Isoform Analysis of a Prader-Willi Syndrome Model at the Earlham Institute
From May 26 to August 1, 2025, Yalan Bi, LongTREC Doctoral Candidate at the Max Planck Institute for Molecular Genetics, had the opportunity to carry out a research secondment at the Earlham Institute, supervised by Wilfried Haerty. This secondment offered valuable growth, both in scientific expertise and personal development.
My goal? Analysing human iPSC-derived cardiomyocyte data from wild type and a SNORD116 mutation, linked to Prader-Willi Syndrome (PWS), at three time points using IsoTools2.
Yalan reflects on her experience:
What I Learned ๐
The analysis covered transcript identification, gene model characterisation for expression and structural variation, and alternative and differential splicing. I also compared transcripts identified by IsoTools and IsoQuant.
Takeaways ๐ฑ
With the Haerty lab, I discussed the challenges of identifying transcript boundaries, transcription start sites (TSS) and polyadenylation sites (PAS), and the coordination between proximal and distal termini. We explored modelling differential usage of TSS, PAS and UTRs over time.
Impact ๐
I assessed transcript expression variability using relative entropy. Wild-type genes were enriched in cardiovascular and metabolic pathways, consistent with normal development, while SNORD116 mutation genes were related to lipid metabolism and stress responses, suggesting compensatory mechanisms in PWS. Following discussions with the Haerty lab, I proposed an approach using Jensen-Shannon distance to quantify how the structural variability of genes changes between conditions.
Overall, this secondment applied IsoTools2 to a disease model and developed new ways to measure isoform variability.
