Control iPSC lines with clinically annotated genetic variants for versatile multi-lineage differentiation
Matthew R Hildebrandt,
Miriam S Reuter,
L Stephen Lesperance,
Patrick M Brauer,
Rebecca S Mok,
Deivid de Carvalho Rodrigues,
Elisa C Martinez,
Michael J Szego,
Juan Carlos Zúñiga-Pflücker,
Michele K Anderson,
Steven A Prescott,
Norman D Rosenblum,
Binita M Kamath,
Stephen W. Scherer,
Posted 10 Jun 2019
bioRxiv DOI: 10.1101/666560 (published DOI: 10.1016/j.stemcr.2019.11.003)
Posted 10 Jun 2019
Induced Pluripotent Stem Cells (iPSC) derived from healthy individuals are important controls for disease modeling studies. To create a resource of genetically annotated iPSCs, we reprogrammed footprint-free lines from four volunteers in the Personal Genome Project Canada (PGPC). Multilineage directed differentiation efficiently produced functional cortical neurons, cardiomyocytes and hepatocytes. Pilot users further demonstrated line versatility by generating kidney organoids, T-lymphocytes and sensory neurons. A frameshift knockout was introduced into MYBPC3 and these cardiomyocytes exhibited the expected hypertrophic phenotype. Whole genome sequencing (WGS) based annotation of PGPC lines revealed on average 20 coding variants. Importantly, nearly all annotated PGPC and HipSci lines harboured at least one pre-existing or acquired variant with cardiac, neurological or other disease associations. Overall, PGPC lines were efficiently differentiated by multiple users into cell types found in six tissues for disease modeling, and clinical annotation highlighted variant-preferred lines for use as unaffected controls in specific disease settings.
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