Isoform Analysis Group

The Isoform Analysis Group aims to inspire and enable gene isoform analysis across all the health and natural sciences. We seek to do this by developing the bioinformatic infrastructure necessary to analyze isoforms (enable) and use it to show the importance of isoforms in human health and disease (inspire).

Background
Alternative splicing, alternative transcription start sites, and alternative termination sites collectively augment the functional repertoire of genomes, facilitating the generation of diverse isoforms from a single gene (illustrated in Figure 1). The choice of isoform holds tremendous biological relevance; for instance, pivotal genes in apoptosis have isoforms—one promoting and the other inhibiting apoptosis. In other words, only measuring gene-level changes is rather useless for these genes – we need to know about the isoforms.

We now know of hundreds of such lab-validated cases where individual isoforms drive biological changes. It is, therefore, astonishing that only ~10% of researchers across a wide range of bioinformatics fields seem to be analyzing isoforms (Figure 2), indicating we are currently neither seeing nor understanding the full picture.

The Challenge
If we generalize from Figure 2 to other research fields and diseases, it becomes abundantly clear that no single group or consortium could ever do this work alone! There is simply too much work to be done in too many research fields.
Therefore, the only viable solution is to inspire and enable other researchers to analyze isoforms.

Inspiring isoform analysis
To inspire isoform analysis, we have so far taken a bioinformatic approach and reanalyzed hundreds of high-throughput datasets covering many different high-throughput approaches. For each dataset and data modality, we investigate the additional biological information hidden at the isoform level. This work, which we are in the process of publishing, shows that isoforms are a central part of the cellular response to any intervention (experimental, disease, or otherwise) independent of which research field interrogated. Summarizing across these studies we find that ~50% of the cellular response is, at least to some extent, mediated by the isoform level changes that are currently overlooked. With this work, we hope to inspire researchers worldwide to analyze isoforms within their scope of interest.

Enabling isoform analysis
While our work highlights the broad impact of isoform-level changes, understanding their specific biological functions remains challenging. For while we know a lot about the biological function of most genes, we know next to nothing about the biological function of the underlying isoforms. Committed to addressing this gap, our group endeavors to develop accessible methods for interpreting isoform data, empowering researchers to unlock the full potential of isoform analysis in elucidating complex biological processes.

Long-term vision
We believe the scientific field needs to change how it thinks about molecular and cellular biology. Although it will require a colossal effort, we must progress from the current ‘gene-centric’ research paradigm to a more nuanced ‘isoform-centric’ paradigm. The Isoform Analysis Group will work hard to make this reality possible.

Group defining papers

• Dam et al. Expression and Splicing Mediate Distinct Biological Signals
  doi.org/10.1101/2022.08.29.505720
• Vitting-Seerup et al. IsoformSwitchAnalyzeR: analysis of changes in genome-wide patterns of alternative splicing and its functional consequences
  doi.org/10.1093/bioinformatics/btz247 
• Vitting-Seerup et al. The Landscape of Isoform Switches in Human Cancers
  doi.org/10.1158/1541-7786.mcr-16-0459