Associate Director Scientific Strategy, Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute
The Claussnitzer lab pioneers Variant-to-Function (V2F) strategies for metabolic diseases.
Large-scale genetic studies have succeeded in identifying more than 1,800 associations between genetic loci and obesity-, and type 2 diabetes-related traits in humans. Yet, the next grand challenge — dissecting the molecular and cellular mechanisms by which these variants affect disease (Variant-to-Function, V2F) — has still to be solved and requires being able to determine the effect of genetic variants on molecular and cellular programs.
The Claussnitzer lab has pioneered a principled V2F framework for going from variants to genes to cells to biological pathways in the context of metabolic disease (Fig. 1). While these V2F studies help us to learn useful functional insights for metabolic disease, such one-locus-at-a-time approaches are currently not scalable, and it would take us decades to unlock the mechanisms encoded by the 1000s of genetic risk loci for metabolic disease.
The long-term goal of the Claussnitzer lab is to pioneer scalable V2F strategies to systematically unlock the consequences of genetic metabolic risk variation at the molecular and cellular level using adipocytes as model systems. To achieve this, the Claussnitzer lab develops and appplies high-dimensional molecular and cellular profiling techniques to large-scale natural genetic variation screens and CRISPR perturbation screens to generate a foundational data set that will allow to systematically link genetic variants (V) to regulatory elements (RE) to genes (G) to morphological and cellular functions (M/F) in disease across adipocyte cell state transitions. Adipocytes are the ideal model system for modeling V2F effects and learning fundamental rules of genetic networks since they play a major role in the pathogenesis of metabolic disease and undergo substantial remodeling at the regulatory and cellular level over the course of differentiation and in response to metabolic stimuli.