Grant Award Details
- To establish a high throughput single cell base editing approach (scBE-seq) in hiPSC, and apply it to the interrogation of pathogenicity of a large number of SNVs introduced into 2 genes known to play a role in neurodevelopmental diseases.
Grant Application Details
- Development of a stem-cell based approach to interpret global effects of genetic variants contributing to neurodevelopmental disease risk
We are developing a strategy to characterize the disease-relevance of hundreds of mutations across diverse genetic backgrounds using stem cells
Understanding how mutations impact cellular function can identify treatments for genetic diseases, but currently less than 1% of identified mutations have a known function.
Major Proposed Activities
- Identify optimal conditions for SNV library introduction in hiPCSs and characterize the global impact of individual mutations in ERCC2 and MECP2 on transcription, chromatin state, and mutational rates
- Develop a computational pipeline to design SNV libraries and analyze data from our method, scBE-seq
- Employ scBE-seq to study the impact of libraries of mutations in ERCC2 and MECP2 during the in vitro neurodifferentiation of hiPSCs into cortical organoids
- Analyze scBE-seq data and compare with orthogonal datasets for clinical interpretation of genetic variation
An overrepresentation of European human genome sequencing data has generated inequities in regenerative and precision medicine efforts. We propose here to develop a more equitable strategy to characterize the disease-relevance of mutations from diverse populations. Our project will identify new preventative strategies, treatments, and cures for genetic diseases applicable to a variety of ethnic groups, and will therefore benefit the State of California and its highly ethnically diverse citizens.