Progress 10/01/05 to 09/30/10
Outputs
OUTPUTS: This project has terminated. We completed the gene expression profiling of imaginal discs in 24 mutant backgrounds, the sequencing of the regulatory regions of the same mutations in 100 wild-type lines of flies, and the measurement of wing shape in the mutant and wild-type lines. Unfortunately, nothing particularly noteworthy emerged from the analyses and the take-home message is that performance of systems genetics is considerably more complex than we had envisaged. In the 5 years since the project commenced, the arrival of genomewide association study technology dramatically changed the genetics research landscape and has forced us to reevaluate the role of Drosophila genetics. Students from the laboratory are now pursuing new strategies. PARTICIPANTS: Ian Dworkin, Post-doctoral Fellow, Now Assistant Professor at Michigan State University. TARGET AUDIENCES: Nothing significant to report during this reporting period. PROJECT MODIFICATIONS: Not relevant to this project.
Impacts
There was no activity on this project for the last two years since the PI left NC State. Data analysis has continued, but as indicated above, there are no substantial impacts of the findings to date other than the two negative results that (i) networks of gene expression are pervasive but do not correlate with aspects of wing shape or the known developmental biology of the wing,and (ii) candidate gene genetic association studies in Drosophila are of limited value as it is impossible to interpret the significance in light of new standards.
Publications
- Dworkin IM, E Kennerly, D Tack, J Hutchinson, J Brown, J Mahaffey & Gibson G. 2009. Genomic consequences of background effects on scalloped mutant expressivity in the wing of Drosophila melanogaster. Genetics 181: 1065-1076.
- Goering LM, P Hunt, C Heighington, C Busick, P Pennings, J Hermisson, S Kumar & G Gibson. 2009. Association of orthodenticle with natural variation for early embryonic patterning in Drosophila melanogaster. J Exp Zool B. Mol Dev Evol 312B: 841-854.
- Drosophila 12 Genomies Consortium. 2007. Evolution of genes and genomes in the Drosophila phylogeny. Nature 450: 203-218.
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Progress 10/01/06 to 09/30/07
Outputs
OUTPUTS: We have made incremental project toward the goals of the project. Promoter regions of two dozen genes have been sequenced in 100 lines, and analysis of this data is ongoing. The wing imaginal disc microarray has been developed, and applied to a first large dataset, but we are still evaluating the results.
PARTICIPANTS: Ian Dworkin, Post-Doc Lisa Goering, Post-Doc Julie Brown, Research Technician Stephanie Williams, Undergraduate
TARGET AUDIENCES: The general genetics research community
PROJECT MODIFICATIONS: None
Impacts
The project cannot be evaluated in terms of short-term impacts. We are investigating basic genetic principles whose value can only be evaluated over the long term. Two post-doctoral fellows have graduated to faculty positions elsewhere.
Publications
- Passador-Gurgel, G., W-P. Hsieh, P.K. Hunt, N. Deighton, and G. Gibson (2007) Quantitative trait transcripts for nicotine resistance in Drosophila melanogaster. Nature Genetics 39: 264-268
- Ocorr, K.A., T. Crawley, G. Gibson and R. Bodmer (2007) Genetic variation for cardiac dysfunction in Drosophila. PLoS ONE 2: e601
- Hsieh, W.P., G.Passador-Gurgel, E.A. Stone and G. Gibson (2007) Mixture modeling of transcript abundance classes in natural populations. Genome Biol. 8(6): R98
- Bushel, P.R., R.D. Wolfinger and G. Gibson (2007) Simultaneous clustering of gene expression data with clinical chemistry and pathological evaluations reveals phenotypic prototypes. BMC Syst Biol. 1: 15.
- Gibson, G. and Goldstein, D. (2007) Human genetics: the hidden text of genome-wide associations. Curr Biol. 17: R929-R932.
- Gibson, G. (2007) Human evolution: thrifty genes and the dairy queen. Curr Biol. 17: R295-R296.
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Progress 10/01/05 to 09/30/06
Outputs
Research on the quantitative genetics of wing shape using systems biology approaches is proceeding apace. We have one manuscript published in Genetics that shows that heterozygosity for the vast majority of genes involved in patterning the shape of the wing have subtle but highly significant effects on wing shape. Intriguingly, two major growth factor pathways (EGF and TGF) produce overlapping phenotypes rather than a modular collection of effects. A second manuscript will be submitted shortly, for the first time showing that whole genome expression profiling can be used to identify genes that modify major effect mutations for morphogenesis. In addition, we have designed and received a custom Illumina BeadArray platform for studying wing imaginal disc patterning, and over the next four months will be carrying out over 200 hybridizations designed to study the association between gene expression and quantitative aspects of wing patterning. Other work in the lab related
to this project has also been highly successful. A paper has just been accepted in the premier journal Nature Genetics that shows that nicotine resistance in fruitflies is affected by activity of the enzyme Ornithine amino transferase, and by Glutamate/GABA activity in the nervous system. Encouraged by these results, we are pushing the work in a new direction, namely systems biology of metabolic syndrome (obesity, insulin resistance, and heart arrhythmia) in Drosophila, and expect that this will be a focus of future reports.
Impacts
This particular research will not have an immediate impact. It is part of a long-term research program that addresses very fundamental questions about the nature of genetic variation. While the methods and ideas are sure to influence thinking in relation to animal and plant breeding, they will probably have a greater influence in the domain of evolutionary genetics, and possibly human genetics. The central idea that we are advocating is that a major source of genetic susceptibility for disease is the breakdown of homeostatic (buffering) mechanisms. Before we can get there, though, we need to be able to describe genetic variation at the nucleotide level, hence the esoteric work being conducted. The Quantitative Trait Transcript (QTT) method that we have just had accepted at Nature Genetics is a good example: reviewers commented that the approach should have broad application in agricultural and biomedical genetics.
Publications
- Passador-Gurgel, G., W-P. Hsieh, P.K. Hunt, N. Deighton, and G. Gibson (2006) Quantitative trait transcripts for nicotine resistance in Drosophila melanogaster. Nature Genetics, in press.
- Dworkin, I.D. and G. Gibson (2006) Epidermal Growth Factor Receptor and Transforming Growth Factor-beta Signaling Contributes to Variation for Wing Shape in Drosophila melanogaster. Genetics, 173: 1417-1431.
- Ayroles, J.F. and G. Gibson (2006) Analysis of Variance of Microarray Data. Methods Enzymol. 411: 214-233.
- Gibson, G. (2006) The plastic transcriptome Curr Biol. 16: R285-287.
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Progress 10/01/04 to 09/30/05
Outputs
The purpose of this proposal is to apply systems biology approaches to quantitative genetic dissection of the role of signal transduction using wing patterning in Drosophila as a model trait. The objective is to be able to extract predictive information from highly complex datasets linking genotypic, transcriptional, and phenotypic variation, and to use genetic manipulation to evaluate the causal links. In Year 1, our three specific aims were to (i) establish a panel of 50 viable P-element mutations introgressed into two wildtype isogenic backgrounds and characterize the phenotypic matrix in this resource; (ii) establish a new panel of 210 nearly isogenic lines from two localities to supplement our 5-year old collection; and (iii) initiate sequencing of approximately 20 kb of regulatory DNA from 10 genes involved in wing patterning in the 210 nearly isogenic lines. The first two specific aims have been completed successfully, and work on the third aim has commenced.
Post-Doc Ian Dworkin has characterized the phenotypic effects of introgression of 50 wing patterning mutants in a study that makes two significant points. First, ninety percent of these mutations have quantitative effects as heterozygotes, implying that polymorphisms in signal transduction pathways does potentially contribute to natural variation. Second, while some of the quantitative effects are easily interpreted in light of the expression pattern and known function of the genes, overall there is surprisingly little correspondence between quantitative phenotypic effects and gene ontology. That is, the matrix of phenotypes does not clearly match functional assignments based on membership of a particular signaling pathway, and the network of quantitative interactions is likely to be difficult to predict and possibly non-modular. We have also completed the analysis of data from the previous grant cycle, resulting in two publications that together clearly establish that a specific SNP
polymorphism in the regulatory region of Egfr accounts for as little as 1 percent of wing shape variation. The importance of this work is that it establishes for the first time that linkage disequilibrium mapping in flies can dissect QTL to the level of individual nucleotides. Work of this nature has rarely been performed outside humans, though it has major implications for the nature of variation for numerous agronomically important traits. The picture of quantitative genetic variation that we are finding contrasts somewhat with the conclusions based on much lower-resolution linkage mapping of QTL in pedigrees that have dominated the past decade of research. Specifically, for the first time we are able to switch the focus from major-effect factors, back to the crucial role of modifiers and standard segregating variation. Finally, three other reviewed manuscripts, one demonstrating genetic variation for signal transduction during embryogenesis, were published in 2005, along with four
commentaries, a book chapter, and a review of transcription profiling.
Impacts
This particular research will not have an immediate impact. It is part of a long-term research program that addresses very fundamental questions about the nature of genetic variation. While the methods and ideas are sure to influence thinking in relation to animal and plant breeding, they will probably have a greater influence in the domain of evolutionary genetics, and possibly human genetics. The central idea that we are advocating is that a major source of genetic susceptibility for disease is the breakdown of homeostatic (buffering) mechanisms. Before we can get there, though, we need to be able to describe genetic variation at the nucleotide level, hence the esoteric work being conducted. Other research recently initiated in our laboratory, motivated in part by this Drosophila work, will have a more direct clinical/translational bearing. We have begun to investigate the genetic basis for disease and drug response in canine breeds, and expect that the
pharmacogenetic approaches being developed may influence research on a range of livestock on campus.
Publications
- Palsson, A., J. Dodgson, I. Dworkin and G. Gibson. (2005) Tests for the replication of an association between Egfr and natural variation in Drosophila melanogaster wing morphology. BMC Genet. 6: 44.
- Dworkin, I., A. Palsson, and G. Gibson. (2005) Replication of an Egfr-wing shape association in a wild-caught cohort of Drosophila melanogaster. Genetics 169: 2115-2125.
- Moser, J.M., T. Freitas, P. Arasu and G. Gibson. (2005) Gene expression profiles associated with the transition to parasitism in Ancylostoma caninum larvae. Mol Biochem Parasitol. 143: 39-48.
- Thomson, S., E. Kennerly, N. Olby, J. Mickelson, D. Hoffmann, P. Dickinson, G. Gibson, and M. Breen. (2005) Microarray analysis of differentially expressed genes of primary tumors in the canine central nervous system. Veterinary Pathology 42: 550-558.
- Goering, L.M. and G. Gibson. (2005) Genetic variation for dorsal-ventral patterning of the Drosophila melanogaster eggshell. Evol Devt , 7: 81-88.
- Gibson, G. and B.S. Weir (2005) The quantitative genetics of transcription. Trends Genet. 21: 616-623.
- Gibson, G. (2005) The Origins of Stability Science 310: 237.
- Gibson G. (2005) Q & A. Curr Biol. 15: R531-R532.
- Gibson, G. (2005) The synthesis and evolution of a supermodel. Science 307: 1890-1891.
- Gibson, G. (2005) Mutational accumulation of the transcriptome. Nature Genetics 37: 458-460.
- Gibson, G. (2005) Population genomics: patterns of genetic variation within populations. Chapter 99 in Encyclopedia of Genetics, Genomics, Proteomics and Bioinformatics. L. Jorde, P. Little, M. Dunn and S. Subramaniam, eds. Wiley and Sons, London..
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Progress 10/01/03 to 09/30/04
Outputs
This project is nearing completion as we have essentially completed each of the specific aims of the original proposal. In the past year, we have published the two major studies summarizing the wing-shape results in the journal Genetics, and submitted two follow-up studies for publication, and published a half-dozen other papers including a major review. A proposal to the NIH to continue the research in new directions has received a high-priority score and is likely to be funded in 2005. The major results of our investigations are (1) that the properties of linkage disequilibrium mapping are highly specific to each species under investigation, and (2) that we can map quantitative trait loci to the single nucleotide level. Consequently, Drosophila turns out not to be a good model for the experimental design in agricultural genetics, but it possesses distinct advantages that allow more fine-scale dissection of quantitative traits and hence insight into the nature of
segregating variation than is possible with mammals. Specifically, we have identified several single nucleotide polymorphisms (SNPs) that explain as little as one percent of the segregating variation for wing shape in natural populations. Statistical methods were developed for describing wing shape objectively and rigorously, and it was demonstrated that sex and population of origin greatly impact the architecture of genetic variation. The quantitative trait nucleotides (QTN) for wing shape are not the same as those for photoreceptor determination or embryonic eggshell patterning, nor do they correspond to the SNPs that show evidence for heterogeneous population structure. All of these results hint at hitherto unrecognized complexity in the relationship between molecular and phenotypic variation. Our studies emphasize the highly polygenic nature of natural variation, in contrast with the "major effect locus" emphasis that has dominated quantitative genetics in the QTL era. In the
continuation of the project, we will switch our focus from the EGFR locus to the regulatory regions of 25 genes, and include gene expression profiles as an intermediate trait between genotype and phenotype. We are thus working toward a systems biology approach, recognizing that network theory and holistic analysis of biological systems are set to challenge the reductionist single-gene paradigm that has predominated in biomedical and agricultural genetics for the past decade.
Impacts
This research addresses basic questions of the structure of genetic variation, and is most relevant for the insight it gives into general principles of the biology of complex traits and of evolutionary processes. The impact cannot be measured in dollars or yield, but rather in the long-term influence on the way geneticists approach the dissection of complex traits. That our research is having such an impact is evidenced by the renewal of our NIH award, the invitation to review cryptic genetic variation for Nature Reviews Genetics, and the adoption of our microarray analysis methods by investigators in several countries. With Spencer Muse in the Dept of Statistics, I have also completed the Second Edition of our popular textbook "A Primer of Genome Science," adopted by approaching 50 graduate and undergraduate classes and translated into French, Italian, and Chinese. It will be published by Sinauer Associates (Sunderland, MA) in December 2004.
Publications
- Palsson, A., Rouse, A., Riley-Berger, R., Dworkin, I. and Gibson, G. 2004. Nucleotide variation in the Egfr locus of Drosophila melanogaster. Genetics 167:1199-1212.
- Palsson, A. and Gibson, G. 2004. Association between nucleotide variation in Egfr and wing shape in Drosophila melanogaster. Genetics 167:1187-1198.
- Gibson, G., Riley, R., Harshman, L., Kopp, A., Vacha, S., Nuzhdin, S. and Wayne, M. 2004. Extensive sex-specific non-additivity of gene expression in Drosophila melanogaster. Genetics 167:1791-1799.
- Gibson, G. and Dworkin, I.M. 2004. Uncovering cryptic genetic variation. Nature Reviews Genetics 5:681-691.
- Honeycutt, E. and Gibson, G. 2004. Use of regression methods to identify motifs that modulate germline transcription in Drosophila melanogaster. Genetical Research 83:177-188.
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Progress 10/01/02 to 09/30/03
Outputs
Specific Aim 1. Linkage Disequilibrium Mapping with the Drosophila EGFR Pathway. This aim is almost completed. We have completed the sequencing of 11 kb of the EGFR locus and 5 kb of hedgehog in 210 near isogenic lines. This represents by far the largest molecular evolutionary study in a non-mammalian organism to our knowledge. The size of the dataset has allowed us to (i) characterize haplotype structure over the entire locus (an issue of increasing importance and significance in all quantitative genetic mapping, particularly in relation to human disease); (ii) demonstrate the existence of population structure between African and American samples and more subtly between Californian and North Carolinian samples; (iii) conduct a comprehensive analysis of SNP associations that has led to the development of locus-wide tests as a complement to site-wise tests used by Drosophila geneticists to date; and (iv) use comparative genome data to infer the effect of purifying
selection on variation over the extent of the locus. Although we now know that Drosophila cannot be used as a direct model for linkage disequilibrium mapping in humans, it does serve as an indirect paradigm for fine-structure dissection of complex phenotypes. Specific Aim 2. Replication of Associations Using the TDT Approach. We have demonstrated that population-based tests of association similar to those now being employed in human genetic epidemiology can also be applied to Drosophila. A highly significant association between a set of synonymous substitutions in the EGFR and cryptic variation for photoreceptor determination was confirmed in the progeny of 1000 crosses involving freshly caught wild flies using modified TDT and Case-Control designs. This approach has great promise for simplifying association confirmation in model organisms. Specific Aim 3. Fine Structure Dissection of Associations in Different Populations. During the course of this study, the question of population
stratification has become prominent in quantitative genetics. We have thus focused on replicating our results in different populations and with slightly different experimental designs. One of our focal traits, wing shape, is particularly interesting from this perspective as it is stratified by population, but recent results suggest that it is also affected by laboratory breeding procedures. We are exploring the implications for molecular quantitative dissection in flies. Comparison of all of this data as well as parallel studies with the Serotonin receptors and heart rate will keep us, and theoretical colleagues, busy with analysis for a couple of years to come.
Impacts
This research addresses basic questions of the structure of genetic variation, and is most relevant for the insight it gives into general principles of the biology of complex traits and of evolutionary processes. One of our studies was written up in "The Economist" in October 2003, under the heading "Genetics Gets More Complex," nicely summarizing the proposition that although geneticists have increased their ability to identify genes that have large effects, we are beginning to appreciate the complexity of the underlying genetics that actually accounts for most of the variation around us. The methods that we are developing will then help others apply similar approaches to dissection of agriculturally important traits in plants, animals, and microbes. Several groups just at NCSU have adopted some of our methods in the research on, for example, tobacco, lactophilic bacteria, and maize.
Publications
- Hsieh, W.-P., Chu, T.-M., Wolfinger, R., and G. Gibson. (2003) Genetics, 165: 747-757. Mixed model reanalysis of primate data suggests tissue and species biases in oligonucleotide-based gene expression profiles.
- Dworkin, I., A. Palsson, K. Birdsall, and G. Gibson. (2003) Current Biology, 13: 1888-1893. Evidence that EGFR contributes to cryptic genetic variation for photoreceptor determination in natural populations of Drosophila melanogaster.
- Riley, R., W. Jin, and G. Gibson. (2003) Molecular Ecology, 12: 1315-1323. Contrasting selection pressures on components of Ras-mediated signal transduction in Drosophila.
- Palsson, A. and G. Gibson. (2003) Genetics, in press. Association between nucleotide variation in EGFR and wing shape in Drosophila melanogaster.
- Gibson, G. (2003) PLoS Biology 1: 28-29. Microarray analysis: Genome scale hypothesis scanning.
- Gibson, G. (2003) Heredity 90: 1-2. Population genomics: Celebrating individual expression.
- Purugganan, M. and Gibson, G. (2003) Molecular Ecology 12: 1109-1112. Merging ecology, molecular evolution, and functional genetics.
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Progress 10/01/01 to 09/30/02
Outputs
In 2002 we have made substantial progress in understanding the statistical properties of genetic association studies in the fruitfly, Drosophila melanogaster. We have assembled the largest population sequence dataset that I am aware of, consisting of 10 kilobases of the EGFR locus from 200 different wild-type strains of flies. This was used to characterize the distribution of molecular variation, leading to the conclusion that the genetic architecture of a typical gene in Drosophila is quite unlike that of humans or most vertebrates, but remarkably similar to that of maize. Specifically, flies are an order of magnitude more polymorphic than humans, and display very little haplotype structure. These features make association studies much more difficult than envisaged at the start of the project. Nevertheless, we have been able to detect statistically significant associations between a handful of polymorphisms and two aspects of wing shape, as well as eye development.
In the next year, we will likely use this data to argue that genetic variation in flies cannot be dissected with high confidence to the nucleotide level, making conclusions with respect to the evolution of morphological differences much more complex than hitherto thought. We will also expand our analysis to two other candidate genes, and concentrate on the development of novel statistical tools for analysis of very large sequence and morphological datasets. Also in 2002, we completed a study contrasting selection pressures acting at different levels of the Ras signal transduction pathway in Drosophila. We showed that unlike central metabolism, this key regulatory pathway does not experience balancing selection but rather is subject to strong purifying selection. Genes further downstream in the pathway are less constrained, suggesting that the control point of the pathway is at the top, where signals are received from other cells. The next challenge is to relate this control to the
kinetic properties of enzyme function in pleiotropic contexts. Unfortunately, these results do not explain whether the Ras pathway itself contributes to morphological variation.
Impacts
Mapping of the genes that affect susceptibility to disease in animals, or yield and other agriculturally important traits in plants, has entered a new era with advances in genomics in the past two years. Our studies will help in the development of novel statistical tools as well as the interpretation of results pertaining to the genetic basis and evolution of complex traits.
Publications
- R. Riley, W. Jin and G. Gibson. (2003) Contrasting selection pressures on components of the Ras-mediated signal transduction pathway in Drosophila. Molecular Ecology, In press.
- Gibson, G. (2002) Developmental evolution: Getting robust about robustness. Current Biology 12(10): R347-R349
- Gibson, G. (2002) Developmental evolution: A genetic attack on the defense complex. Bioessays 24(6): 487-48
- Gibson, G., and T.F.C. Mackay (2002) Enabling population and quantitative genomics. Genetical Research 80: 1-6.
- Gibson, G. (2002) Microarrays in ecology and evolution: a preview. Molecular Ecology 11: 17-24.
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Progress 10/01/00 to 09/30/01
Outputs
This year we have not published any papers on this project, but we do expect to write at least three papers in 2002. We have made progress on three fronts: we have assembled one of the largest single gene DNA sequence polymorphism datasets for any organism, namely 12 kilobases of the EGFR locus in almost 200 individual lines (including over 250 single nucleotide polymorphism genetic variants); we have thoroughly characterized wing shape and several other phenotypes in the 200 lines; and we have begun work on a new analytical approach known as "Multitrait Association Mapping", which will allow us to make conclusions about the relationship between molecular and phenotypic variation in this model system. One thing we have learnt to date is that the levels of polymorphism are so high, and linkage disequilibrium so low, in Drosophila, that we cannot perform the same types of genome scan as human geneticists are proposing. We are nevertheless well on track toward completing
the aims of the NCARS project.
Impacts
The work to date has simply laid the foundation for our major study, whose major impact will be as a contribution to quantitative genetic analytical methodology.
Publications
- No publications reported this period
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Progress 10/01/99 to 09/30/00
Outputs
In 2000 we had three manuscripts published, and have made substantial progress toward the major goal of the funding period, namely performance of genotype-phenotype asociation studies. The three papers showed (i) that wing shape has a higher heritability than wing size, and can can be characterized using geometric morphometric parameters, (ii) the the genetic architecture of wing shape is extremely complex and involves between 50 and 100 QTL, possibly with sex and temperature-specific effects, many of which map near members of the EGF-signal transduction pathway, and (iii) that quanititative complementation tests can be used to determine whether variation in particular genes is contributing to phenotypic variance for wing shape. Based on these results, we have chosen two genes for detailed analysis: the Epidermal Growth Factor Receptor (EGFR) and argos, an inhibitor of the EGFR. We have sequenced 12 kb of each gene in 36 individuals and characterized over 400 single
nucleotide polymorphisms. In parallel, a set of 150 isogenic lines have been constructed, and these will be phenotyped and genotype in 2001, completing the low-resolution phase of our study.
Impacts
The work to date has simply laid the foundation for our major study, whose major impact will be as a contribution to quantitative genetic analytical methodology.
Publications
- Birdsall, K., Zimmerman, E., Teeter, K. and Gibson, G. (2000) Genetic variation for the positioning of wing veins in Drosophila melanogaster. Evol. Dev 2: 16-24
- Zimmerman, E., Palsson, A. and Gibson, G. (2000) Quantitative trait loci affecting components of wing shape in Drosophila melanogaster. Genetics 155: 671-683
- Palsson, A. and Gibson, G. (2000) Quantitative developmental genetic analysis reveals that the ancestral dipteran wing vein prepattern is conserved in Drosophila melanogaster. Dev Genes Evol 210: 617-622
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Progress 10/01/98 to 09/30/99
Outputs
Our work from 1999 has been written up as three papers, one of which is accepted for publication in Evolution and Development, one has been revised according to reviewers' requests at Genetics, and the third will be submitted in January 2000. 1. Genetic variation for the positioning of wing veins in Drosophila melanogaster. This study established that wing shape is more tightly regulated than wing size across environments. We introduced the use of relative warps as a robust statistical approach for the characterization of shape variation within a species. Despite large differences in wing size, cell number, and cell density across regions of the wing in flies of both sexes and grown at different temperatures, wing shape is remarkably genotype-specific. This led us to develop the hypothesis that wing shape is controlled in large part by gene activity at the level of wing vein determination and differentiation. 2. Quantitative Trait Loci affecting Components of Wing
Shape in Drosophila melanogaster. Two composite multiple regression-interval mapping experiments were performed to identify candidate quantitative trait loci affecting components of wing shape in Drosophila melanogaster. One analysis used a panel of recombinant inbred lines and an existing high resolution genetic map based on transposon insertion sites. The other involved a reciprocal backcross design and single nucleotide polymorphism (SNP) markers. A large number of genes were found to regulate various aspects of wing shape in different compartments of the wing, and support was found for linkage of genes in the EGF and TGF pathways with significant QTLs. This study presents the first use of relative warps for QTL mapping. It established the Ras pathway as our major candidate pathway for assoiciation studies that will be performed over the next two years. 3. Quantitative developmental genetic analysis reveals that the ancestral dipteran wing vein prepattern is conserved in Drosophila
melanogaster. Quantitative complementation tests were used to provide a quick test of the hypothesis that particular wing morphogenesis genes contribute to segregating phenotypic variation. Analysis of 15 loci known to be involved in wing patterning in Drosophila melanogaster suggests that the genes decapentaplegic, thickveins, EGFR, argos and hedgehog, each of which are involved in secreted growth factor signaling, may contribute to wing shape variation. We also found an atavistic mutation that in certain genetic backgrounds reveals that the ancestral wing venation pattern is highly conserved in Drosophila after more than 100 million years of apparent disuse. In addition to these studies, we have published three other papers (see below) dealing with quantitative variation in Drosophila, and made substantial progress in development of heart rate and behavior as model systems for quantiative genetic analysis in Drosophila.
Impacts
In 1999 we established the foundation for large scale association tests by identifying the epidermal and transforming growth factor pathways as likely regulators of wing shape. Since these pathways are central to many aspects of development throughout the animal kingdom, as well as to oncogenesis, definition of the functional effects of variation in the genes is of great interest.
Publications
- No publications reported this period
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