Diviner uncovers hundreds of novel human (and other) exons though comparative analysis of proteins

Eukaryotic genes are often composed of multiple exons that are stitched together by splicing out the intervening introns. These exons may be conditionally joined in different combinations to produce a collection of related, but distinct, mRNA transcripts. For protein-coding genes, these products of alternative splicing lead to production of related protein variants (isoforms) of a gene. Complete labeling of the protein-coding content of a eukaryotic genome requires discovery of mRNA encoding all isoforms, but it is impractical to enumerate all possible combinations of tissue, developmental stage, and environmental context; as a result, many true exons go unlabeled in genome annotations.

One way to address the combinatoric challenge of finding all isoforms in a single organism A is to leverage sequencing efforts for other organisms - each time a new organism is sequenced, it may be under a new combination of conditions, so that a previously unobserved isoform may be sequenced. We present Diviner, a software tool that identifies previously undocumented exons in organisms by comparing isoforms across species. We demonstrate Diviner's utility by locating hundreds of novel exons in the genomes of human, mouse, and rat, as well as in the ferret genome. Further, we provide analyses supporting the notion that most of the new exons reported by Diviner are likely to be part of a true (but unobserved) isoform of the containing species.