Academic journal article Genetics

Sequential Elimination of Major-Effect Contributors Identifies Additional Quantitative Trait Loci Conditioning High-Temperature Growth in Yeast

Academic journal article Genetics

Sequential Elimination of Major-Effect Contributors Identifies Additional Quantitative Trait Loci Conditioning High-Temperature Growth in Yeast

Article excerpt

ABSTRACT

Several quantitative trait loci (QTL) mapping strategies can successfully identify major-effect loci, but often have poor success detecting loci with minor effects, potentially due to the confounding effects of major loci, epistasis, and limited sample sizes. To overcome such difficulties, we used a targeted backcross mapping strategy that genetically eliminated the effect of a previously identified major QTL underlying high-temperature growth (Htg) in yeast. This strategy facilitated the mapping of three novel QTL contributing to Htg of a clinically derived yeast strain. One QTL, which is linked to the previously identified major-effect QTL, was dissected, and NCS2 was identified as the causative gene. The interaction of the NCS2 QTL with the first major-effect QTL was background dependent, revealing a complex QTL architecture spanning these two linked loci. Such complex architecture suggests that more genes than can be predicted are likely to contribute to quantitative traits. The targeted backcrossing approach overcomes the difficulties posed by sample size, genetic linkage, and epistatic effects and facilitates identification of additional alleles with smaller contributions to complex traits.

THE identification of the responsible alleles for common, genetically complex phenotypes has remained difficult(Mackay2001;BartonandKeightley 2002; Glazier et al. 2002; Botstein and Risch 2003; Flint et al. 2005). Difficulties arise from the lack of simple correspondence between phenotype and genotype caused by pleiotropy, genetic heterogeneity, gene-environment interactions, multifactorial inheritance, and epistasis. The study of complex traits has therefore benefited from understanding their genetic bases in model organisms (Steinmetz et al. 2002; Yalcin et al. 2004; Kroymann and Mitchell-Olds 2005; Mackay and Anholt 2006; Valdar et al. 2006; Keurentjes et al. 2007).

Yeast, Saccharomyces cerevisiae, is an informative model to dissect quantitative traits and several phenotypes have been investigated so far, including high-temperature growth (Htg) (Steinmetz et al. 2002; Sinha et al. 2006), sporulation (Deutschbauer and Davis 2005; Ben-Ari et al. 2006; Gerke et al. 2006), mRNA expression profiles (Brem et al. 2002, 2005; Yvert et al. 2003), small molecule sensitivities (Perlstein et al. 2007), cell morphology (Nogami et al. 2007), telomere length (Gatbonton et al. 2006), ethanol tolerance and growth (Hu et al. 2007; Smith and Kruglyak 2008), flocculation (Brauer et al. 2006), and physiological wine traits (Marullo et al. 2007). In addition, the full genome sequence of the laboratory strain, S288c (Goffeau et al. 1996), and of a few dozens of other strains (Wei et al. 2007, http://www.broad.mit.edu/annotation/genome/saccharomyces_cerevisiae/Info.html/ and http://www.sanger.ac.uk/Teams/Team71/durbin/sgrp/index.shtml) provide resources for complex trait dissection.

S. cerevisiae is an opportunistic pathogen (Enache-Angoulvant and Hennequin 2005) and the ability of clinical isolates to grow at high temperature facilitates their pathogenesis (McCusker et al. 1994). In a previous study of the Htg phenotype, we identified a 32-kb interval on chromosome XIV containing three Htg genes forming a QTL with a complex genetic architecture (Steinmetz et al. 2002). The three genes did not show an obvious role in Htg:MKT1 encodes a protein involved in the post-transcriptional regulation of HO mRNA, END3 encodes a gene product involved in endocytosis, actin cytoskeleton organization, and cell wall morphogenesis, and RHO2 encodes a small GTPase involved in establishment of cell polarity and in microtubule assembly. Moreover, common, rare, coding and noncoding polymorphisms were found to be causative, with alleles having additive and epistatic effects (Steinmetz et al. 2002; Sinha et al. 2006). Interactions between genes and strain background were detected as well, with the causative variants in these genes making backgrounddependent contributions to growth at high temperature (Sinha et al. …

Search by... Author
Show... All Results Primary Sources Peer-reviewed

Oops!

An unknown error has occurred. Please click the button below to reload the page. If the problem persists, please try again in a little while.