Morgan Brady, Ph.D.

Genetic background is one of the largest contributors to phenotypic variation in mouse embryonic stem cells (mESCs). Despite this, many studies analyze a limited number of mutant genes in otherwise isogenic backgrounds, making it difficult to elucidate complex regulatory networks influencing cellular phenotypic variability. Previous work from the Baker laboratory and collaborators utilized a panel of Diversity Outbred (DO) mESCs to establish that natural genetic variation can be used together with systems biology to identify causal variants influencing ground state pluripotency. Using an unbiased and high-resolution mapping approach enabled by the DO panel, quantitative trait locus (QTL) mapping identified loci coordinating pluripotency-related gene regulation throughout the genome. Building off this work, my current research utilizes the Jackson Laboratory’s DO mESC panel together with systems genetics to define regulatory networks that drive cell state heterogeneity and influence lineage bias in early mouse development. Using single cell transcriptomics to further interrogate cell composition and gene expression QTLs will allow us to model regulatory networks and predict cell differentiation propensity. Ultimately, understanding the molecular mechanisms driving phenotypic variation in pluripotent stem cell cultures will enable the building of translational models for developmental programs and in vitro systems for stem cell therapy, organoid development, and pharmacological purposes.