We strive to merge human genetics with model organism genetics such that findings in one drive discovery in the other.
We strive to merge human genetics with model organism genetics such that findings in one drive discovery in the other.
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Our lab is interested in understanding basic mechanisms of gene regulation. Instead of studying a specific gene/pathway, we follow the genetics and let biological systems tell us what's important. We are particularly interested in rare disease genetics and identifying novel disease genes with a focus on genes involved in transcriptional and post-transcriptional regulation.
The basic working hypothesis of our lab is that aberrations in functionally-related genes, can lead to similar phenotypes. This hypothesis provides the logical framework for the paradigm we follow in the lab. First, we identify a disease-causing gene. We utilize model organisms, such as C. elegans, to understand the biology of this disease-causing gene and determine what other genes function in the biological pathway. If the human orthologs of these functionally-related genes have not been associated with a disease, these human genes become candidate disease genes. We can then look for putative pathogenic variants in these candidate disease genes in patient cohorts. If we find patients with deleterious variants in these genes, this gene would represent a novel disease gene. For a proof-of-principle, please refer to our manuscript where we identified RACGAP1 as a novel disease gene. This paradigm merges human genetics with model organism genetics such that findings in one drive discovery in the other.
We utilize genetics/genomics, molecular biology, cell biology, biochemistry, and computational approaches to address the questions we seek to answer.
four major ongoing projects
four major ongoing projects
Project 1: Systematically identifying candidate disease genes
We are taking advantage of decades of work in model organisms to identify pairs of functionally-related genes, where the human ortholog of one gene in the pair is associated with a disease, while the other one is not. We are also attempting to leverage model organism data to identify functionally relevant amino acids to help with variant interpretation.
Project 2: Establish pathogenicity of novel disease genes
After identifying patients who have putative deleterious variants in a novel disease gene, we try to establish the pathogenicity of these variants. One recent example includes establishing SPOUT1 as a novel disease gene, which is mutated in the new neurodevelopmental disorder SpADMiSS (SPOUT1 Associated Development delay Microcephaly Seizures Short stature).
Project 3: Understand the in vivo consequences of pathogenic variants
After establishing the pathogenicity of variants, we seek to better understand the in vivo consequences of the variants. We use CRISPR to introduce the variant into the C. elegans ortholog and assess variant effects on numerous phenotypes including spatiotemporal expression patterns, locomotory behavior, organismal health, etc. We can then use powerful genetic/genomic and biochemical approaches to understand what biological pathways are affected.
Project 4: Tool development
We are actively developing new tools that will facilitate the other 3 projects. These include developing novel CRISPR-based methods that would enable efficient and robust manipulation of the C. elegans genome, as well as utilizing deep neural networks to help automate laborious phenotyping assays.
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