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.

Motivation: metal-binding proteins have a central role in maintaining life processes. Nearly one-third of known protein structures contain metal ions that are used for a variety of needs, such as catalysis, DNA/RNA binding, protein structure stability, etc. Identifying metal-binding proteins is thus crucial for understanding the mechanisms of cellular activity. However, experimental annotation of protein metal-binding potential is severely lacking, while computational techniques are often imprecise and of limited applicability.

Computational exploration of similarities among metal-binding protein structural motifs elucidates the origins of life. Biological redox reactions drive planetary biogeochemical cycles. Using a novel, structure-guided sequence analysis of proteins, we explored the patterns of evolution of enzymes responsible for these reactions. Our analysis reveals that the folds that bind transition metal–containing ligands have similar structural geometry and amino acid sequences across the full diversity of proteins. Similarity across folds reflects the availability of key transition metals over geological time and strongly suggests that transition metal–ligand binding had a small number of common peptide origins. We observe that structures central to our similarity network come primarily from oxidoreductases, suggesting that ancestral peptides may have also facilitated electron transfer reactions. Last, our results reveal that the earliest biologically functional peptides were likely available before the assembly of fully functional protein domains over 3.8 billion years ago. Thus, life is a special, very complex form of motion of matter, but this form did not always exist, and it is not separated from inorganic nature by an impassable abyss; rather, it arose from inorganic nature as a new property in the process of evolution of the world. We must study the history of this evolution if we want to solve the problem of the origin of life. [A. I. Oparin (1)]