Deep learning of a bacterial and archaeal universal language of life enables transfer learning and illuminates microbial dark matter

Abstract The majority of microbial genomes have yet to be cultured, and most proteins identified in microbial genomes or environmental sequences cannot be functionally annotated. As a result, current computational approaches to describe microbial systems rely on incomplete reference databases that cannot adequately capture the functional diversity of the microbial tree of life, limiting our ability to model high-level features of biological sequences. Here we present LookingGlass, a deep learning model encoding contextually-aware, functionally and evolutionarily relevant representations of short DNA reads, that distinguishes reads of disparate function, homology, and environmental origin. We demonstrate the ability of LookingGlass to be fine-tuned via transfer learning to perform a range of diverse tasks: to identify novel oxidoreductases, to predict enzyme optimal temperature, and to recognize the reading frames of DNA sequence fragments. LookingGlass enables functionally relevant representations of otherwise unknown and unannotated sequences, shedding light on the microbial dark matter that dominates life on Earth.