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Flatt Group - Evolution & Mechanisms of Life History and Aging.

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“…integrating an understanding of mechanisms into life history theory will be one of the most exciting tasks facing evolutionary biologists in the 21st century.”

Barnes & Partridge (2003), in Animal Behaviour

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Our Research

The Flatt group studies the genetic and physiological mechanisms underlying the evolution of life history and aging.

The questions we ask include:

  • Which genes and molecular polymorphisms underlie the evolution of life history and aging in natural and evolved laboratory populations?
  • What is the genetic and physiological basis of life history variation along clinal gradients? What are the mechanisms underlying climatic (thermal) adaptation?
  • What is the role of chromosomal inversion polymorphisms in shaping life history? What are the mechanisms of selection that act on inversions? And what are the genic targets of selection contained within inversions?
  • What are the genetic and physiological mechanisms that underlie life history trade-offs? How – mechanistically – do “costs of reproduction” work? What is the nature of life history pleiotropy?
  • How do hormones physiologically mediate and modulate life history trade-offs?
  • What are the mechanisms underlying life history plasticity?

To address these questions we combine the tools of evolutionary and functional genetics, population genomics, physiology, experimental evolution and artificial selection, mainly by using the fruit fly (Drosophila melanogaster) as an experimental model.

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Currently we are interested in two major problems:

(1) Population Genomic Basis of Life History Adaptation

Life history traits are central to our understanding of adaptation because they represent direct targets of selection. However, while much progress has been made in uncovering the molecular mechanisms underlying fitness-related traits, mainly by studying large-effect mutants in model organisms, little is known about naturally occurring genetic variants that affect these traits. The central aim of this project is to identify naturally occurring polymorphisms that underlie evolutionary changes in life history, using Drosophila melanogaster as a model. Over the past few years, we have been using two complementary approaches to tackle this problem: to generate "catalogs" of candidate variants we have applied whole-genome Pool-sequencing to (1) North American populations clinally differentiated for life history and (2) a >30-year-long artificial selection experiment for longevity. Both approaches are "designed" to maximize among-population life-history differentiation and thus to increase our ability to map life-history variants via sequencing. In a second step, we have begun to perform experiments to examine the life-history effects of some of these candidate mechanisms. Based on our genomic analyses, we have prioritized three candidate mechanisms for experiments: (1) for the cline, we have identified clinal SNP polymorphisms in several genes involved in insulin signaling, a pathway known from molecular studies to regulate life-history physiology, including a clinal 2-SNP polymorphism in the transcription factor gene foxo; (2) a clinal chromosomal inversion polymorphism, In(3R)Payne, to which 79% of the most strongly clinal SNPs in the genome map; and (3), in the selection experiment, we have found strong enrichment of immunity genes among our top candidates. To date, our experiments show that (1) the foxo polymorphism has pleiotropic on egg-to-adult survival, body size and starvation resistance, in assays based on synthetic recombinant inbred lines; (2) the In(3R)Payne polymorphism is maintained by clinal selection, independent of neutrality and admixture, and affects body size, a strongly clinal trait; and (3) the long-lived selection lines survive pathogenic infections much better than the controls. We are currently working on in-depth functional experiments to better characterize these and other candidate mechanisms.

Further reading:
Kapun, M., Schmidt, C., Durmaz, E., Schmidt, P.S., and T. Flatt. 2016. Parallel effects of the inversion In(3R)Payne on body size across the North American and Australian clines in Drosophila melanogaster. Journal of Evolutionary Biology, in press.

Kapun, M., Fabian, D.K., Goudet, J., and T. Flatt. 2016. Genomic Evidence for Adaptive Inversion Clines in Drosophila melanogaster. Molecular Biology and Evolution 33:1317-1336.

Flatt, T. 2016. Genomics of clinal variation in Drosophila: disentangling the interactions of selection and demography. Molecular Ecology 25:1023-1026.

Fabian, D. K., Lack, J. B., Mathur, V., Schlötterer, C., Schmidt, P.S., Pool, J.E, and T. Flatt. 2015. Spatially varying selection shapes life history clines among populations of Drosophila melanogaster from sub-Saharan Africa. Journal of Evolutionary Biology, 28:826-840.

Klepsatel, P., Galikova, M, Huber, C.D., and T. Flatt. 2014. Similarities and differences in altitudinal versus latitudinal variation for morphological traits in Drosophila melanogaster. Evolution 68:1385-1398.

Kapun, M., van Schalwyk, H., McAllister, B., Flatt, T., and C. Schlötterer. 2014. Inference of chromosomal inversion dynamics from Pool-Seq data in natural and laboratory populations of D. melanogaster. Molecular Ecology 23:1813-1827.

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 21:4748–4769.

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 21:4931-4941 [Cover Article, with Cover Image] [Commentary by M. K. Burke and A. D. Long. 2012. What paths do advantageous alleles take during short-term evolutionary change? Molecular Ecology 21:4913-4916].

Flatt, T., and P.S. Schmidt. 2009. Integrating evolutionary and molecular genetics of aging. Biochimica et Biophysica Acta 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) Mechanisms Underlying the Reproduction-Longevity 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 whereby hormonal signaling mediates the trade-off between reproduction and life span.

Further reading:
Rodrigues, M.A., and T. Flatt. 2016. Endocrine uncoupling of the trade-off between reproduction and somatic maintenance in eusocial insects. Current Opinion in Insect Science, in press.

Flatt, T. 2015. Organ plasticity: Paying the costs of reproduction. eLife 2015;4:e09556. DOI: 10.7554/eLife.09556.

Hansen, M.,* Flatt, T.*, and H. Aguilaniu*. 2013. Reproduction, Fat Metabolism, and Life Span: What Is the Connection? Cell Metabolism 17:10-19. [*Equal contribution].

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

Flatt, T., and A. Heyland (Editors). 2011. Mechanisms of Life History Evolution. The Genetics and Physiology of Life History Traits and Trade-Offs. Oxford University Press, Oxford, UK. 478 pages, 75 illustrations, ISBN 978-0-19-956877-2.

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.

Funding

Funding
Our current and past research has been generously funded by:

  • Swiss National Science Foundation (SNSF)
  • Novartis Research Foundation
  • University of Lausanne (UNIL)
  • Department of Ecology and Evolution (DEE at UNIL)
  • Wissenschaftskolleg zu Berlin
  • Austrian Science Foundation (FWF)
  • Vetmeduni Vienna
  • Vienna Graduate School of Population Genetics (funded by FWF)
  • Austrian Research Promotion Agency (FFG) and Brainpower Austria
  • Roche Research Foundation (RRF)
  • Swiss Study Foundation
  • Dr. Max Husmann Foundation
  • Emilia Guggenheim-Schnurr Foundation

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Thomas Flatt
Office room: 2203
Phone: +4121 692 4203
Fax: +4121 692 4165
thomas.flatt[@]unil.ch

Administrative assistant
Office room: 3106
Phone: +4121 692 4200
Fax: +4121 692 4265
anne.cuendet[@]unil.ch

Biophore - CH-1015 Lausanne  - Switzerland  -  Tel. +41 21 692 41 60  -  Fax +41 21 692 41 65
Swiss University