Grzegorz Kudla, PhD

I am a molecular biologist with an interest in developing new experimental and computational tools for studying the relationships between sequence, structure, and function of RNA and proteins. I pioneered high-throughput assays of variant effects and applied them to study principles of gene regulation in bacteria, yeast and human cells. I discovered the effects of codon usage on translation initiation in bacteria and yeast; on mRNA toxicity in bacteria; and on mRNA expression levels and mRNA nuclear export in human cells. I performed the first systematic studies of intragenic epistasis, identifying networks of genetic interactions within a snoRNA and in a synthetic RNA aptamer. I also developed CRAC, a high-throughput method to study protein-RNA interactions, and CLASH and COMRADES, high-throughput methods for measuring RNA-RNA interactions in living cells. I applied CLASH and similar methods to study the microRNA interactome and structures of small RNAs, virus genomes, lncRNAs, and RNA homodimers. More recently, my group has been using multiplex assays of variant effects for disease variant interpretation in human protein coding genes. We completed deep mutational scanning of PAX6, a transcription factor that orchestrates eye development, ADSL, and enzyme involved in purine biosynthesis, and the insulin receptor. This allowed us to classify thousands of previously uncharacterized variants as either benign or pathogenic, identify transcription factor variants with sequence-specific effects on regulation, and receptor variants that can be activated by monoclonal antibodies.