title: An evaluation of high-throughput approaches to QTL mapping in Saccharomyces cerevisiae.
abstract: Dissecting the molecular basis of quantitative traits is a significant challenge and is essential for understanding complex diseases. Even in model organisms, precisely determining causative genes and their interactions has remained elusive, due in part to difficulty in narrowing intervals to single genes and in detecting epistasis or linked quantitative trait loci. These difficulties are exacerbated by limitations in experimental design, such as low numbers of analyzed individuals or of polymorphisms between parental genomes. We address these challenges by applying three independent high-throughput approaches for QTL mapping to map the genetic variants underlying 11 phenotypes in two genetically distant Saccharomyces cerevisiae strains, namely (1) individual analysis of >700 meiotic segregants, (2) bulk segregant analysis, and (3) reciprocal hemizygosity scanning, a new genome-wide method that we developed. We reveal differences in the performance of each approach and, by combining them, identify eight polymorphic genes that affect eight different phenotypes: colony shape, flocculation, growth on two nonfermentable carbon sources, and resistance to two drugs, salt, and high temperature. Our results demonstrate the power of individual segregant analysis to dissect QTL and address the underestimated contribution of interactions between variants. We also reveal confounding factors like mutations and aneuploidy in pooled approaches, providing valuable lessons for future designs of complex trait mapping studies.
authors.affiliation: European Molecular Biology Laboratory, Genome Biology Unit, 69117 Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Wilkening
authors.forename: Gen
authors.initials: G
authors.lastname: Lin
authors.forename: Emilie S
authors.initials: ES
authors.lastname: Fritsch
authors.forename: Manu M
authors.initials: MM
authors.lastname: Tekkedil
authors.forename: Simon
authors.initials: S
authors.lastname: Anders
authors.forename: Raquel
authors.initials: R
authors.lastname: Kuehn
authors.forename: Michelle
authors.initials: M
authors.lastname: Nguyen
authors.forename: Raeka S
authors.initials: RS
authors.lastname: Aiyar
authors.forename: Michael
authors.initials: M
authors.lastname: Proctor
authors.forename: Nikita A
authors.initials: NA
authors.lastname: Sakhanenko
authors.forename: David J
authors.initials: DJ
authors.lastname: Galas
authors.forename: Julien
authors.initials: J
authors.lastname: Gagneur
authors.forename: Adam
authors.initials: A
authors.lastname: Deutschbauer
authors.forename: Lars M
authors.initials: LM
authors.lastname: Steinmetz
mesh_terms: D000782:Aneuploidy; D002874:Chromosome Mapping; D014644:Genetic Variation; D016681:Genome, Fungal; D023281:Genomics / Q000379:methods*; D009154:Mutation; D010641:Phenotype; D040641:Quantitative Trait Loci; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*
chemical_list: D029701:Saccharomyces cerevisiae Proteins
keywords: QTL mapping; bulk segregant analysis; individual segregant analysis; next generation sequencing; reciprocal hemizygosity scanning; yeast