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    Time travel into the genome

    12/04/2015

    An international team of researchers has decoded the genome of the turquoise killifish. Biochemist Manfred Schartl from Würzburg was involved in the project. The results are interesting for ageing researchers but also provide insight into the evolution of sex determination.

    Neues Modellsystem in der Alternsforschung: der Türkise Prachtgrundkärpfling (Nothobranchius furzeri) (Foto: FLI / Nadine Grimm)
    New model system for aging research: Turquoise killifish (Nothobranchius furzeri) (Photo: FLI / Nadine Grimm)

    When observing the colorful Turquoise killifish swimming in its aquarium, it is difficult to believe that it can serve as a model system for human aging; but it does. An ever-growing number of researchers interested in aging are working with this fish due to its extremely short lifespan that – even under optimal housing conditions – does not extend beyond four to twelve months, hallmarked by fast growth and rapid aging. Indeed, the aging process of N. furzeri and humans share many common features, both being vertebrates. An international team of scientists from the Leibniz Institute on Aging – Fritz Lipmann Institute (FLI) – especially Kathrin Reichwald, Alessandro Cellerino, Christoph Englert and Matthias Platzer – alongside cooperating institutes, have now succeeded in deciphering and analyzing N. furzeri's genome. This milestone toward understanding the genetic control of human aging, and the results – together with a parallel study from colleagues at Stanford University – have now been published in the renowned Cell journal.

    Genome takes researchers into the past

    Looking into the genome of N. furzeri is also like travelling in a time machine. For the first time, the researchers could observe first steps of sex chromosome development in real time. An expert in the evolution of sex determination, Manfred Schartl from the Biocenter of the University of Würzburg has significantly contributed to the work. 

    "We know that nature has frequently redesigned the process of sex determination in many organisms during evolution – and that independently of one another," Manfred Schartl explains. In mammals this process is more than 300 million years old, whereas the development in N. furzeri is "relatively new" from the scientists' point of view: It took place about three million years ago. And what is more: "We had the benefit of being able to compare different fish populations from different river systems with each other, some of which were still in their primitive state, while the process of sex determination had already evolved in others," Schartl further. A look into the genome hence provides information as to when the changes first took place which are responsible for the existence of male and female specimens of a species. "These findings are new for us," Schartl says.

    Peering deep into the genome of N. furzeri is akin to traveling in a time machine. In this little fish, researchers can observe the development of sex chromosomes which occurred in mammals 300 million years ago. A new gene for sex determination has also been discovered. Gene gdf6, which in humans is relevant for bone growth, serves as genetic switch in N. furzeri, turning the fish embryos into males. "We already assumed the sex determination to be an evolutionary young mechanism, because X and Y chromosome of N. furzeri still look very similar", Kathrin Reichwald – Postdoc at the FLI and first author of the study – describes. "But finding this genetic switch is a real surprise"

    Nothobranchius genome publicly available

    Crucially, for those researchers who use N. furzeri as a model system, the sequencing of its genome and a large number of transcriptome data (i.e. which genes are switched on or off during the process of aging) are now publicly available to the research community. "The quality of this sequence is comparable to the first sequencing of the human genome as published 15 years ago, which revolutionized biomedical research at that time", enthuses Matthias Platzer – research group leader at the FLI and involved in both the human and fish genome sequencing progressions. "Certainly, a lot of details are still unclear especially with regard to the function of genes. But the most important cornerstone for further genetic analyses has been laid".

    "Hot Spots of Aging" on genome

    By comparing the aging process of fish brain, liver and skin, the FLI researchers found that the genes which are responsible for aging in N. furzeri are not spread randomly, but rather, are concentrated into specific small regions of the genome. "The discovery of  these aging hot spots in the genome lets us assume that the genes within these regions are somehow coordinated in their activation or de-activation ", comments Alessandro Cellerino. The Neurobiologist at the Scuola Normale Superiore in Pisa, Italy, is an associated Fellow at the FLI and, twelve years ago, was one of the first to propose N. furzeri as an aging model system. "Knowing how aging-relevant genes are organized and how they can be (in)activated may help to identify key mechanisms regulating human aging as well", Cellerino continues.

    Aging as Déjà-vu

    Another analysis focused on the patterns of gene activation during diapause, which the embryos of N. furzeri may undergo during the dry seasons. Astonishingly, the activation patterns share similarities with those observed during aging: protein production is increased, while cell division is hindered. In aging, this gene expression presumably occurs to compensate for the accumulation of protein damages; during diapause, the same genes may be activated to prepare the whole embryo to catch up with the interrupted development and be ready to hatch as the rainy season starts. Christoph Englert, a Professor for Molecular Genetics at Jena University and research group leader at the FLI has been working with N. furzeri for years.  He explains that "we are the first to show these similarities between gene activation in diapause and aging in vertebrates. This could be a new starting point to discover even more aging-relevant genes".

    (Source: Leibniz-Instituts für Alternsforschung / Dr. Evelyn Kästner)

    Insights into sex chromosome evolution and aging from the genome of a short-lived fish. Reichwald K, Petzold A, Koch P, Downie BR, Hartmann N, Pietsch S, Baumgart M, Chalopin D, Felder M, Bens M, Sahm A, Szafranski K, Taudien S, Groth M, Arisi I, Weise A, Bhatt SS, Sharma V, Kraus JM, Schmid F, Priebe S, Liehr T, Görlach M, Than ME, Hiller M, Kestler HA, Volff JN, Schartl M, Cellerino A, Englert C, Platzer M. Cell 2015. DOI: 10.1016/j.cell.2015.10.071

    Contakt

    Prof. Dr. Dr. Manfred Schartl, T: (0931) 31-84148, phch1@biozentrum.uni-wuerzburg.de  


    Background

    Nothobranchius furzeri owes its name to its discoverer Richard E. Furzer. The American had discovered the then unknown Nothobranchius species in former Rhodesia – today's Zimbabwe –in 1968 and taken it back home. The killifish belongs to the so-called toothcarps. The name comes from the Dutch word for drainage ditch (Kill). The fish were discovered in such ditches in the Dutch colonies of North America. Killifish are the oviparous species among toothcarps. Though the term is now obsolete scientifically, it is still commonly used by aquarists. (Source: Max-Planck-Gesellschaft)

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