Causes and consequences of genetic variation in budding yeast

Abstract

The complex evolutionary forces that shape genomes result in sequences that are part utility and part history. The randomness involved in this process makes it difficult to imagine ever being able to read a genome and completely understand the effect of every base. But with large–scale mapping approaches, we can relate specific genetic variants present in natural populations to specific differences in traits of interest. The budding yeast Saccharomyces cerevisiae is one of the most useful model organisms in the study of genetics, and also has a long history of association with human activity. In this dissertation, I explore several methodological aspects related both to mapping traits in S. cerevisiae and to understanding how specific regions of budding yeast genomes have evolved over time. I begin by discussing the two main approaches to positionally mapping trait variation: association and linkage. Both of these approaches are aided by the recent sequencing of hundreds of S. cerevisiae isolates, along with the less extensive but complementary sequencing of other members of the Saccharomyces genus. Genome–wide association is a simple way of taking advantage of the extensive diversity of available sequences, but suffers from inflated false positive rates due to population structure. Linkage mapping has traditionally been more widely applied in yeast, since it is relatively simple to generate very large pools of individuals that are ideal for mapping. This approach remains powerful, but the great number of sequences now available makes it appealing to create larger crosses that incorporate more of this diversity. However, simply mapping trait variation to specific loci does not directly inform us about the mechanisms by which genetic variants affect phenotypes, or about how this variation has arrived at its current state. I also discuss some specific evolutionary aspects of budding yeast genomes. In particular, the ability of these substantially diverged yeasts to hybridize creates interesting possibilities for adaptation. I describe the development and application of an approach for identifying introgressed regions that remain from past hybridization events, and that therefore may have played significant evolutionary roles. Overall, the extensive genetic and phenotypic variation uncovered in budding yeast opens up exciting opportunities to discover the genetic basis of complex traits, and to investigate the larger picture of how evolutionary forces have shaped and continue to shape these experimentally and economically important organisms.