Emma Farley, PhD
Enhancers control the location and timing of gene expression and harbor the majority of variants associated with phenotypic variation and disease. As such, enhancers provide the instructions for tissue-specific gene expression, development, and cellular integrity. The majority of variants associated with phenotypic variation, evolutionary adaptations, and disease are thought to lie within enhancers. Yet, pinpointing causal enhancer variants from the sea of inert variants is a major challenge. Transcription factors bind to sites within the enhancers to regulate the timing and location of gene expression. Despite decades of study, how enhancers encode tissue-specific activity and the mechanisms by which single nucleotide variants (SNVs) alter phenotypes are poorly understood. Emma Farley will discuss their work to pinpoint and predict what changes within enhancers lead to phenotypic changes across different species, including the heart of the marine invertebrate Ciona robust and the mouse and human limb. They have discovered that many enhancers contain suboptimal affinity binding sites (also known as low-affinity sites), and that single nucleotide changes that increase the affinity of these sites, even slightly, cause organismal-level phenotypes such as extra digits or a second beating heart. Genomic analysis of many enhancers illustrates affinity optimizing SNVs lead to gain-of-function gene expression across a variety of cell types and enhancers. Their studies illustrate that the prevalence of suboptimal affinity binding sites within enhancers creates a vulnerability in genomes whereby SNVs that optimize affinity, even slightly, can be pathogenic. Searching for affinity-optimizing SNVs within genomes provides a generalizable approach to identify causal variants that underlie enhanceropathies. More broadly, this work demonstrates the conservation of regulatory principles governing enhancers and provides a framework for searching for violations in regulatory principles to pinpoint causal variants underlying phenotypic variation, evolutionary adaptations, and disease.
Hosted by: Vijay Ramani, PhD
DatesApril 10, 2023
AudienceGladstone and UCSF
The Convergence Seminar is organized by Gladstone’s Institute for Data Science and Biotechnology. This seminar series brings together scientists from varying disciplines to solve complex scientific questions and accelerate the path to cures.
Diversity, Equity, and Inclusion
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