Genomic characterization of a pathogenic isolate of Saccharomyces cerevisiae reveals an extensive and dynamic landscape of structural variation

Abstract

The budding yeast Saccharomyces cerevisiae has been extensively characterized for many decades and is a critical resource for the study of numerous facets of eukaryotic biology. Recently, the analysis of whole genome sequencing data from over 1000 natural isolates of S. cerevisiae has provided critical insights into the evolutionary landscape of this species by revealing a population structure comprised of numerous genomically diverse lineages. These survey-level analyses have been largely devoid of structural genomic information, mainly because short read sequencing is not suitable for detailed characterization of genomic architecture. Consequently, we still lack a complete perspective of the genomic variation the exists within the species. Single molecule long read sequencing technologies, such as Oxford Nanopore and PacBio, provide sequencing-based approaches with which to rigorously define the structure of a genome, and have empowered yeast geneticists to explore this poorly described realm of eukaryotic genomics. Here, we present the comprehensive genomic structural analysis of a pathogenic isolate of S. cerevisiae, YJM311. We used long read sequence analysis to construct a haplotype-phased, telomere-to-telomere length assembly of the YJM311 diploid genome and characterized the structural variations (SVs) therein. We discovered that the genome of YJM311 contains significant intragenomic structural variation, some of which imparts notable consequences to the genomic stability and developmental biology of the strain. Collectively, we outline a new methodology for creating accurate haplotype-phased genome assemblies and highlight how such genomic analyses can define the structural architectures of S. cerevisiae isolates. It is our hope that through continued structural characterization of S. cerevisiae genomes, such as we have reported here for YJM311, we will comprehensively advance our understanding of eukaryotic genome structure-function relationships, structural diversity, and evolution.