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Transgenerational Epigenetic Inheritance & Evolution

Peter Sarkies

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Medical Research Council (MRC)
Transposons, parasitic DNA segments that can copy themselves independently of the replication of their host genome, are abundant across metazoan organisms. Left unchecked, transposons pose a severe threat to genome integrity, thus organisms have evolved robust mechanisms in order to keep transposons in check. However, transposons are also an important source of genetic diversity, with many examples now documented of how transposon insertions lead to potentially beneficial genetic changes to organisms- indeed up to 40% of primate-specific gene regulatory elements are thought to have originated in this way. Thus the mechanisms that control transposons may themselves be regulated to ensure that they do not completely stifle transposon activity, thereby removing an important source of evolutionary novelty. We are interested in how this delicate balance is maintained, and whether it can be altered in order to facilitate adaptation of organisms to the environment. To address the question of how transposon silencing mechanisms are regulated to control the origin of evolutionary novelty we are using nematodes as a model system. Our main focus is piwi-interacting small RNAs (piRNAs), a transposon silencing pathway that is active in the germline and is conserved across metazoans. Just as in drosophila and mammal, piRNAs in the model nematode C. elegans are able to silence transposons and are important in maintaining the fertility of the animal over many generations. In addition, piRNAs are capable of establishing epigenetic changes that can be inherited for many generations independently of the presence of the initial piRNA trigger. However, we recently discovered that piRNAs are not found universally across the nematode phylum. In fact the entire piRNAs pathway is has been lost several times independently in different nematode lineages. Moreover, even in C. elegans, we showed in collaboration with Shawn Ahmed (University of North Carolina), that the loss of fertility that occurs in animals lacking the piRNA pathway can be completely suppressed by mutations compromising insulin signalling pathways. These two unusual aspects of the nematode piRNA system mean that nematodes offer a unique advantage to study what happens to genome evolution in the absence of the piRNA pathway. By using comparative genomics between different nematode species we are trying to decipher the effects of piRNAs on long-term genome evolution. Moreover, we are using in lab evolution in C. elegans to test in the short term what happens to genome evolution in the absence of the piRNA pathway. Together these two approaches will enable us to answer the fundamental questions of how transposons contribute to evolutionary novelty, and how cellular epigenetic pathways influence this process. Moreover, our work will give insight into the ways in which aberrant transposon silencing, as is known to occur in cancer, may contribute to the development of the disease.

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