Genotype-to-Phenotype Associations with Frequented Region Variants

A pangenome represents the entire sequence content and variation of a population. As collections of complete reference quality genomes become more common, so does the prevalence of pangenomes, necessitating the need for scalable computational methods for their analysis. Previously, we developed FindFRs for identifying Frequented Regions in pangenome graphs, where a Frequented Region is a subgraph that is frequently traversed by multiple sequences. In this work, we propose FindFRs3, which is an updated version of FindFRs capable of identifying Frequented Regions with improved runtime and memory efficiency, enabling the analysis of much larger pangenome graphs. In addition, FindFRs3 identifies Frequented Region Variants (the unique subpaths through each region). We demonstrate the utility of these variants by using them as input features for machine learning models that can predict genotype-to-phenotype associations in a large yeast pangenome. Biological insights gained from these variants show that this novel technique allows for a more nuanced and detailed analysis of larger pangenomes.