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In Vitro Genetics

We conduct unbiased, genomewide screens for quantitative trait loci ("QTL") that modulate drug response phenotypes, combining high throughput screening methods with genetically diverse stem cells. We differentiate stem cells to therapeutically relevant cell types of interest and conduct phenotypic screens of compound action to identify  genes that are causal drivers of drug response. 

Leverage  These stem cell lines constitute a permanent replicable genetic population that enables genetic screens in multiple isogenic cell types. Each new model leverages and extends the resource, enabling biological studies across panels of different cell/tissue types.

 

Translation.   We validate the modifier genes identified in the mouse genetic screens using orthologous human iPSC derived models. 

In Vitro Models.    Our core resource is a collection of over 1,000 mouse ES cell lines derived from Diversity Outbred embryos. We differentiate these pluripotent stem cell lines to establish isogenic panels of lineage-restricted stem cells and terminally differentiated cell types of pharmacological interest. For example, we have produced 350 neural progenitor cell lines (NPCs) from the ES cell panel, and we have conducted genetic screens of 300 astrocyte lines produced from the NPCs.

eQTLs. Along with mapping QTL for functional phenotypes such as compound response, we also conduct eQTL studies using bulk and single cell transcriptomes. An example is shown below with 200 ESC and NPC lines (derived from the ESC) using bulk RNAseq.

 

eQTLs in ES and NPC cell lines

Shared vs unique eQTL in ESC and NPC 

eQTL in DO mouse liver vs ESC.

Diversity Outbred Mice

Diversity Outbred (DO) mice are an outbred stock produced by many generations of random interbreeding of eight inbred founder strains. DO mice were designed for mapping complex traits and capture over 90% of the genomic variation in laboratory and wild-derived inbred mouse strains. DO mice are available from The Jackson Laboratory (Stock # J:DO 009376).