Highly accurate isoform identification for the human transcriptome

We explore a new hypothesis in genome annotation, namely whether computationally predicted protein structures can help to identify which of multiple possible gene isoforms represents a functional protein product. Guided by structure predictions, we evaluated over 140,000 isoforms of human protein-coding genes assembled from over 10,000 RNA sequencing experiments across many human tissues. We illustrate our new method with examples where structure provides a guide to function in combination with expression and evolutionary evidence. Additionally, we provide the complete set of structures as a resource to better understand the function of human genes and their isoforms. These results demonstrate the promise of protein structure prediction as a genome annotation tool, allowing us to refine even the most highly-curated catalog of human proteins. One-Sentence SummaryWe describe the use of 3D protein structures on a genome-wide scale to evaluate human protein isoforms for biological functionality.