The ADAR1 editome reveals drivers of editing-specificity for ADAR1-isoforms.

Adenosine deaminase acting on RNA ADAR1 promotes A-to-I conversion in double-stranded and structured RNAs. ADAR1 has two isoforms transcribed from different promoters: cytoplasmic ADAR1p150 is interferon-inducible while ADAR1p110 is constitutively expressed and primarily localized in the nucleus. Mutations in ADAR1 cause Aicardi - Goutières syndrome (AGS), a severe autoinflammatory disease associated with aberrant IFN production. In mice, deletion of ADAR1 or the p150 isoform leads to embryonic lethality driven by overexpression of interferon-stimulated genes. This phenotype is rescued by deletion of the cytoplasmic dsRNA-sensor MDA5 indicating that the p150 isoform is indispensable and cannot be rescued by ADAR1p110. Nevertheless, editing sites uniquely targeted by ADAR1p150 remain elusive. Here, by transfection of ADAR1 isoforms into ADAR-less mouse cells we detect isoform-specific editing patterns. Using mutated ADAR variants, we test how intracellular localization and the presence of a Z-DNA binding domain-α affect editing preferences. These data show that ZBDα only minimally contributes to p150 editing-specificity while isoform-specific editing is primarily directed by the intracellular localization of ADAR1 isoforms. Our study is complemented by RIP-seq on human cells ectopically expressing tagged-ADAR1 isoforms. Both datasets reveal enrichment of intronic editing and binding by ADAR1p110 while ADAR1p150 preferentially binds and edits 3'UTRs.

Distinguishing Felsenstein Zone from Farris Zone Using Neural Networks.

Maximum likelihood and maximum parsimony are two key methods for phylogenetic tree reconstruction. Under certain conditions, each of these two methods can perform more or less efficiently, resulting in unresolved or disputed phylogenies. We show that a neural network can distinguish between four-taxon alignments that were evolved under conditions susceptible to either long-branch attraction or long-branch repulsion. When likelihood and parsimony methods are discordant, the neural network can provide insight as to which tree reconstruction method is best suited to the alignment. When applied to the contentious case of Strepsiptera evolution, our method shows robust support for the current scientific view, that is, it places Strepsiptera with beetles, distant from flies.

Learning From an Artificial Neural Network in Phylogenetics.

We show that an iterative ansatz of deep learning and human intelligence guided simplification may lead to surprisingly simple solutions for a difficult problem in phylogenetics. Distinguishing Farris and Felsenstein trees is a longstanding problem in phylogenetic tree reconstruction. The Artificial Neural Network F-zoneNN solves this problem for 4-taxon alignments evolved under the Jukes-Cantor model. It distinguishes between Farris and Felsenstein trees, but owing to its complexity, lacks transparency in its mechanism of discernment. Based on the simplification of F-zoneNN and alignment properties we constructed the function FarFelDiscerner. In contrast to F-zoneNN, FarFelDiscerner's decision process is understandable. Moreover, FarFelDiscerner is significantly simpler than F-zoneNN. Despite its simplicity this function infers the tree-type almost perfectly on noise-free data, and also performs well on simulated noisy alignments of finite length. We applied FarFelDiscerner to the historical Holometabola alignments where it places Strepsiptera with beetles, concordant with the current scientific view.