Academic journal article Genetics

Regulatory Rewiring in a Cross Causes Extensive Genetic Heterogeneity

Academic journal article Genetics

Regulatory Rewiring in a Cross Causes Extensive Genetic Heterogeneity

Article excerpt

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.

KEYWORDS complex traits; genetic mapping; invasive growth; regulatory networks; yeast

GENETIC studies in humans and model organisms have reported unexplained heritabilityformany traits (Manolio et al. 2009). A possible contributor to this "missing" heritability is genetic heterogeneity-individuals exhibiting similar phenotypes owing to different genetic and molecular mechanisms (Risch 2000; McClellan and King 2010; Wray and Maier 2014). Genetic heterogeneity can reduce the statistical power of mapping studies (Manchia et al. 2013; Wray and Maier 2014) and may involve multiple variants segregating in the same gene (allelic heterogeneity) or different genes (nonallelic heterogeneity) (Risch 2000). Work to date has shown that allelic heterogeneity is widespread (e.g., McClellan and King 2010; Ehrenreich et al. 2012; Long et al. 2014) and often involves two or more null or partial loss-of-function variants segregating in a single phenotypically important gene (e.g., Nogee et al. 2000; Sutcliffe et al. 2005; Will et al. 2010). However, the prominence and underlying mechanisms of nonallelic heterogeneity are less understood.

In this paper we describe an example of nonallelic heterogeneity using heritable variation in the ability of Saccharomyces cerevisiae strains to undergo haploid invasive growth as our model. Invasive growth is a phenotype that is triggered by low carbon or nitrogen availability and is thought to be an adaptive response that allows yeast cells to adhere to and penetrate surfaces (Cullen and Sprague 2000). Invasion typically requires expression of FLO11, which encodes a cell surface glycoprotein that facilitates cell-cell and cell-surface adhesion (Lo and Dranginis 1998; Rupp et al. 1999). In addition to FLO11, S. cerevisiae possesses other cell surface proteins that can contribute to adhesion-related traits [as described in Guo et al. (2000) and Halme et al. (2004) and elsewhere]. In some cases, these cell surface proteins are regulated by multiple signaling cascades (Bruckner and Mosch 2012), potentially providing an opportunity for genetic variants in different pathways to have similar effects on invasion.

Here we examinethe genetic basis of variation inthe ability to invade on two carbon sources-glucose and ethanol-in a cross of the laboratory strain BY4716 (BY) and the clinical isolate YJM789 (YJM) (Liti et al. 2009). YJM is highly invasive on both carbon sources (Figure 1A). In contrast, BY cannot grow invasively on either carbon source (Figure 1A). This is because BY carries a nonsense allele of FLO8 (Figure 1B; see also Materials and Methods), which encodes a transcriptional activator that is regulated by the Ras-cAMP-PKA pathway. …

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