The piRNA pathway has a conserved role in transposon silencing and genome maintenance during germline development. Adaptation to new genome pathogens by the Drosophila piRNA genome defense system appears to be driven by transposition into heterochromatic clusters, which produce the primary piRNAs that to initiate silencing. The HP1 homolog Rhino binds to clusters and is evolving rapidly under positive selection, suggesting that it may co-evolve with invading mobile elements. piRNA clusters and Rhino thus function at the adaptive interface between the piRNA pathway and transposons.
Aims1 and 2 combine evolutionary divergence and conservation with genetic, genomic, computational and cytological tools to define this critical interface. The ability to differentiate cluster transcripts from mRNAs is critical to the specificity of the piRNA dense system, and our recent data suggest that stalled spicing may mark cluster transcripts for processing into silencing RNAs.
Aim 3 focuses on the role of splicing in piRNA precursor sorting into the silencing pathway. These studies address mechanisms that maintain the inherited genome and are likely to directly impact reproductive health.
Germline transmission of an unaltered genome is essential to species propagation. Transposons make up close to half of the human genome, and these mobile elements can induce mutations and represent a major treat to genome integrity. The piRNA pathway is an adaptive genome defense system that controls existing transposons and responds to new elements that invade the germline. The proposed studies address the basic mechanisms that allow this system to respond to invading genome pathogens, which is critical to reproductive health.
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