Abstract

Transcriptomics continues to provide ever-more evidence that in morphologically complex eukaryotes, each protein-coding genetic locus can give rise to multiple transcripts that differ in length, exon content and/or other sequence features. In humans, more than 60% of loci give rise to multiple transcripts in this way. Motifs that mediate protein-protein interactions can be present or absent in these transcripts. Interactions are typically recorded for representative proteins or even genes, although exploratory transcriptomics has revealed great spatiotemporal diversity in the output of genes at both the transcript and protein-isoform levels. The increasing availability of high-resolution protein structures has made it possible to identify the domain-domain interactions that underpin many protein interactions. To explore the impact of transcript and isoform diversity we use full-length human cDNAs to interrogate the protein-coding transcriptional output of genes, identifying variation in the inclusion of protein interaction domains. We map these data to a set of high-quality protein interactions, and characterise the variation in network connectivity likely to result. We find strong evidence for altered interaction potential in nearly 20% of genes, with those encoding signalling proteins and pathways over-represented. We develop case studies demonstrating that the interactome can be affected by mechanisms other than altered protein-protein interaction, and bring together evidence that interactome rewiring is significant in human disease.