PRBB-CRG Sessions David McCandlish

28/03/202512:00MARIE CURIEPRBB-CRG SessionsDavid McCandlishCold Spring Harbor Laboratory"Understanding complex genotype-phenotype maps"Host: Nora MartinAbstract:The relationship between an organism’s genome sequence and its measurable traits and behaviors—the genotype-phenotype map—is a fundamental concept in genetics. Beyond its central role in the evolution of natural populations, understanding the genotype-phenotype map is crucial for applications such as predicting and treating genetic diseases, studying somatic evolution in cancer, advancing animal and plant breeding, and enabling protein design and synthetic biology. Recent progress in high-throughput assays, genetic engineering, and deep learning have dramatically expanded our ability to measure and predict genotype-phenotype relationships, but modeling and understanding the structure of the genotype-phenotype map remains challenging due to the enormous size and large dimensionality of the space of possible genotypes. In this talk I will present two different directions my group is pursuing to address these challenges. First, I will discuss a collaborative project in which we are supplementing natural allelic diversity and gene knockouts with CRISPR-derived allelic series to better characterize genetic interactions governing tomato reproductive traits. Second, I will discuss our ongoing efforts to extend Gaussian process-based models of genetic interactions beyond short nucleic acid and protein motifs. By leveraging GPU acceleration, we are scaling up these methods with the goal of analyzing whole genes or genome-wide collections of SNPs. Together, these approaches provide new insights into the structure of the genotype-phenotype map and offer scalable strategies for exploring genetic interactions across diverse biological systems.