simulans proteins or domains and their interacting partners in D. I further demonstrate that this autoimmunity is dependent on known incompatibilities between D. simulans hinge and chromo domains of Rhino, exhibit expanded regulation of D. Consistent with this prediction, full-length D. I tested a key prediction of the autoimmunity hypothesis that foreign heterospecific piRNA proteins will exhibit enhanced autoimmunity, due to the absence of historical selection against off-target effects. I examined three adaptively evolving piRNA proteins, Rhino, Deadlock, and Cutoff, for evidence of interspecific divergence in autoimmunity between Drosophila melanogaster and Drosophila simulans. However, empirical tests of this model remain limited, particularly with regards to selection against genomic autoimmunity. Ongoing cycles of selection for expanded control of invading TEs, followed by selection for increased specificity to reduce impacts on host genes, are proposed to explain the frequent signatures of adaptive evolution among piRNA pathway proteins. Although TE defense is critical to ensuring germline genome integrity, it is equally critical that the piRNA pathway avoids autoimmunity in the form of silencing host genes. The Piwi-interacting RNA (piRNA) pathway is a genomic defense system that controls the movement of transposable elements (TEs) through transcriptional and post-transcriptional silencing.

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