title: Regulatory Rewiring in a Cross Causes Extensive Genetic Heterogeneity.
abstract: Genetic heterogeneity occurs when individuals express similar phenotypes as a result of different underlying mechanisms. Although such heterogeneity is known to be a potential source of unexplained heritability in genetic mapping studies, its prevalence and molecular basis are not fully understood. Here we show that substantial genetic heterogeneity underlies a model phenotype--the ability to grow invasively--in a cross of two Saccharomyces cerevisiae strains. The heterogeneous basis of this trait across genotypes and environments makes it difficult to detect causal loci with standard genetic mapping techniques. However, using selective genotyping in the original cross, as well as in targeted backcrosses, we detected four loci that contribute to differences in the ability to grow invasively. Identification of causal genes at these loci suggests that they act by changing the underlying regulatory architecture of invasion. We verified this point by deleting many of the known transcriptional activators of invasion, as well as the gene encoding the cell surface protein Flo11 from five relevant segregants and showing that these individuals differ in the genes they require for invasion. Our work illustrates the extensive genetic heterogeneity that can underlie a trait and suggests that regulatory rewiring is a basic mechanism that gives rise to this heterogeneity.
authors.affiliation: Molecular and Computational Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, California 21546.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Matsui
authors.affiliation: Molecular and Computational Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, California 21546.
authors.forename: Robert
authors.initials: R
authors.lastname: Linder
authors.affiliation: Molecular and Computational Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, California 21546.
authors.forename: Joann
authors.initials: J
authors.lastname: Phan
authors.affiliation: Molecular and Computational Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, California 21546.
authors.forename: Fabian
authors.initials: F
authors.lastname: Seidl
authors.affiliation: Molecular and Computational Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, California 21546 ian.ehrenreich@usc.edu.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Ehrenreich
mesh_terms: D002874:Chromosome Mapping; D003433:Crosses, Genetic; D018740:Genetic Heterogeneity; D005838:Genotype; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics*; D010641:Phenotype; D040641:Quantitative Trait Loci / Q000235:genetics*; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*
chemical_list: C110690:FLO11 protein, S cerevisiae; D008562:Membrane Glycoproteins; D029701:Saccharomyces cerevisiae Proteins
keywords: complex traits; genetic mapping; invasive growth; regulatory networks; yeast