An in vitro neurogenetics platform for precision disease modeling in the mouse

The power and scope of disease modeling can be markedly enhanced through the incorporation of broad genetic diversity. In the the mouse, the introduction of pathogenic mutations into a single inbred strain sometimes fails to mimic human disease. We describe a cross-species precision disease modeling platform that exploits mouse genetic diversity to bridge cell-based modeling with whole organism analysis. We developed a universal protocol that permitted robust and reproducible neural differentiation of genetically diverse human and mouse pluripotent stem cell lines, then carried out a proof of concept study of the neurodevelopmental gene DYRK1A. The results in vitro reliably predicted the effects of genetic background on DYRK1A loss of function phenotypes and identified optimal mouse strains for in vivo disease modeling. Transcriptomic comparison of responsive and unresponsive strains identified novel molecular pathways conferring sensitivity or resilience to DYRK1A loss, and highlighted differential mRNA isoform usage as an important genetic determinant of response This cross-species strategy will be an powerful tool in the functional analysis of candidate disease variants identified through human genetic studies. Teaser: Genetically diverse mouse embryonic stem cells provide a rapid approach to precision modeling of human disease.