Today, I am happy to share with you our recent manuscript, “The Preclinical Animal Network (PCAN): Integrative high-throughput phenotyping of standardized mouse models for Prader-Willi syndrome”, available on @biorxivpreprint
https://www.biorxiv.org/content/10.1101/2025.10.24.684371
#PraderWilliSyndrome #PWS #GenomicImprinting #RareDisease #DigitalTwin #MouseGenetics #FPWR
Prader-Willi-Syndrome (PWS) is a rare genetic disorder, firstly described by Prader, Labhart and Willi in 1956 [1]. Individuals with PWS typically have feeding issues in early childhood, followed by obesity, but possible symptoms include social behavioural and intellectual problems:
https://en.wikipedia.org/wiki/Prader%E2%80%93Willi_syndrome
[1] Prader, A., Labhart, A. & Willi, H. Ein Syndrom von Adipositas, Kleinwuchs, Kryptorchismus
und Oligophrenie nach myatonieartigem Zustand im Neugeborenenalter. Schweiz. Med.
Wochenschr. 86, 1260–1261 (1956).
#PWS is caused by a loss of function of genes on chromosome 15. These genes are peculiar, because they are in normal condition always expressed only from the paternal allele, the allele which is coming from the father, and not from both maternal and alleles – due to an epigenetic phenomenon called #GenomicImprinting. PWS patients either have parts of the paternal allele deleted or they have maternal uniparental disomy (#UPD) – a condition with effectively two maternal alleles instead of paternal and maternal alleles. This leads to a condition where some genes are not expressed at all, thus, their proteins and functions are missing for the proper development and functioning of the human body.
Although the genetic cause of #PWS is known, therapeutic treatment primarly targets its symptoms. #PreclinicalResearch (often in mice) is essential to make progress on understanding the functioning of the involved genes and to develop new targeted therapies. In this research project we developed new PWS mouse models and analysed their phenotype (e.g., body features, behaviour and metabolism) using standardized experimental and analytical pipelines.
My contribution was the analysis of the phenotypic data that was collected at #MaryLyonCentre, #MRC in #HarwellCampus. Although the experiments were carried out at one specialized laboratory under tightly controlled environmental conditions, we quickly figured out that environmental variability dominates the phenotypic variance in the studied mice. By using a variance decomposition model from twin studies, the #ACEmodel, we were able to disentangle genetic from non-genetic, environmental contributions, to have robust estimates of the effects of certain gene deletions.
Further, we could use the estimated, fitted parameters of the #ACEmodel to simulate #DigitalTwin mice, reproducing the effects we observed in the data and at the same time reducing the reliance on animal use.
Finally, this work would not have been possible without the input and work from all my co-authors from UK, France, Italy and USA. I am grateful that I could be part of this journee and want to thank also the #FoundationForPraderWilliResearch (#FPWR) for their generous funding! I hope that this research may at some day contribute to improve the life of patients with #PraderWilliSyndrome (#PWS) or other #RareDiseases.
Robert Wolff