Genetic dissection of complex traits in yeast: insights from studies of gene expression and other phenotypes in the BYxRM cross

Abstract

The genetic basis of many phenotypes of biological and medical interest, including susceptibility to common human diseases, is complex, involving multiple genes that interact with one another and the environment. Despite decades of effort, we possess neither a full grasp of the general rules that govern complex trait genetics nor a detailed understanding of the genetic basis of specific complex traits. We have used a cross between two yeast strains, BY and RM, to systematically investigate the genetic complexity underlying differences in global gene expression and other traits. The number and diversity of traits dissected to the locus, gene, and nucleotide levels in the BYxRM cross make it arguably the most extensively characterized system with regard to causal effects of genetic variation on phenotype. We summarize the insights obtained to date into the genetics of complex traits in yeast, with an emphasis on the BYxRM cross. We then highlight the central outstanding questions about the genetics of complex traits and discuss how to answer them using yeast as a model system.

Figure 1

Crossing scheme used to create the BY×RM mapping population. Haploid parental strains are crossed to form a heterozygous diploid (“hybrid”) that is then sporulated to produce recombinant haploid offspring. More than 100 segregants were sampled from the BY×RM cross.

Figure 2

Primer on the genetics of global gene expression. (A) Example of a transcript where BY and RM differ, and a single locus has a major effect on the expression level of the segregants. (B) Example of a transcript showing transgressive segregation, where BY and RM have comparable expression levels but the segregants exhibit much more variation than is seen in the parents. (C) Plot of local (blue) and distant (red) linkages across the entire genome. A number of locations in the genome show linkage to many distant transcripts (vertical bands). These loci are referred to as hot spots. (A–C are illustrations and do not represent actual data.)

Figure 3

Compendium of the hot spots observed in the BY×RM cross. The locations (A) and descriptions (B) of a subset of the hot spots in the genome. This plot is a modified version of a plot in Smith and Kruglyak (2008). Causal genes for each of these hot spots are named, although in some cases it is unclear whether coincident hot spots across traits are due to different closely linked genes or to the pleiotropic effects of a single gene. For instance, the AMN1 gene expression hot spot is likely due to multiple genes with effects on different transcripts (Yvert et al. 2003). Red horizontal line in A indicates the threshold for calling a locus a hot spot. References for B are provided in the text.

Figure 4

Genetic architecture across a population. (A) QTLs causing variation in a trait segregate with varying allele frequencies across 15 strains in a population. The upward red arrows and downward blue arrows are opposite effect alleles that cause relative increases or decreases in the trait value of an individual. (B) As a result of the large number of loci affecting the trait in the population, in an intercross, both the number and locations of QTLs will depend on the two parental strains chosen for the cross. In the three inter-crosses chosen here, QTLs “C” and “I” appear to be common, but identifying the causal polymorphisms in the other 12 strains would reveal that the minor alleles are actually rare.