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Lab ImageDr. Thomas Flatt

Institute of Population Genetics, University of Veterinary Medicine Vienna
Department of Biomedical Sciences,
Veterinaerplatz 1
Vienna, Austria A-1210
Austria

thomas.flatt@vetmeduni.ac.at

PI: YES
Taxa Studied: Invertebrate Animals
Techniques Employed: Quantitative PCR (qPCR), Microarrays, Solexa (Illumina) Sequencing, Bioinformatics/Sequence Analysis, QTL Mapping, SNP Mapping, In Situ Hybridization, Antibody Staining, Sectioning for Histology, Epifluoresence Microscopy, Confocal Microscopy, Transgenesis, Mutagenesis, Other, RNA interference(RNAi), Experimental evolution, artificial selection, mutant and transgene analysis, complementation testing, epistasis / gene interaction analysis, phenotypic manipulations, measuring demographic and life history traits, lifespan/survival assays, endocrine manip
Research Description: My lab studies the genetic and physiological mechanisms underlying the evolution of life history traits, with a particular emphasis on aging. How do life history traits evolve, within and among species, to generate phenotypic variation? What are the mechanisms underlying life history plasticity and trade-offs? Our central focus is on understanding how hormonal signaling pathways (e.g., insulin, juvenile hormone, and ecdysone) affect the phenotypic expression and evolution of aging and trade-offs between reproduction and lifespan, immune function, and somatic maintenance. To address these problems we combine the tools of evolutionary genetics, molecular genetics, and physiology in the fruit fly (Drosophila melanogaster) and closely related species. Currently we are interested in three problems: (1) Trade-Offs between Life Span and Reproduction Trade-offs between reproduction and lifespan are ubiquitous, but little is known about their underlying mechanisms. Recent work suggests that reproduction and life span might be linked by molecular signals produced by reproductive tissues. In the nematode C. elegans life span is extended if worms lack proliferating germ cells in the presence of an intact somatic gonad. This suggests that the gonad is the source of signals which physiologically modulate organismal aging. Our recent work has shown that such gonadal signals are also present in the fruit fly D. melanogaster, suggesting that the regulation of lifespan by the reproductive system is evolutionarily conserved. Ablation of germline stem cells in the fly extends lifespan and modulates components of insulin/insulin-like growth factor signaling (IIS) in peripheral tissues, a conserved pathway important in regulating growth, metabolism, reproduction, and aging. Thus, signals from the germline might converge onto IIS to regulate aging. Using a combination of experimental evolution and hormonal manipulation, we have also found that juvenile hormone (JH), a hormone downstream of IIS, mediates the physiological but not necessarily the evolutionary trade-off between lifespan and reproduction in Drosophila. Our current work focuses on understanding the details of how hormonal signaling mediates the trade-off between reproduction and life span. Further reading: Flatt, T., Min, K.-J., DÉ??Alterio, C., Villa-Cuesta, E., Cumbers, J., Lehmann, R., Jones, D.L., and M. Tatar. 2008. Drosophila germ-line modulation of insulin signaling and lifespan. Proceedings of the National Academy of Sciences USA 105:6368-6373. Flatt, T., and D.E.L. Promislow. 2007. Physiology: still pondering an age-old question. Science 318:1255-1256. Flatt, T., and T.J. Kawecki. 2007. Juvenile hormone as a regulator of the trade-off between reproduction and life span in Drosophila melanogaster. Evolution 61:1980-1991. (2) Trade-Offs between Reproduction and Immunity To defend themselves against pathogens, insects like Drosophila use an innate immune system, a primary defense evolutionarily conserved among metazoans. Insects have multiple mechanisms to combat pathogens. Infection or wounding stimulates proteolytic cascades in the host, causing blood clotting and activation of a prophenoloxidase cascade leading to melanization. Cellular immunity involves haemocytes which mediate phagocytosis, nodulation, and encapsulation of pathogens. Infections also induce an antimicrobial peptide (AMP) response. In a systemic infection, AMPs are produced in the fat body (equivalent of liver) and secreted into the hemolymph (blood). Preliminary evidence suggests that reproduction might compromise immune function, but the mechanisms underlying this trade-off remain unclear. Interestingly, in vertebrates, reproductive hormones such as testosterone can have immuno-suppressive effects. Similarly, work in C. elegans suggests that reproduction suppresses immunity by modulating insulin signaling. We have recently identified immuno-modulatory effects of two reproductive hormones in Drosophila, juvenile hormone (JH) and 20-hydroxy-ecdysone (20E), downstream of insulin signaling. However, whether and how these hormones co-regulate reproduction and immunity in the fly remains unclear. Since the effects of reproduction on immunity are likely to be evolutionarily conserved, D. melanogaster promises to provide an excellent system for identifying the endocrine mechanisms underlying the trade-off between innate immunity and reproduction. Further reading: Flatt, T., Heyland, A., Rus, F., Porpiglia, E., Sherlock, C., Yamamoto, R., Garbuzov, A., Palli, S.R., Tatar, M., and N. Silverman. 2008. Hormonal regulation of the humoral innate immune response in Drosophila melanogaster. Journal of Experimental Biology 211: 2712-2724. (3) Functionally Significant Genetic Variation in Aging We are also interested in the evolutionary and functional genetics of aging and related life history traits in natural populations. While molecular geneticists typically focus on major effects of induced mutations or transgenes, evolutionary geneticists work on much more subtle phenotypic differences caused by standing natural genetic variation, the substrate on which evolutionary change by natural selection is based upon. Although it is becoming increasingly clear that both molecular and evolutionary geneticists have been studying qualitatively different forms of genetic variation at the same loci, it is still unclear whether this also holds for genes affecting life span. For example, not all candidate loci with major effects on longevity may exhibit segregating allelic variation in natural populations. Thus, while the major lifespan effects identified by molecular gerontology may be of biomedical interest, they may be of only limited relevance for our understanding of the evolution of aging in natural populations. On the other hand, the rapid progress made by molecular biologists in identifying candidate mechanisms affecting aging enables evolutionary biologists to determine whether there is standing genetic variation for longevity genes in natural populations and whether they are under selection. We are interested in functionally characterizing natural allelic variation in genes known to affect Drosophila life span. Further reading: Flatt, T., and P.S. Schmidt. 2009. Integrating evolutionary and molecular genetics of aging. In: Masoro, E. J. (editor), É??Biochemical and Molecular Mechanisms of Aging - from Model Systems to Human LongevityÉ?Ě, Biochimica et Biophysica Acta (BBA É?? General Subjects) 1790:951-962 . Flatt, T., and T.J. Kawecki. 2004. Pleiotropic effects of Methoprene-tolerant (Met), a gene involved in juvenile hormone metabolism, on life history traits in Drosophila melanogaster. Genetica 122:141-160. Flatt, T. 2004. Assessing natural variation in genes affecting Drosophila lifespan. Mechanisms of Ageing and Development 125:155-159.
Lab Web Page: http://i122server.vu-wien.ac.at/pop/Flatt_website/flatt_home.html
Willing to Host Undergraduates: YES
Actively Seeking Undergraduates: NO
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