Cellular resources for studying genetic effects on biology
hPSCs provide unprecedented access to the human tissues affected in disease. We established a human cellular and genetic resource of hPSCs from > 800 donors across a range of diagnoses and ancestral backgrounds, along with SNP analysis and WGS to characterize genetic variation. To achieve a more equitable representation of diverse genetic backgrounds in functional studies, and accelerate scientific discovery, ongoing efforts are focused on reprogramming cell lines from underrepresented populations. Our lab is using these resources to investigate the biological implications of human genetic variation.
Human cellular models to study development and disease
We developed efficient approaches to differentiate hPSCs into several cell types, including NPCs, neurons, and astrocytes by including developmental patterning using small molecules alongside transcription factor programming. Now widely used, these methods generate scalable and homogenous populations across hundreds of cell lines, suitable for high-throughput phenotyping and genetic association analyses. Collaboratively, we also developed protocols for co-culturing lines from different genetic backgrounds (“cell villages”) to eliminate well-to-well variability and decrease costs. Ongoing activities include innovating on cell village approaches to extend their applications across several cell types and model systems, and to combine them with perturbation and phenotyping assays.
Molecular and cellular mechanisms of 22q11.2del
The 22q11.2 deletion (22q11.2del) is the most common chromosomal deletion in humans. It also confers significant risk for psychiatric conditions including autism and schizophrenia, but underlying mechanisms are unresolved. We recently discovered that 22q11.2del acts through a previously undescribed genomic model, influencing genes and cellular phenotypes relevant to neuropsychiatric disorders through 3D genome conformation. Ongoing work is focused on understanding the impact of 22q11.2del on cellular phenotypes and resolving the mechanisms by which it creates risk for neuropsychiatric disorders.
Cellular phenotypes linked to human genetic variation
We are using both pooled and arrayed approaches to identify common and distinct pathways between rare variants of large effect and common variants of small effects implicated in complex traits and disease, using multimodal phenotyping assays (such as RNA sequencing, morphological profiling, and optical electrophysiology).
Using a co-culture system, we found that astrocytes enhance synaptic gene-expression programs in neurons, and neurons induce the expression of synaptic cell adhesion molecules in astrocytes. Both programs are enriched for genes associated with schizophrenia risk. We also discovered that neuron-glia interaction alters the expression of cholesterol biosynthesis genes. We are using genetic perturbation and pharmacological approaches to investigate the mechanisms underlying these pathways, and their role is psychiatric disorders.