Understanding Host Tolerance to Transposable Elements

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Transposable elements (TE) are mobile genetic parasites, whose unregulated activity in germline causes DNA damage, and results in sterility. Host genomes can avoid these fitness costs of TEs either by regulating TE proliferation, or by altering gametogenesis to tolerate TE-induced DNA damage. Although TE regulation through piRNAs is studied extensively, little is known about mechanisms of gametogenic tolerance to TE activity. To study tolerance I take advantage of a unique phenomenon called hybrid dysgenesis in Drosophila melanogaster where naïve females devoid of P-element DNA transposon typically produce sterile offspring when mated with P-element carrying males. However, tolerant individuals are capable of producing viable gametes in spite of transposition. By performing Quantitative trait loci (QTL) mapping in a panel of highly recombinant inbred lines two genomic regions associated with natural tolerance to P-element transposition were isolated. Transcriptome analysis of multiple tolerant and sensitive genotypes shows evidence suggesting variation in the double-stranded break (DSB) repair efficiency. Tolerant genotypes show increased expression of components of the Tat interactive protein 60-kDa (TIP60) complex involved in DSB repair and also exhibited increased chorion gene expression- an indicator of enhanced DSB repair. By integrating the data from QTL mapping, gene expression as well as in-phase SNP analysis, I identified two strong candidate genes that could influence tolerance: brat and Nipped-A, a member of the TIP60 complex. Loss-of-function mutation in brat was found to promote hybrid dysgenesis by increasing ovarian atrophy in the dysgenic females. Furthermore, tolerant genotypes displayed high resilience to X-ray mediated DNA damage. These results reveal gametogenic regulation and enhanced DSB repair as two potential mechanisms of germline tolerance to TEs.

transposition, hybrid dysgenesis, P-elements, QTL mapping, double-stranded breaks