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Thomas Flatt

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Research Interests

We study the genetic and physiological mechanisms underlying variation in life history traits, in particular aging, to answer questions such as:

- How are life history traits developmentally and physiologically integrated?

- What are the mechanisms underlying trade-offs among life history traits?

- How do physiological mechanisms mediate life history plasticity?

- Which genes contribute to life history variation within and among species?

To address these problems we combine the tools of evolutionary genetics, quantitative genetics, experimental evolution and artificial selection, molecular genetics, physiology and genomics in the fruit fly (Drosophila melanogaster) and closely related species.

Currently we are interested in three problems:

 

(1) Functional Genetic Variation for Lifespan and other Life History Traits

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. To this end, we are working on the genomic characterization of latitudinal and altitudinal life history adaptations as well as of lines that were artificially selected for increased lifespan.

Further reading:

Fabian, D, Kapun, M., Nolte, V., Kofler, R., Schmidt, P.S., Schlötterer, C., Flatt, T. 2012. Genome-wide patterns of latitudinal differentiation among populations of Drosophila melanogaster from North America. Molecular Ecology, published online: 22 August 2012. DOI: 10.1111/j.1365-294X.2012.05731.x

Orozco-terWengel, P., Kapun, M., Nolte, V., Kofler, R., Flatt, T., Schlötterer, C. 2012. Adaptation of Drosophila to a novel laboratory environment reveals temporally heterogeneous trajectories of selected alleles. Molecular Ecology, published online: 21 June 2012. DOI: 10.1111/j.1365-294X.2012.05673.x

Flatt, T., and P.S. Schmidt. 2009. Integrating evolutionary and molecular genetics of aging. In: Masoro, E. J. (editor), “Biochemical and Molecular Mechanisms of Aging - from Model Systems to Human Longevity”, Biochimica et Biophysica Acta (BBA – 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.

 

(2) Hormonal Regulation of the Reproduction-Lifespan Trade-Off

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, as of yet unidentified endocrine signals from the germline might converge onto IIS to regulate aging. Using a combination of experimental evolution, hormonal manipulation, and genetics 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. In particular, we are currently studying the role of the steroid hormone ecdysone in this regulation.

Further reading:

Flatt, T. 2011. Survival costs of reproduction in Drosophila. Experimental Gerontology 46:369-375.

Galikova, M., Klepsatel, P., Senti, G., and T. Flatt. 2011. Steroid hormone regulation of C. elegans and Drosophila aging and life history. Experimental Gerontology 46:141-147.

Flatt, T., Min, K.-J., D’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.

 

(3) Endocrine Coordination of Reproduction and Humoral 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.

 

 

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