title: High-resolution mapping of complex traits with a four-parent advanced intercross yeast population.
abstract: A large fraction of human complex trait heritability is due to a high number of variants with small marginal effects and their interactions with genotype and environment. Such alleles are more easily studied in model organisms, where environment, genetic makeup, and allele frequencies can be controlled. Here, we examine the effect of natural genetic variation on heritable traits in a very large pool of baker's yeast from a multiparent 12th generation intercross. We selected four representative founder strains to produce the Saccharomyces Genome Resequencing Project (SGRP)-4X mapping population and sequenced 192 segregants to generate an accurate genetic map. Using these individuals, we mapped 25 loci linked to growth traits under heat stress, arsenite, and paraquat, the majority of which were best explained by a diverging phenotype caused by a single allele in one condition. By sequencing pooled DNA from millions of segregants grown under heat stress, we further identified 34 and 39 regions selected in haploid and diploid pools, respectively, with most of the selection against a single allele. While the most parsimonious model for the majority of loci mapped using either approach was the effect of an allele private to one founder, we could validate examples of pleiotropic effects and complex allelic series at a locus. SGRP-4X is a deeply characterized resource that provides a framework for powerful and high-resolution genetic analysis of yeast phenotypes and serves as a test bed for testing avenues to attack human complex traits.
authors.affiliation: Centre for Genetics and Genomics, Queen's Medical Centre, University of Nottingham, Nottingham, NG7 2UH, United Kingdom.
authors.forename: Francisco A
authors.initials: FA
authors.lastname: Cubillos
authors.forename: Leopold
authors.initials: L
authors.lastname: Parts
authors.forename: Francisco
authors.initials: F
authors.lastname: Salinas
authors.forename: Anders
authors.initials: A
authors.lastname: Bergström
authors.forename: Eugenio
authors.initials: E
authors.lastname: Scovacricchi
authors.forename: Amin
authors.initials: A
authors.lastname: Zia
authors.forename: Christopher J R
authors.initials: CJ
authors.lastname: Illingworth
authors.forename: Ville
authors.initials: V
authors.lastname: Mustonen
authors.forename: Sebastian
authors.initials: S
authors.lastname: Ibstedt
authors.forename: Jonas
authors.initials: J
authors.lastname: Warringer
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: D002874:Chromosome Mapping / Q000379:methods*; D003433:Crosses, Genetic; D005787:Gene Frequency; D005800:Genes, Fungal; D056726:Genetic Association Studies; D014644:Genetic Variation; D018869:Heat-Shock Response / Q000235:genetics; D006801:Humans; D008957:Models, Genetic; D010802:Phylogeny; D040641:Quantitative Trait Loci; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism
keywords: artificial selection; genetics; meiotic recombination; quantitative traits; yeast
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