title: Natural genetic variation in yeast longevity.
abstract: The genetics of aging in the yeast Saccharomyces cerevisiae has involved the manipulation of individual genes in laboratory strains. We have instituted a quantitative genetic analysis of the yeast replicative lifespan by sampling the natural genetic variation in a wild yeast isolate. Haploid segregants from a cross between a common laboratory strain (S288c) and a clinically derived strain (YJM145) were subjected to quantitative trait locus (QTL) analysis, using 3048 molecular markers across the genome. Five significant, replicative lifespan QTL were identified. Among them, QTL 1 on chromosome IV has the largest effect and contains SIR2, whose product differs by five amino acids in the parental strains. Reciprocal gene swap experiments showed that this gene is responsible for the majority of the effect of this QTL on lifespan. The QTL with the second-largest effect on longevity was QTL 5 on chromosome XII, and the bulk of the underlying genomic sequence contains multiple copies (100-150) of the rDNA. Substitution of the rDNA clusters of the parental strains indicated that they play a predominant role in the effect of this QTL on longevity. This effect does not appear to simply be a function of extrachromosomal ribosomal DNA circle production. The results support an interaction between SIR2 and the rDNA locus, which does not completely explain the effect of these loci on longevity. This study provides a glimpse of the complex genetic architecture of replicative lifespan in yeast and of the potential role of genetic variation hitherto unsampled in the laboratory.
authors.affiliation: Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana 70112, USA.
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Stumpferl
authors.forename: Sue E
authors.initials: SE
authors.lastname: Brand
authors.forename: James C
authors.initials: JC
authors.lastname: Jiang
authors.forename: Boguslawa
authors.initials: B
authors.lastname: Korona
authors.forename: Anurag
authors.initials: A
authors.lastname: Tiwari
authors.forename: Jianliang
authors.initials: J
authors.lastname: Dai
authors.forename: Jae-Gu
authors.initials: JG
authors.lastname: Seo
authors.forename: S Michal
authors.initials: SM
authors.lastname: Jazwinski
mesh_terms: D002874:Chromosome Mapping; D004275:DNA, Ribosomal / Q000235:genetics; D015966:Gene Expression Regulation, Fungal; D014644:Genetic Variation; D008136:Longevity; D008969:Molecular Sequence Data; D040641:Quantitative Trait Loci; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000254:growth & development; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae / Q000235:genetics; D056565:Sirtuin 2 / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D004275:DNA, Ribosomal; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae; C087778:SIR2 protein, S cerevisiae; D056565:Sirtuin 2