A three-dimensional model of the yeast genome

Abstract

The three-dimensional configuration of chromosomes in the nucleus of budding yeast has been determined from a kilobase-resolution map of intra- and inter-chromosomal interactions identified by high-throughput chromosome conformation capture. The genome resembles a water lily in overall shape, with 32 chromosome arms jutting out from a base of clustered centromeres at one pole of the nucleus. The 3D map, a snapshot that ignores the dynamic nature of chromosomes, provides a first glimpse into the architecture of a eukaryotic genome at high resolution, highlighting the three-dimensional complexity of the genome of even this simple organism. Further work should unveil the general organizing principles by which the DNA sequence specifies this structure. The topologies of, and spatial relationships between, chromosomes are important but poorly understood. Here, a high-throughput method is used to study intra- and inter-chromosomal interactions in Saccharomyces cerevisiae. A map of the haploid genome is generated at kilobase resolution, and is used to construct a three-dimensional model of the yeast genome. The findings provide a glimpse of the interface between the form and function of a eukaryotic genome. Layered on top of information conveyed by DNA sequence and chromatin are higher order structures that encompass portions of chromosomes, entire chromosomes, and even whole genomes1,2,3. Interphase chromosomes are not positioned randomly within the nucleus, but instead adopt preferred conformations4,5,6,7. Disparate DNA elements co-localize into functionally defined aggregates or ‘factories’ for transcription8 and DNA replication9. In budding yeast, Drosophila and many other eukaryotes, chromosomes adopt a Rabl configuration, with arms extending from centromeres adjacent to the spindle pole body to telomeres that abut the nuclear envelope10,11,12. Nonetheless, the topologies and spatial relationships of chromosomes remain poorly understood. Here we developed a method to globally capture intra- and inter-chromosomal interactions, and applied it to generate a map at kilobase resolution of the haploid genome of Saccharomyces cerevisiae. The map recapitulates known features of genome organization, thereby validating the method, and identifies new features. Extensive regional and higher order folding of individual chromosomes is observed. Chromosome XII exhibits a striking conformation that implicates the nucleolus as a formidable barrier to interaction between DNA sequences at either end. Inter-chromosomal contacts are anchored by centromeres and include interactions among transfer RNA genes, among origins of early DNA replication and among sites where chromosomal breakpoints occur. Finally, we constructed a three-dimensional model of the yeast genome. Our findings provide a glimpse of the interface between the form and function of a eukaryotic genome.