Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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Stress tolerance and lifespan in C. elegans are modulated by natural allelic variation in CMK-1
Snoek, L.B. ; Sterken, M.G. ; Bevers, R.P.J. ; Volkers, J.M. ; Hof, A. van 't; Brenchley, R. ; Lehner, B. ; Cossins, A. ; Kammenga, J.E. - \ 2016
Genetic control of aging in C. elegans has primarily been studied using
derived mutants of the strain N2. These mutants often display extreme
lifespan accompanied by increased stress resistance. Yet, identification of
genes that underlie variation in lifespan and stress tolerance in natural
populations remains a major challenge. We investigated gene expression
architecture and longevity and found that stress tolerance and lifespan in C.
elegans are modulated by natural allelic variation in cmk-1.
Variation in gene expression levels was linked to genomic loci (eQTL)
using fully sequenced recombinant inbred populations derived from
divergent wild-type strains N2 and CB4856. In these strains regulatory loci
were identified under standard and under heat-stress conditions. After
verification, the causal regulator was identified by screening knock-out
mutants of candidate genes. Moreover, lifespan was measured under
standard conditions and in strains that received a heat shock treatment.
We identified a major stress-related regulatory locus that affects expression
variation in more than 100 genes and one of the causal genes was found to
be cmk-1. The effects of this variation include modulation of insulin-like
signaling targets supporting a model in which allelic variation in cmk-1
regulates a subset of daf-16 targets under stress conditions, leading to
increased stress resistance and prolonged lifespan.
In conclusion, genes affecting lifespan variation in nature may not be those
identified by mutagenizing a single C. elegans strain. Our data suggests that
pathways previously associated with aging are affected, but not by the usual
suspects.
Stress tolerance and lifespan in C. elegans are modulated by natural allelic variation in cmk-1
Sterken, M.G. ; Snoek, L.B. ; Bevers, R.P.J. ; Volkers, R.J.M. ; Hof, A. van 't; Brenchley, R. ; Lehner, B. ; Cossins, A. ; Kammenga, J.E. - \ 2015
In: Proceedings of Molecular Biology of Ageing 2015. - - p. 134 - 134.
Genetic control of aging in C. elegans has primarily been studied using derived mutants of the strain N2. These mutants often display extreme lifespan accompanied by increased stress resistance. Yet, identification of genes that underlie variation in lifespan and stress tolerance in natural populations remains a major challenge. We investigated gene expression architecture and longevity and found that stress tolerance and lifespan in C. elegans are modulated by natural allelic variation in cmk-1. Variation in gene expression levels was linked to genomic loci (eQTL) using fully sequenced recombinant inbred populations derived from divergent wild-type strains N2 and CB4856. In these strains regulatory loci were identified under standard and under heat-stress conditions. After verification, the causal regulator was identified by screening knock-out mutants of candidate genes. Moreover, lifespan was measured under standard conditions and in strains that received a heat shock treatment. We identified a major stress-related regulatory locus that affects expression variation in more than 100 genes and one of the causal genes was found to be cmk-1. The effects of this variation include modulation of insulin-like signaling targets supporting a model in which allelic variation in cmk-1 regulates a subset of daf-16 targets under stress conditions, leading to increased stress resistance and prolonged lifespan. In conclusion, genes affecting lifespan variation in nature may not be those identified by mutagenizing a single C. elegans strain. Our data suggests that pathways previously associated with aging are affected, but not by the usual suspects.
Stress tolerance and lifespan in C. elegans are modulated by natural allelic variation in cmk-1
Sterken, M.G. ; Snoek, L.B. ; Bevers, R.P.J. ; Volkers, J.M. ; Hof, A. van 't; Brenchley, R. ; Lehner, B. ; Cossins, A. ; Kammenga, J.E. - \ 2015
Polymorphic regions and genes affecting gene transcription regulation of stress response and prolonged lifespan
Sterken, M.G. ; Snoek, L.B. ; Bevers, R.P.J. ; Volkers, R.J.M. ; Hof, A. van 't; Brenchley, R. ; Cleef, E. van; Bartels, R. ; Laven, Y. ; Riksen, J.A.G. ; Valba, O. ; Chavali, S. ; Lang, B. ; Francesconi, M. ; Bot, J. ; Nechaev, S. ; Vasieva, O. ; Babu, M. ; Lehner, B. ; Cossins, A. ; Kammenga, J.E. - \ 2014
In: Proceedings of Evolutionary Biology of Caenorhabditis and other Nematodes. - - p. 33 - 33.
Stress and cellular stress responses underlie many age-related diseases and understanding the causal link between the two is essential for promoting healthy aging strategies. There is accumulating evidence that exposure to a mild stressor induces an adaptive response that increases eukaryotic lifespan. Insight in the biological pathways associated with lifespan has been provided by, amongst others, transcriptome analysis. But so far it is unclear how natural genetic variation affects the complex transcriptional architecture which links stress response and lifespan. Here we report the detection of polymorphic regions in the genome (eQTL) and genes that regulate stress induced gene expression levels and prolong lifespan in the nematode C. elegans. Using 106 fully sequenced recombinant inbred lines (genetic mosaics and introgression lines) we found that heat-shock profoundly affected polymorphic distant gene expression regulators (distant-eQTL). A strong distant-eQTL affecting many transcripts was detected on the top left arm of chromosome IV. This eQTL coincided with a lifespan QTL and was validated by the gene expression profiles of introgression lines. Based on gene-network assisted candidate gene selection on the distant-eQTL, gene expression analysis of mutants carrying these candidate genes (cmk-1, egl-4, daf-11, eor-1 and unc-70) confirmed the eQTL. We found egl-4, and cmk-1 to be causally affecting gene expression patterns, stress resistance and prolonged lifespan. Our results show that natural variation affects stress response and lifespan by affecting thermo sensory circuits. This is the first study which unveils the transcriptional architecture and identifies genes linking stress response and lifespan based on natural genetic variation which opens up opportunities to genetically dissect age-related diseases.
“All” the sequence polymorphisms between Hawaii (CB4856) and Bristol (N2)
Snoek, L.B. ; Brenchley, R. ; Hof, A. van 't; Bevers, R.P.J. ; Bono, M. de; Hajnal, A. ; Schmid, T. ; Weber, K. ; Francesconi, M. ; Lehner, B. ; Cossins, A. ; Kammenga, J.E. - \ 2012
In: Abstracts of papers presented at the Evolution of Caenorhabditis and Other Nematodes, Cold Spring Harbor Laboratory, New York, USA, 3-6 April 2012. - - p. 47 - 47.
“All” the sequence polymorphisms between Hawaii (CB4856) and Bristol (N2) Basten L Snoek¹, Rachel Brenchley², Arjen van 't Hof², Roel P Bevers¹, Mario de Bono³, Alex Hajnal4, Tobias Schmid4, Kate Weber³, Mirko Francesconi5, Ben Lehner5, Andy Cossins², Jan E Kammenga¹ 1Wageningen University, Nematology, Wageningen, 7608PB, Netherlands, ²University of Liverpool, Institute of Integrative Biology, Liverpool, L69 7ZB, United Kingdom, ³Medical Research Council, Molecular Biology, Cambridge, CB2 0QH, United Kingdom, 4 University of Zurich, Molecular Life Sciences, Zurich, CH-8057 , Switzerland, 5EMBL-Centre for Genomic Regulation, Systems Biology, Barcelona, 08003, Spain The decreasing costs and increasing throughput of next generation sequencing over the last 5 years has put sequencing of different genotypes of one species within reach , also for C. elegans. The availability of the full genome sequences of individual genotypes will identify “all” the genetic polymorphisms between them. These can be used in several ways: I) to clone new mutations, II) to calculate genetic distances, III) to find genomic sites of positive selection and IV) to find the genes (and polymorphisms) causal for natural phenotypic variation. Since most induced mutations are made in an N2 background a different stain is used to find the exact site of this mutation, often this is CB4856. Most studies on the sources of natural variation have been done on a population derived from a cross between CB4856 and N2. Even though CB4856 is so frequently used it yet has to be sequenced. Here, we present the full genome sequence of CB4856 in a format that enables easy access to the worm community. Three independent strains of CB4856 were sequenced in three different labs (Kammenga/Cossins, De Bono and Hajnal). The Kammenga/Cossins approach used the sequences of 102 recombinant inbred lines, including CB4856 and N2, which together contain the full N2 and CB4856 genome. This led to a mean coverage over 500x. The de Bono and Hajnal labs both sequenced the CB4856 with 10x coverage. These were independently aligned to the N2 reference sequence after which polymorphisms were extracted. We found almost 93,000 SNPs between N2 and CB4856. Of those almost 11,000 led to an amino acid change in almost 6,300 genes. The polymorphisms were not distributed equally over the genome. Differences in SNP frequency between, as well as within, chromosomes were found. Also loci with a high frequency of amino acid polymorphisms could be identified. Several groups of genes were enriched for SNPs and amino acid changes; these include the chemo receptors, c-type lectins and f-box proteins. Funded by: ERASysBio+ project GRAPPLE - Iterative modelling of gene regulatory interactions underlying stress, disease and ageing in C. elegans EU 7th Framework Programme under the Research Project PANACEA, contract nr 222936.
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