title: Improved linkage analysis of Quantitative Trait Loci using bulk segregants unveils a novel determinant of high ethanol tolerance in yeast.
abstract: BACKGROUND
  Bulk segregant analysis (BSA) coupled to high throughput sequencing is a powerful method to map genomic regions related with phenotypes of interest. It relies on crossing two parents, one inferior and one superior for a trait of interest. Segregants displaying the trait of the superior parent are pooled, the DNA extracted and sequenced. Genomic regions linked to the trait of interest are identified by searching the pool for overrepresented alleles that normally originate from the superior parent. BSA data analysis is non-trivial due to sequencing, alignment and screening errors.
  
  
  RESULTS
  To increase the power of the BSA technology and obtain a better distinction between spuriously and truly linked regions, we developed EXPLoRA (EXtraction of over-rePresented aLleles in BSA), an algorithm for BSA data analysis that explicitly models the dependency between neighboring marker sites by exploiting the properties of linkage disequilibrium through a Hidden Markov Model (HMM). Reanalyzing a BSA dataset for high ethanol tolerance in yeast allowed reliably identifying QTLs linked to this phenotype that could not be identified with statistical significance in the original study. Experimental validation of one of the least pronounced linked regions, by identifying its causative gene VPS70, confirmed the potential of our method.
  
  
  CONCLUSIONS
  EXPLoRA has a performance at least as good as the state-of-the-art and it is robust even at low signal to noise ratio's i.e. when the true linkage signal is diluted by sampling, screening errors or when few segregants are available.
authors.forename: Jorge
authors.initials: J
authors.lastname: Duitama
authors.forename: Aminael
authors.initials: A
authors.lastname: Sánchez-Rodríguez
authors.forename: Annelies
authors.initials: A
authors.lastname: Goovaerts
authors.forename: Sergio
authors.initials: S
authors.lastname: Pulido-Tamayo
authors.forename: Georg
authors.initials: G
authors.lastname: Hubmann
authors.forename: María R
authors.initials: MR
authors.lastname: Foulquié-Moreno
authors.affiliation: VIB Laboratory of Systems Biology & Laboratory for Genetics and Genomics, Centre of Microbial and Plant Genetics, KU Leuven, Gaston Geenslaan 1, Leuven B-3001, Belgium. johan.thevelein@mmbio.vib-kuleuven.be.
authors.forename: Johan M
authors.initials: JM
authors.lastname: Thevelein
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Verstrepen
authors.forename: Kathleen
authors.initials: K
authors.lastname: Marchal
mesh_terms: D000465:Algorithms; D002874:Chromosome Mapping; D000431:Ethanol / Q000494:pharmacology*; D008040:Genetic Linkage; D015810:Linkage Disequilibrium; D008390:Markov Chains; D010641:Phenotype; D040641:Quantitative Trait Loci; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics
chemical_list: D000431:Ethanol