title: Revealing the genetic structure of a trait by sequencing a population under selection.
abstract: One approach to understanding the genetic basis of traits is to study their pattern of inheritance among offspring of phenotypically different parents. Previously, such analysis has been limited by low mapping resolution, high labor costs, and large sample size requirements for detecting modest effects. Here, we present a novel approach to map trait loci using artificial selection. First, we generated populations of 10-100 million haploid and diploid segregants by crossing two budding yeast strains of different heat tolerance for up to 12 generations. We then subjected these large segregant pools to heat stress for up to 12 d, enriching for beneficial alleles. Finally, we sequenced total DNA from the pools before and during selection to measure the changes in parental allele frequency. We mapped 21 intervals with significant changes in genetic background in response to selection, which is several times more than found with traditional linkage methods. Nine of these regions contained two or fewer genes, yielding much higher resolution than previous genomic linkage studies. Multiple members of the RAS/cAMP signaling pathway were implicated, along with genes previously not annotated with heat stress response function. Surprisingly, at most selected loci, allele frequencies stopped changing before the end of the selection experiment, but alleles did not become fixed. Furthermore, we were able to detect the same set of trait loci in a population of diploid individuals with similar power and resolution, and observed primarily additive effects, similar to what is seen for complex trait genetics in other diploid organisms such as humans.
authors.affiliation: The Wellcome Trust Sanger Institute, Hinxton, United Kingdom. leopold.parts@sanger.ac.uk
authors.forename: Leopold
authors.initials: L
authors.lastname: Parts
authors.forename: Francisco A
authors.initials: FA
authors.lastname: Cubillos
authors.forename: Jonas
authors.initials: J
authors.lastname: Warringer
authors.forename: Kanika
authors.initials: K
authors.lastname: Jain
authors.forename: Francisco
authors.initials: F
authors.lastname: Salinas
authors.forename: Suzannah J
authors.initials: SJ
authors.lastname: Bumpstead
authors.forename: Mikael
authors.initials: M
authors.lastname: Molin
authors.forename: Amin
authors.initials: A
authors.lastname: Zia
authors.forename: Jared T
authors.initials: JT
authors.lastname: Simpson
authors.forename: Michael A
authors.initials: MA
authors.lastname: Quail
authors.forename: Alan
authors.initials: A
authors.lastname: Moses
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Louis
authors.forename: Richard
authors.initials: R
authors.lastname: Durbin
authors.forename: Gianni
authors.initials: G
authors.lastname: Liti
mesh_terms: D000483:Alleles; D002874:Chromosome Mapping; D004271:DNA, Fungal / Q000235:genetics; D004171:Diploidy; D005786:Gene Expression Regulation; D005787:Gene Frequency; D015723:Gene Library; D008040:Genetic Linkage; D005828:Genetics, Population / Q000379:methods*; D016678:Genome; D006238:Haploidy; D006239:Haplotypes; D008954:Models, Biological; D010641:Phenotype; D040641:Quantitative Trait Loci; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000254:growth & development; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA / Q000379:methods*; D015398:Signal Transduction; D013696:Temperature
chemical_list: D004271:DNA, Fungal