title: Sequential elimination of major-effect contributors identifies additional quantitative trait loci conditioning high-temperature growth in yeast.
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.
authors.affiliation: European Molecular Biology Laboratory, Heidelberg, Germany.
authors.forename: Himanshu
authors.initials: H
authors.lastname: Sinha
authors.forename: Lior
authors.initials: L
authors.lastname: David
authors.forename: Renata C
authors.initials: RC
authors.lastname: Pascon
authors.forename: Sandra
authors.initials: S
authors.lastname: Clauder-Münster
authors.forename: Sujatha
authors.initials: S
authors.lastname: Krishnakumar
authors.forename: Michelle
authors.initials: M
authors.lastname: Nguyen
authors.forename: Getao
authors.initials: G
authors.lastname: Shi
authors.forename: Jed
authors.initials: J
authors.lastname: Dean
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Davis
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Oefner
authors.forename: John H
authors.initials: JH
authors.lastname: McCusker
authors.forename: Lars M
authors.initials: LM
authors.lastname: Steinmetz
mesh_terms: D002874:Chromosome Mapping; D004843:Epistasis, Genetic; D015966:Gene Expression Regulation, Fungal; D008040:Genetic Linkage; D006358:Hot Temperature; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics*; D012331:RNA, Fungal / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*
chemical_list: D012331:RNA, Fungal; D029701:Saccharomyces cerevisiae Proteins
references.citation: FEMS Yeast Res. 2007 Sep;7(6):941-52
references.pmid: 17537182
references.citation: Nat Genet. 2004 Nov;36(11):1197-202
references.pmid: 15489855
references.citation: Genetics. 1989 Jan;121(1):185-99
references.pmid: 2563713
references.citation: Annu Rev Genomics Hum Genet. 2006;7:339-67
references.pmid: 16756480
references.citation: Genetics. 2002 Aug;161(4):1395-410
references.pmid: 12196388
references.citation: Nat Rev Genet. 2004 Aug;5(8):618-25
references.pmid: 15266344
references.citation: Mol Cell. 2006 Oct 6;24(1):139-48
references.pmid: 17018299
references.citation: Nat Genet. 2007 Feb;39(2):199-206
references.pmid: 17206143
references.citation: Nat Genet. 2007 Apr;39(4):496-502
references.pmid: 17334364
references.citation: Mol Biol Cell. 2003 Nov;14(11):4329-41
references.pmid: 14551258
references.citation: Genetics. 2006 Oct;174(2):985-97
references.pmid: 16951083
references.citation: Genome Res. 2003 Jul;13(7):1654-64
references.pmid: 12805272
references.citation: Genetics. 2006 Jul;173(3):1813-6
references.pmid: 16624899
references.citation: Nature. 2005 Aug 4;436(7051):701-3
references.pmid: 16079846
references.citation: Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1572-7
references.pmid: 15659551
references.citation: Hum Mutat. 2002 Apr;19(4):315-23
references.pmid: 11933186
references.citation: Nature. 2005 May 5;435(7038):95-8
references.pmid: 15875023
references.citation: Nat Genet. 2003 Sep;35(1):57-64
references.pmid: 12897782
references.citation: Yeast. 1994 Dec;10(13):1793-808
references.pmid: 7747518
references.citation: PLoS Genet. 2007 Feb 23;3(2):e31
references.pmid: 17319748
references.citation: Science. 2002 Apr 26;296(5568):752-5
references.pmid: 11923494
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 31;104(31):12825-30
references.pmid: 17652520
references.citation: Genetics. 2007 Feb;175(2):891-905
references.pmid: 17179089
references.citation: Nat Genet. 2006 Aug;38(8):879-87
references.pmid: 16832355
references.citation: Nat Rev Genet. 2005 Apr;6(4):271-86
references.pmid: 15803197
references.citation: Philos Trans R Soc Lond B Biol Sci. 2005 Jul 29;360(1459):1503-11
references.pmid: 16048792
references.citation: Stat Appl Genet Mol Biol. 2007;6:Article12
references.pmid: 17474878
references.citation: Genetics. 1994 Apr;136(4):1261-9
references.pmid: 8013903
references.citation: PLoS Biol. 2008 Apr 15;6(4):e83
references.pmid: 18416601
references.citation: Clin Infect Dis. 2005 Dec 1;41(11):1559-68
references.pmid: 16267727
references.citation: PLoS Genet. 2006 Nov 17;2(11):e195
references.pmid: 17112318
references.citation: Science. 2002 Dec 20;298(5602):2345-9
references.pmid: 12493905
references.citation: PLoS Genet. 2006 Feb;2(2):e13
references.pmid: 16462944
references.citation: Genetics. 1996 Aug;143(4):1807-17
references.pmid: 8844166
references.citation: Genetics. 2007 Mar;175(3):1479-87
references.pmid: 17194785
references.citation: Hum Mol Genet. 2002 Oct 1;11(20):2463-8
references.pmid: 12351582
references.citation: Nature. 2006 Jan 19;439(7074):326-30
references.pmid: 16327777
references.citation: J Infect Dis. 1994 Apr;169(4):859-67
references.pmid: 8133102
references.citation: PLoS Genet. 2006 Mar;2(3):e35
references.pmid: 16552446
references.citation: Nat Genet. 2003 Mar;33 Suppl:228-37
references.pmid: 12610532
references.citation: Science. 1998 Aug 21;281(5380):1194-7
references.pmid: 9712584
references.citation: Nat Rev Genet. 2001 Jan;2(1):11-20
references.pmid: 11253063
references.citation: Nat Genet. 1998 Jan;18(1):19-24
references.pmid: 9425894
references.citation: Nat Rev Genet. 2002 Jan;3(1):11-21
references.pmid: 11823787
references.citation: Science. 1996 Oct 25;274(5287):546, 563-7
references.pmid: 8849441
references.citation: Nature. 2002 Mar 21;416(6878):326-30
references.pmid: 11907579
references.citation: Proc Natl Acad Sci U S A. 2006 Apr 4;103(14):5320-5
references.pmid: 16569694
references.citation: Curr Opin Genet Dev. 2004 Jun;14(3):253-7
references.pmid: 15172667
references.citation: Proc Natl Acad Sci U S A. 2001 Jan 2;98(1):31-6
references.pmid: 11134512
references.citation: Yeast. 2006 Mar;23(4):293-306
references.pmid: 16544271
references.citation: Nat Genet. 2005 Dec;37(12):1333-40
references.pmid: 16273108
references.citation: Yeast. 1999 Oct;15(14):1541-53
references.pmid: 10514571