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          Institute: MPI für molekulare Genetik     Collection: Department of Vertebrate Genomics     Display Documents



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ID: 552732.0, MPI für molekulare Genetik / Department of Vertebrate Genomics
A new dominant peroxiredoxin allele identified by whole-genome re-sequencing of random mutagenized yeast causes oxidant-resistance and premature aging.
Authors:Timmermann, B.; Jarolim, S.; Russmayer, H.; Kerick, M.; Michel, S.; Krüger, A.; Bluemlein, K.; Laun, P.; Grillari, J.; Lehrach, H.; Breitenbach, M.; Ralser, M.
Language:English
Research Context:EC (Brussels, Europe) for project MIMAGE (contract no. 512020; to M.B.) and to the Austrian Science Fund FWF (Vienna, Austria) for grant S9302-B05 (to M.B.) and S9306 (to JG).
Date of Publication (YYYY-MM-DD):2010-08-13
Title of Journal:Aging (Albany NY)
Journal Abbrev.:Aging (Albany NY)
Volume:2
Issue / Number:8
Start Page:475
End Page:486
Copyright:© Timmermann et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Review Status:not specified
Audience:Experts Only
Abstract / Description:The combination of functional genomics with next generation sequencing facilitates new experimental strategies for addressing complex biological phenomena. Here, we report the identification of a gain-of-function allele of peroxiredoxin (thioredoxin peroxidase, Tsa1p) via whole-genome re-sequencing of a dominantSaccharomyces cerevisiae mutant obtained by chemical mutagenesis. Yeast strain K6001, a screening system for lifespan phenotypes, was treated with ethyl methanesulfonate (EMS). We isolated an oxidative stress-resistant mutant (B7) which transmitted this phenotype in a background-independent, monogenic and dominant way. By massive parallel pyrosequencing, we generated an 38.8 fold whole-genome coverage of the strains, which differed in 12,482 positions from the reference (S288c) genome. Via a subtraction strategy, we could narrow this number to 13 total and 4 missense nucleotide variations that were specific for the mutant. Via expression in wild type backgrounds, we show that one of these mutations, exchanging a residue in the peroxiredoxin Tsa1p, was responsible for the mutant phenotype causing background-independent dominant oxidative stress-resistance. These effects were not provoked by altered Tsa1p levels, nor could they be simulated by deletion, haploinsufficiency or over-expression of the wild-type allele. Furthermore, via both a mother-enrichment technique and a micromanipulation assay, we found a robust premature aging phenotype of this oxidant-resistant strain. Thus, TSA1-B7 encodes for a novel dominant form of peroxiredoxin, and establishes a new connection between oxidative stress and aging. In addition, this study shows that the re-sequencing of entire genomes is becoming a promising alternative for the identification of functional alleles in approaches of classic molecular genetics.
Free Keywords:Aging,
whole genome resequencing,
redox homeostasis,
peroxiredoxin
Comment of the Author/Creator:Corresponding author: Markus Ralser, PhD
E-mail: ralser@molgen.mpg.de
External Publication Status:published
Document Type:Article
Communicated by:Hans Lehrach
Affiliations:MPI für molekulare Genetik
External Affiliations:1.Department of Cell Biology, University of Salzburg, 5020 Salzburg, Austria;
2.Institute of Applied Microbiology, University of Natural Resources and Applied Life Sciences, 1180 Vienna, Austria.
Identifiers:ISSN:1945-4589 [ID No:1]
URL:http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=... [ID No:2]
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