body pigmentation in insects and other organisms is typically variable within and between species and is often associated with fitness. Regulatory variants with large effects at bab1, t and e affect variation in abdominal pigmentation in several populations of Drosophila melanogaster. Recently, we performed a genome wide association (GWA) analysis of variation in abdominal pigmentation using the inbred, sequenced lines of the Drosophila Genetic Reference Panel (DGRP). We confirmed the large effects of regulatory variants in bab1, t and e; identified 81 additional candidate genes; and validated 17 candidate genes (out of 28 tested) using RNAi knockdown of gene expression and mutant alleles. However, these analyses are imperfect proxies for the effects of segregating variants. Here, we describe the results of an extreme quantitative trait locus (xQTL) GWA analysis of female body pigmentation in an outbred population derived from light and dark DGRP lines. We replicated the effects on pigmentation of 28 genes implicated by the DGRP GWA study, including bab1, t and e and 7 genes previously validated by RNAi and/or mutant analyses. We also identified many additional loci. The genetic architecture of Drosophila pigmentation is complex, with a few major genes and many other loci with smaller effects.}, number={2}, journal={Fly}, publisher={Informa UK Limited}, author={Dembeck, Lauren M and Huang, Wen and Carbone, Mary Anna and Mackay, Trudy F C}, year={2015}, month={Apr}, pages={75–81} }
 @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{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} }
 @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{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{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{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{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{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{harbison_carbone_ayroles_stone_lyman_mackay_2009, title={Co-regulated transcriptional networks contribute to natural genetic variation in Drosophila sleep}, volume={41}, ISSN={["1546-1718"]}, DOI={10.1038/ng.330}, abstractNote={Trudy Mackay and colleagues measure sleep phenotypes in 40 wild-derived Drosophila lines, and report candidate genes and transcriptional networks associated with sleep regulation. Sleep disorders are common in humans, and sleep loss increases the risk of obesity and diabetes1. Studies in Drosophila2,3 have revealed molecular pathways4,5,6,7 and neural tissues8,9,10 regulating sleep; however, genes that maintain genetic variation for sleep in natural populations are unknown. Here, we characterized sleep in 40 wild-derived Drosophila lines and observed abundant genetic variation in sleep architecture. We associated sleep with genome-wide variation in gene expression11 to identify candidate genes. We independently confirmed that molecular polymorphisms in Catsup (Catecholamines up) are associated with variation in sleep and that P-element mutations in four candidate genes affect sleep and gene expression. Transcripts associated with sleep grouped into biologically plausible genetically correlated transcriptional modules. We confirmed co-regulated gene expression using P-element mutants. Quantitative genetic analysis of natural phenotypic variation is an efficient method for revealing candidate genes and pathways.}, number={3}, journal={NATURE GENETICS}, author={Harbison, Susan T. and Carbone, Mary Anna and Ayroles, Julien F. and Stone, Eric A. and Lyman, Richard F. and Mackay, Trudy F. C.}, year={2009}, month={Mar}, pages={371–375} }
 @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} }
 @misc{propper_moore_mills-koonce_halpern_hill-soderlund_calkins_carbone_cox_2008, title={Gene-environment contributions to the development of infant vagal reactivity: The interaction of dopamine and maternal sensitivity}, volume={79}, ISSN={["1467-8624"]}, DOI={10.1111/j.1467-8624.2008.01194.x}, abstractNote={This study investigated dopamine receptor genes (DRD2 and DRD4) and maternal sensitivity as predictors of infant respiratory sinus arrhythmia (RSA) and RSA reactivity, purported indices of vagal tone and vagal regulation, in a challenge task at 3, 6, and 12 months in 173 infant–mother dyads. Hierarchical linear modeling (HLM) revealed that at 3 and 6 months, RSA withdrawal in response to maternal separation was greater (suggesting expected physiological regulation) in infants without the DRD2 risk allele than those with the risk allele. At 12 months, infants with the risk allele who were also exposed to maternal sensitivity showed levels of RSA withdrawal comparable to infants who were not at genetic risk. Findings demonstrate the importance of developmental analysis of gene–environment interaction.}, number={5}, journal={CHILD DEVELOPMENT}, author={Propper, Cathi and Moore, Ginger A. and Mills-Koonce, W. Roger and Halpern, Carolyn Tucker and Hill-Soderlund, Ashley L. and Calkins, Susan D. and Carbone, Mary Anna and Cox, Martha}, year={2008}, pages={1377–1394} }
 @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{propper_willoughby_halpern_carbone_cox_2007, title={Parenting quality, DRD4, and the prediction of externalizing and internalizing behaviors in early childhood}, volume={49}, ISSN={0012-1630 1098-2302}, url={http://dx.doi.org/10.1002/dev.20249}, DOI={10.1002/dev.20249}, abstractNote={AbstractRecent research has found that the dopamine D4 receptor (DRD4) gene and maternal insensitivity may interact to predict externalizing behavior in preschoolers. The current study attempted to replicate and extend this finding in a sample of 18–30‐month‐old children. The current study examined two distinct dimensions of parenting (warm‐responsive and negative‐intrusive) as predictors of childhood externalizing and internalizing behavior. Further, race was investigated as a moderator of gene–environment relationships. Results revealed that high warm‐responsive parenting was associated with decreased externalizing behavior only for African American children possessing the short polymorphism of DRD4. The data indicate that children may be differentially susceptible to different aspects of parenting depending on their genotype, and it is important to consider differences in racial composition when studying these relationships. © 2007 Wiley Periodicals, Inc. Dev Psychobiol 49: 619‐632, 2007.}, number={6}, journal={Developmental Psychobiology}, publisher={Wiley}, author={Propper, C. and Willoughby, M. and Halpern, C.T. and Carbone, M.A. and Cox, M.}, year={2007}, pages={619–632} }
 @article{carbone_jordan_lyman_harbison_leips_morgan_deluca_awadalla_mackay_2006, title={Phenotypic variation and natural selection at Catsup, a pleiotropic quantitative trait gene in Drosphila}, volume={16}, ISSN={["1879-0445"]}, DOI={10.1016/j.cub.2006.03.051}, abstractNote={Quantitative traits are shaped by networks of pleiotropic genes [1Mackay T.F.C. The genetic architecture of quantitative traits.Annu. Rev. Genet. 2001; 35: 303-339Crossref PubMed Scopus (753) Google Scholar]. To understand the mechanisms that maintain genetic variation for quantitative traits in natural populations and to predict responses to artificial and natural selection, we must evaluate pleiotropic effects of underlying quantitative trait genes and define functional allelic variation at the level of quantitative trait nucleotides (QTNs). Catecholamines up (Catsup), which encodes a negative regulator of tyrosine hydroxylase [2Stathakis D.G. Burton D.Y. McIvor W.E. Krishnakumar S. Wright T.R. O'Donnell J.M. The Catecholamines up (Catsup) protein of Drosophila melanogaster functions as a negative regulator of tyrosine hydroxylase activity.Genetics. 1999; 153: 361-382Crossref PubMed Google Scholar], the rate-limiting step in the synthesis of the neurotransmitter dopamine, is a pleiotropic quantitative trait gene in Drosophila melanogaster [2Stathakis D.G. Burton D.Y. McIvor W.E. Krishnakumar S. Wright T.R. O'Donnell J.M. The Catecholamines up (Catsup) protein of Drosophila melanogaster functions as a negative regulator of tyrosine hydroxylase activity.Genetics. 1999; 153: 361-382Crossref PubMed Google Scholar, 3O'Donnell J.M. Wang Z. Chaudhuri A. Effects of perturbation of catecholamine regulation on resistance of Drosophila melanogaster to environmental stress.in: Blau N. Thony B. Pterins, Folates, and Related Biogenic Amines. SPS Publications, Heilbronn2004: 94-100Google Scholar, 4Mackay T.F.C. Roshina N.V. Leips J.W. Pasyukova E.G. Complex genetic architecture of Drosophila longevity.in: Masaro E.J. Austad S.N. Handbook of the Biology of Aging. Sixth Edition. Elsevier Press, Burlington2005: 181-216Crossref Scopus (24) Google Scholar]. We used association mapping to determine whether the same or different QTNs at Catsup are associated with naturally occurring variation in multiple quantitative traits. We sequenced 169 Catsup alleles from a single population and detected 33 polymorphisms with little linkage disequilibrium (LD). Different molecular polymorphisms in Catsup are independently associated with variation in longevity, locomotor behavior, and sensory bristle number. Most of these polymorphisms are potentially functional variants in protein coding regions, have large effects, and are not common. Thus, Catsup is a pleiotropic quantitative trait gene, but individual QTNs do not have pleiotropic effects. Molecular population genetic analyses of Catsup sequences are consistent with balancing selection maintaining multiple functional polymorphisms.}, number={9}, journal={CURRENT BIOLOGY}, author={Carbone, Mary Anna and Jordan, Katherine W. and Lyman, Richard F. and Harbison, Susan T. and Leips, Jeff and Morgan, Theodore J. and DeLuca, Maria and Awadalla, Philip and Mackay, Trudy F. C.}, year={2006}, month={May}, pages={912–919} }
 @article{carbone_llopart_deangelis_coyne_mackay_2005, title={Quantitative trait loci affecting the difference in pigmentation between Drosophila yakuba and D. santomea}, volume={171}, ISSN={["1943-2631"]}, DOI={10.1534/genetics.105.044412}, abstractNote={AbstractUsing quantitative trait locus (QTL) mapping, we studied the genetic basis of the difference in pigmentation between two sister species of Drosophila: Drosophila yakuba, which, like other members of the D. melanogaster subgroup, shows heavy black pigmentation on the abdomen of males and females, and D. santomea, an endemic to the African island of São Tomé, which has virtually no pigmentation. Here we mapped four QTL with large effects on this interspecific difference in pigmentation: two on the X chromosome and one each on the second and third chromosomes. The same four QTL were detected in male hybrids in the backcrosses to both D. santomea and D. yakuba and in the female D. yakuba backcross hybrids. All four QTL exhibited strong epistatic interactions in male backcross hybrids, but only one pair of QTL interacted in females from the backcross to D. yabuka. All QTL from each species affected pigmentation in the same direction, consistent with adaptive evolution driven by directional natural selection. The regions delimited by the QTL included many positional candidate loci in the pigmentation pathway, including genes affecting catecholamine biosynthesis, melanization of the cuticle, and many additional pleiotropic effects.}, number={1}, journal={GENETICS}, author={Carbone, MA and Llopart, A and DeAngelis, M and Coyne, JA and Mackay, TFC}, year={2005}, month={Sep}, pages={211–225} }
 @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{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{dembeck_huang_carbone_mackay, title={Genetic basis of natural variation in body pigmentation in Drosophila melanogaster}, volume={9}, number={2}, journal={Fly}, author={Dembeck, L. M. and Huang, W. and Carbone, M. A. and Mackay, T. F. C.}, pages={75–81} }
 @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} }
 @article{ramaswami_deng_zhang_carbone_mackay_li, title={Genetic mapping uncovers cis-regulatory landscape of RNA editing}, volume={6}, journal={Nature Communications}, author={Ramaswami, G. and Deng, P. and Zhang, R. and Carbone, M. A. and Mackay, T. F. C. and Li, J. B.} }
 @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{magwire_yamamoto_carbone_roshina_symonenko_pasyukova_morozova_mackay, title={Quantitative and molecular genetic analyses of mutations increasing Drosophila life span}, volume={6}, number={7}, journal={PLoS Genetics}, author={Magwire, M. M. and Yamamoto, A. and Carbone, M. A. and Roshina, N. V. and Symonenko, A. V. and Pasyukova, E. G. and Morozova, T. V. and Mackay, T. F. C.} }
 @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.} }
 @article{garcia_carbone_mackay_anholt, title={Regulation of Drosophila lifespan by bellwether promoter alleles}, volume={7}, journal={Scientific Reports}, author={Garcia, J. F. and Carbone, M. A. and Mackay, T. F. C. and Anholt, R. R. H.} }
 @article{huang_lyman_lyman_carbone_harbison_magwire_mackay, title={Spontaneous mutations and the origin and maintenance of quantitative genetic variation}, volume={5}, journal={Elife}, author={Huang, W. and Lyman, R. F. and Lyman, R. A. and Carbone, M. A. and Harbison, S. T. and Magwire, M. M. and Mackay, T. F. C.} }
 @article{mackay_richards_stone_barbadilla_ayroles_zhu_casillas_han_magwire_cridland_et al., title={The Drosophila melanogaster genetic reference panel}, volume={482}, number={7384}, journal={Nature}, author={Mackay, T. F. C. and Richards, S. and Stone, E. A. and Barbadilla, A. and Ayroles, J. F. and Zhu, D. H. and Casillas, S. and Han, Y. and Magwire, M. M. and Cridland, J. M. and et al.}, pages={173–178} }
 @article{shorter_geisz_ozsoy_magwire_carbone_mackay, title={The effects of royal jelly on fitness traits and gene expression in Drosophila melanogaster}, volume={10}, number={7}, journal={PLoS One}, author={Shorter, J. R. and Geisz, M. and Ozsoy, E. and Magwire, M. M. and Carbone, M. A. and Mackay, T. F. C.} }
 @article{carnes_campbell_huang_butler_carbone_duncan_harbajan_king_peterson_weitzel_et al., title={The genomic basis of postponed senescence in Drosophila melanogaster}, volume={10}, number={9}, journal={PLoS One}, author={Carnes, M. U. and Campbell, T. and Huang, W. and Butler, D. G. and Carbone, M. A. and Duncan, L. H. and Harbajan, S. V. and King, E. M. and Peterson, K. R. and Weitzel, A. and et al.} }