"Decoding Variant Function Across Genes, Cell Types, and Evolutionary Timescales"

Understanding the biological mechanisms underlying complex traits requires identifying which variants are causal, which genes they affect, and in which cell types their effects are mediated. In this talk, I will present complementary approaches developed by our lab to address these questions. First, I will describe strategies that resolve individual steps from association to function by prioritizing causal variants, linking variants to their target genes, and identifying the cell types through which genetic effects act. Second, I will show how population-scale single-cell data allow us to study these dimensions jointly and directly connect genetic variation to target genes and relevant cellular contexts. Finally, I will discuss how evolutionary information provides an additional lens for interpreting complex-trait architecture. I will show how evolutionary constraint reveals the influence of negative selection across different timescales on complex-trait variation, and how antagonistic pleiotropy can allow high-effect variants to persist despite this selection. Together, these approaches illustrate how functional genomic and evolutionary information can help move from genetic association to biological mechanism.