The Genomic Basis of Adaptation

We are interested in the genomics of adaptation, using the fruit fly Drosophila melanogaster as an experimentally tracable model. The components of fitness, so-called life-history traits (e.g., growth, size, fecundity, survival, lifespan), are fundamentally important for adaptation because they represent the targets of selection at the phenotypic level. However, still little is known about the genetic basis of variation and evolutionary changes in such fitness-related traits. Similarly, the mechanisms that maintain the large amount of genetic variation in fitness components in natural populations remain incompletely understood. The questions we ask in our research group include:

 

  • What are the loci underlying life-history adaptation?
  • How does lifespan evolve? What are the costs of longevity?
  • Why does reproduction shorten lifespan?
  • What is the genomic basis of local adaptation along clines?
  • How do inversions and supergenes shape adaptation?

 

We study these questions in the context of life-history clines across latitudinal gradients, inversion polymorphisms maintained by spatially varying selection, and the evolution of aging and trade-offs associated with longevity. To address these longstanding problems we combine genetics, genomics, physiology, and experimental evolution and apply them to natural and laboratory populations of D. melanogaster that are phenotypically differentiated for fitness-related traits.

 

  • What loci underlie life-history evolution?

    "...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)

     

    We have a major interest in identifying the genes and molecular polymorphisms that underpin variation in fitness components (so-called life-history traits), such as body size, reproduction and lifespan, and in determining how they contribute to adaptation. The identification of such life-history polymorphisms allows addressing fundamental questions about the genetic basis of adaptation, including:

     

    • Which pathways underpin life-history variation?
    • Are these mechanisms evolutionarily conserved?
    • What are the effects of life-history polymorphisms?
    • What is the molecular basis of life-history pleiotropy?
    • To what extent is life-history evolution ‘predictable’?

     

    Over the past 9 years, we have been using two complementary approaches to identify naturally occurring polymorphisms that underlie evolutionary changes in life history: to generate "catalogs" of candidate variants we have applied whole-genome next-generation sequencing to (1) life-history clines, i.e. natural populations of fruit flies that are clinally (latitudinally) differentiated for major life history traits (e.g., size, fecundity, lifespan, stress resistance, and reproductive dormancy) along the North American east coast and (2) a >30-year-long artificial selection experiment for longevity, first published by Luckinbill et al. (1984) in Evolution.

    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 are performing experiments to examine and validate the putative life-history effects of these candidates.

    Based on our genomic analyses, we have prioritized three candidate mechanisms for functional assays: (1) clinally varying alleles in insulin signaling, a pathway known to regulate life-history physiology; (2) a clinal chromosomal inversion polymorphism to which 80% of the most strongly clinal SNPs in the genome map; and (3) immunity genes that - interestingly - are quantitatively enriched among the candidate genes in the above-mentioned "evolve and resequence" experiment for longevity.

     

    Some of our work on life-history clines

    Durmaz, E., Benson, C., Kapun, M., Schmidt, P., and T. Flatt. 2018. An Inversion Supergene in Drosophila Underpins Latitudinal Clines in Survival Traits. Journal of Evolutionary Biology 31: 1354-1364.

    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 29:1059-1072.

    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.

    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.

    Fabian, D.K., Kapun, M., Nolte, V., Kofler, R., Schmidt, P.S., Schlötterer, C. and T. Flatt. 2012. Genome-wide patterns of latitudinal differentiation among populations of Drosophila melanogaster from North America. Molecular Ecology 21:4748–4769.

     

    Some of our work on aging and longevity

    Fabian, D.K., Garschall, K., Klepsatel, P., Santos-Matos, G., Sucena, E., Kapun, M., Lemaitre, B., Schlötterer, C., Arking, R., and T. Flatt. 2018. Evolution of longevity improves immunity in Drosophila. Evolution Letters 2(6):567-579.

    Flatt, T., and L. Partridge. 2018. Horizons in the Evolution of Aging. BMC Biology 16(1):93.

    Garschall, K., Dellago, H., Gáliková, M., Schosserer, M.,* Flatt, T.,* and J. Grillari. 2017. Ubiquitous overexpression of the DNA repair factor dPrp19 reduces DNA damage and extends Drosophila life span. npj Aging and Mechanisms of Disease 3:5. [*co-corresponding authors]

    Flatt, T., and P.S. Schmidt. 2009. Integrating evolutionary and molecular genetics of aging. Biochimica et Biophysica Acta 1790:951-962.

    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.

    Flatt, T. 2004. Assessing natural variation in genes affecting Drosophila lifespan. Mechanisms of Ageing and Development 125:155-159.

     

  • How do inversions affect adaptation?

    "Legend has it that, when asked why he robbed banks, Willie Sutton replied, “Because that’s where the money is”... This impeccable logic is equally useful to guide the hunt for genes that are evolving adaptively. Starting with Dobzhansky’s pioneering work, dozens of polymorphic chromosome inversions have been found that show signatures of strong selection... But despite decades of research on inversions, we still know little about which of the genes they carry are the targets of selection or how the polymorphisms themselves are maintained."

    (Kirkpatrick & Kern 2012, in Genetics)

     

    Chromosomal inversions are well known to suppress recombination. This fact, and the observation that many inversions form predictable clines, prompted Theodosius Dobzhansky in the 1940s to postulate that they represent „coadapted gene complexes“, epistatic combinations of linked adaptive loci. An alternative hypothesis posits that inversions evolve because they capture locally adapted alleles and protect them from maladaptive gene flow from other populations. However, although inversions are often considered to play a significant role in adaptation, the genic targets of selection carried by them or how they are selectively maintained is poorly understood. With very few exceptions, phased genomic data required to identify candidate targets of selection within inversions are not yet available, and how inversions affect fitness traits is largely unknown.

    In this project we aim to address these fundamental issues using D. melanogaster as a powerful experimental test bed, by applying population genomics, laboratory and field assays, and experimental genetics approaches to a cosmopolitan, clinally varying inversion polymorphism, In(3R)Payne. Although we have previously shown that this polymorphism is maintained by selection across latitudinal gradients, how selection does so remains unclear; yet, precisely because of its adaptive nature, this chromosomal rearrangement represents an ideal model system for studying the selective mechanisms that act on inversions.

     

    Some of our work on adaptive inversions

    Kapun, M., and T. Flatt. 2018. The adaptive significance of chromosomal inversion polymorphisms in Drosophila melanogaster. Molecular Ecology, in press.

    Durmaz, E., Benson, C., Kapun, M., Schmidt, P., and T. Flatt. 2018. An Inversion Supergene in Drosophila Underpins Latitudinal Clines in Survival Traits. Journal of Evolutionary Biology 31: 1354-1364.

    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 29:1059-1072.

    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.

    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.K., Kapun, M., Nolte, V., Kofler, R., Schmidt, P.S., Schlötterer, C. and T. Flatt. 2012. Genome-wide patterns of latitudinal differentiation among populations of Drosophila melanogaster from North America. Molecular Ecology 21:4748–4769.

     

  • How do trade-offs work mechanistically?

    “It would be instructive to know not only by what physiological mechanisms a just apportionment is made between the nutriment devoted to the gonads and that devoted to the rest of the parental organism, but also what circumstances in the life-history and environment would render profitable the diversion of a greater or lesser share of the available resources towards reproduction.”

    R. A. Fisher (1930), The Genetical Theory of Natural Selection

     

    Trade-offs, for example between fecundity and lifespan (so-called costs of reproduction) are ubiquitous, but still very little is known about their underlying genetic and physiological mechanisms. Interestingly, work in the nematode worm C. elegans indicates that reproduction and life span might be linked by molecular signals produced by reproductive tissues. In this species life span is extended if worms lack proliferating germ cells in the presence of an intact somatic gonad. The gonad might thus be the source of signals which physiologically modulate organismal aging.

    In previous work we have shown that such gonadal signals are also present in 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, modulates insulin signaling in peripheral tissues, and alters carbohydrate and fat metabolism. Thus, as of yet unidentified endocrine signals from the germline might converge onto insulin signaling to regulate aging and adult physiology.

    Our current work focuses on identifying the transcriptomic and hormonal mechanisms that underlie the physiological regulation of the trade-off between reproduction and somatic maintenance in the fly (e.g., survival, lifespan, stress resistance, immunity).

     

    Some of our work on life-history trade-offs and pleiotropy

    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 16:1-8.

    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, co-corresponding authors].

    Flatt, T., and A. Heyland (Eds.). 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.

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

    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.

    Flatt, T., Tu, M.-P., and M. Tatar. 2005. Hormonal pleiotropy and the juvenile hormone regulation of Drosophila development and life history. BioEssays 27:999-1010.

    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

     

Thomas Flatt

Professor  

Office PER 01 - 0.366b
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Department of Biology

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Switzerland