ExoShorkie: predicting RNA-seq coverage of exogenous genomes in yeast by transfer learning.

MOTIVATION: Predicting the RNA-seq coverage of native and exogenous sequences is central to many molecular- and synthetic-biology applications. Substantial progress has been made in developing methods to predict the RNA-seq coverage of native genomic sequences, with the recently developed Shorkie achieving state-of-the-art performance in yeast. However, prediction performance of these methods over exogenous DNA is still unknown. Recent studies measured RNA-seq coverage of large exogenous genomes in yeast, providing a unique opportunity to train machine-learning models on a large exogenous sequence space and to improve both prediction performance and our understanding of regulatory mechanisms. RESULTS: We introduce ExoShorkie, a method we developed by extending Shorkie through transfer learning across multiple exogenous RNA-seq datasets. We demonstrate that ExoShorkie significantly improves prediction performance on held-out exogenous genomes and outperforms both a native-genome-trained Shorkie baseline and Yorzoi, the only competing method for predicting exogenous RNA-seq coverage in yeast, in cross-validation and in leave-one-genome-out evaluations. Furthermore, through interpretability analyses we reveal biologically meaningful regulatory motifs and distinct regulatory rules in exogenous genomes in yeast, providing new insights into transcriptional regulation. AVAILABILITY AND IMPLEMENTATION: ExoShorkie is available at https://github.com/OrensteinLab/ExoShorkie.