How does the structure of a genome evolve?

The frequencies and patterns by which cells acquire mutations profoundly shape their evolutionary trajectories and phenotypic potential. Darwin’s paradigm of gradualism, a central tenet of modern biology, maintains that new mutations arise independently and successively over many generations. Yet, some mutational processes, such as the genome evolution observed in tumorigenesis and microbial pathogenesis, cannot be explained by a gradual model alone. Cells in these biological contexts have been found to rapidly accumulate strikingly complex patterns of genomic structural variations (SVs), suggesting that additional, undefined mutational modes play important roles in genome evolution.Using S. cerevisiae (budding yeast) cells together with selection-based assays and whole genome sequencing (WGS) analyses, we have found that in contrast to Darwinian principles, cells often acquire multiple SVs concomitantly during transient episodes of systemic genomic instability (SGI). These punctuated bursts of mutation produce cells harboring a spectrum of unique karyotypic configurations, ranging from those with a single SV, to others in which every single chromosome has been altered. Our results thus far have established bursts of SGI as significant mechanistic drivers in the rapid formation of profoundly altered genomic architectures.

How do SVs shape the architectures and life histories of populations and species?

The concerted efforts of yeast geneticists to collect and characterize >1000 natural isolates of S. cerevisiae have made it a robust model system with which to study organismal evolution. Using Oxford Nanopore single molecule long read WGS to characterize the genomic structures of these wild isolates, we have initiated a systematic investigation of the structural genomic architectures of wild strains of S. cerevisiae in order to answer the following questions: How much structural variation exists within a species and how does this impact the reproductive potential of that species? How do structural variations enforce reproductive barriers and isolation within and between related species? How does the life cycle of an organism impact the genomic architectures of distinct populations? How does structural genomic evolution modulate phenotypic variation and heterogeneity in populations of related individuals?

How do SVs potentiate phenotypic variation, adaptation, and diversification?

Collectively, the cells comprising microbial populations display markedly heterogeneous phenotypes. This phenotypic variation is thought to improve the adaptive potential and fitness of a population, and has been shown to promote virulence, persistence, and drug resistance in numerous pathogenic microbes. It was widely assumed that single nucleotide variations generated most of the phenotypic diversity observed in these populations. Yet, because SVs have the potential to affect large regions of the genome simultaneously, they likely represent an important, yet under-studied source of phenotypic diversity. We are exploring this premise by investigating the sources of phenotypic variation displayed by pathogenic strains of yeast. Such strains often give rise to subpopulations of cells that form variant colony architectures, the result of stochastic activation of an environmental adaptation response. This work has demonstrated that SVs are dominant modulators of phenotypic variation in clonal populations. Moreover, these studies have defined a molecular system which stochastically unites genomic instability with phenotypic diversification, making it a potent driver of rapid microbial genome evolution.