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The hypoxia-response pathway modulates RAS/MAPK–mediated cell fate decisions in Caenorhabditis elegans
Maxeiner, S. ; Grolleman, J. ; Schmid, Tobias ; Kammenga, J.E. ; Hajnal, Alex - \ 2019
Life Science Alliance 2 (2019)3. - ISSN 2575-1077
Animals need to adjust many cellular functions to oxygen availability to adapt to changing environmental conditions. We have used the nematode Caenorhabditis elegans as a model to investigate how variations in oxygen concentrations affect cell fate specification during development. Here, we show that several processes controlled by the conserved RTK/RAS/MAPK pathway are sensitive to changes in the atmospheric oxygen concentration. In the vulval precursor cells (VPCs), the hypoxia-inducible factor HIF-1 activates the expression of the nuclear hormone receptor NHR-57 to counteract RAS/MAPK–induced differentiation. Furthermore, cross-talk between the NOTCH and hypoxia-response pathways modulates the capability of the VPCs to respond to RAS/MAPK signaling. Lateral NOTCH signaling positively regulates the prolyl hydroxylase EGL-9, which promotes HIF-1 degradation in uncommitted VPCs and permits RAS/MAPK–induced differentiation. By inducing DELTA family NOTCH ligands, RAS/MAPK signaling creates a positive feedback loop that represses HIF-1 and NHR-57 expression in the proximal VPCs and keeps them capable of differentiating. This regulatory network formed by the NOTCH, hypoxia, and RAS/MAPK pathways may allow the animals to adapt developmental processes to variations in oxygen concentration.
Ras/MAPK Modifier Loci Revealed by eQTL in Caenorhabditis elegans
Sterken, Mark G. ; Bemmelen-van der Plaat, Linda van; Riksen, Joost A. ; Rodriguez, Miriam ; Schmid, Tobias ; Hajnal, Alex ; Kammenga, Jan E. ; Snoek, Basten L. - \ 2017
G3 : Genes Genomes Genetics 7 (2017)9. - ISSN 2160-1836 - p. 3185 - 3193.
The oncogenic Ras/MAPK pathway is evolutionarily conserved across metazoans. Yet, almost all our knowledge on this pathway comes from studies using single genetic backgrounds, whereas mutational effects can be highly background dependent. Therefore, we lack insight in the interplay between genetic backgrounds and the Ras/MAPK-signaling pathway. Here, we used a Caenorhabditis elegans RIL population containing a gain-of-function mutation in the Ras/MAPK pathway gene let-60 and measured how gene expression regulation is affected by this mutation. We mapped eQTL and found that the majority (~73%) of the 1516 detected cis-eQTL were not specific for the let-60 mutation, whereas most (~76%) of the 898 detected trans-eQTL were associated with the let-60 mutation. We detected 6 eQTL trans-bands specific for the interaction between the genetic background and the mutation, one of which co-localized with the polymorphic Ras/MAPK modifier amx-2. Comparison between transgenic lines expressing allelic variants of amx-2 showed the involvement of amx-2 in 79% of the trans-eQTL for genes mapping to this trans-band. Together, our results have revealed loci hidden loci affecting Ras/MAPK signaling using sensitized backgrounds in C. elegans. These loci harbor putative polymorphic modifier genes that would not have been detected using mutant screens in single genetic backgrounds.
Remarkably divergent regions punctuate the genome assembly of the Caenorhabditis elegans Hawaiian strain CB4856
Thompson, O.A. ; Snoek, L.B. ; Nijveen, H. ; Sterken, M.G. ; Volkers, R.J.M. ; Brenchley, R. ; Hof, A. van 't; Bevers, R.P.J. ; Cossins, A.R. ; Yanai, I. ; Hajnal, A. ; Schmid, T. ; Perkins, J.D. ; Spencer, D. ; Kruglyak, L. ; Andersen, E.C. ; Moerman, D.G. ; Hillier, L.W. ; Kammenga, J.E. ; Waterston, R.H. - \ 2015
Genetics 200 (2015)3. - ISSN 0016-6731 - p. 975 - 989.
natural variation data - c. elegans - arabidopsis-thaliana - gene - polymorphism - populations - diversity - nematodes - dna - evolutionary
The Hawaiian strain (CB4856) of Caenorhabditis elegans is one of the most divergent from the canonical laboratory strain N2 and has been widely used in developmental, population and evolutionary studies. To enhance the utility of the strain, we have generated a draft sequence of the CB4856 genome, exploiting a variety of resources and strategies. The CB4856 genome when compared against the N2 reference has 327,050 single nucleotide variants (SNVs) and 79,529 insertion-deletion events (indels) that result in a total of 3.3 megabasepairs (Mb) of N2 sequence missing from CB4856 and 1.4 Mb of sequence present in CB4856 not present in N2. As previously reported, the density of SNVs varies along the chromosomes, with the arms of chromosomes showing greater average variation than the centers. In addition, we find 61 regions totaling 2.8 Mb, distributed across all six chromosomes, that have a greatly elevated SNV density, ranging from 2% to 16% SNVs. A survey of other wild isolates show that the two alternative haplotypes for each region are widely distributed, suggesting they have been maintained by balancing selection over long evolutionary times. These divergent regions contain an abundance of genes from large rapidly evolving families encoding F-box, MATH, BATH, seven-transmembrane G-coupled receptors, and nuclear hormone receptors suggesting that they provide selective advantages in natural environments. The draft sequence makes available a comprehensive catalog of sequence differences between the CB4856 and N2 strains that will facilitate the molecular dissection of their phenotypic differences. Our work also emphasizes the importance of going beyond simple alignment of reads to a reference genome when assessing differences between genomes.
Systemic Regulation of RAS/MAPK Signaling by the Serotonin Metabolite 5-HIAA
Schmid, T. ; Snoek, L.B. ; Fröhli, E. ; Bent, M.L. van der; Kammenga, J.E. ; Hajnal, A. - \ 2015
Plos Genetics 11 (2015)5. - ISSN 1553-7404 - 16 p.
caenorhabditis-elegans - c-elegans - natural variation - vulvar induction - complex disease - receptor - protein - gene - kinase - activation
Human cancer is caused by the interplay of mutations in oncogenes and tumor suppressor genes and inherited variations in cancer susceptibility genes. While many of the tumor initiating mutations are well characterized, the effect of genetic background variation on disease onset and progression is less understood. We have used C. elegans genetics to identify genetic modifiers of the oncogenic RAS/MAPK signaling pathway. Quantitative trait locus analysis of two highly diverged C. elegans isolates combined with allele swapping experiments identified the polymorphic monoamine oxidase A (MAOA) gene amx-2 as a negative regulator of RAS/MAPK signaling. We further show that the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), which is a product of MAOA catalysis, systemically inhibits RAS/MAPK signaling in different organs of C. elegans. Thus, MAOA activity sets a global threshold for MAPK activation by controlling 5-HIAA levels. To our knowledge, 5-HIAA is the first endogenous small molecule that acts as a systemic inhibitor of RAS/MAPK signaling.
|Identifying modifiers of Wnt and EGFR/RAS/MAPK signaling through quantitative C. elegans genetics
Maxeiner, S. ; Schmid, T. ; Snoek, L.B. ; Rodriguez Sanchez, M. ; Largey, F. ; Bent, L. van der; Kammenga, J.E. ; Hajnal, A.F. - \ 2014
In: Proceedings of the FEBS-EMBO 2014. - - p. 474 - 474.
A number of studies aim at investigating the origin and potential treatment of monogenic diseases. However, polygenic diseases arising from an interplay between several malfunctioning signaling pathways are the predominant cause of up to 60% of deaths in the human population. Quantitative genetic approaches provide a powerful tool to elucidate genetic risk factors underlying such complex diseases. We use two isolates of C. elegans, N2 Bristol and CB4856 Hawaii to study the influence of naturally occurring polymorphisms on mutant genetic backgrounds well-known to promote diseases such as cancer. We chose the development of the C. elegans vulva as the phenotypic readout of Wnt and EGFR/RAS/MAPK signaling activity, where changes in signaling result in either a multivulva or vulvaless phenotype that can be quantified at single-cell resolution. Previous work has established comprehensive QTL maps spanning the entire genome. We generated these maps by comparing an N2 strain carrying a mutation in ras/let-60 or ß-catenin/bar-1 to animals carrying the let-60 or bar-1 mutation in a mixed N2/CB4856 background (so called mutation included recombinant inbred lines, miRILs). Interestingly, one QTL on the first chromosome (LGI) is shared between the two mutant backgrounds suggesting a link between Wnt and Ras signaling. We are currently identifying polymorphic modifier genes of the two pathways. To this aim, we narrow down a genomic region containing the QTL by generating N2 strains carrying well-defined CB4856 introgressions and by performing RNAi knock-down of candidate genes followed by mutant analysis.
|Bar-1 loss-of-function causes a developmental delay in intertwined with a DAF-16 stress response
Sterken, M.G. ; Bent, M.L. van der; Volkers, R.J.M. ; Riksen, J.A.G. ; Schmid, T. ; Hajnal, A. ; Kammenga, J.E. ; Snoek, L.B. - \ 2014
In: Proceedings of the Berlin C. elegans Meeting 2014. - - p. 241 - 241.
The Wnt/â-catenin pathway is a key development pathway in metazoans. C. elegans has been extensively used as a model species to study the Wnt pathway. Four â-catenins in C. elegans are important gene expression regulators in Wnt signalling. One of these, bar-1, is part of the canonical Wnt pathway. Together with Wnt effector POP-1, BAR-1 forms a transcription activation complex which regulates the transcription of downstream genes. The effects of bar-1 loss-of-function mutations on many phenotypes, like vulval development and neuronal migration, have been studied well. However, the effects on global gene expression remain largely unknown. The transcriptional profiles of the strain EW15, carrying bar-1(ga80)lof, and Bristol N2 were measured in the L4 stage of age-synchronized populations at 48 hours. Gene expression differences were combines whit ChiP-seq data from the modENCODE project to pinpoint involved transcription factors. Genes differentially expressed between EW15 and N2 showed strong signs that development of bar-1(ga80)lof was slowed down. We verified this observation by measuring the timing of egg-hatching and egg-laying. The development delay increased over time, ranging from 0 hours at the moment of egg-hatching to 6 hours at the moment of the egg laying. After correcting for this development delay, gene expression analysis revealed that the expression of many genes involved in the Wnt pathway were activated in the bar-1 mutant. Furthermore, the genes up-regulated in the bar-1 mutant showed enrichment for transcription factor activity. These up-regulated genes show strong indications of DAG-16 involvement by the combination of modENCODE ChiP-seq data as well as known DAF-16 regulated genes. Together our findings show that bar-1 loss-of-function leads to delayed development and an activated Wnt pathway, and indicate that the DAF-16 stress-response is causative of this development delay.
Loss-of-function of b-catenin bar-1 slows development and activates the Wnt pathway in Caenorhabditis elegans
Bent, M.L. van der; Sterken, M.G. ; Volkers, J.M. ; Riksen, J.A.G. ; Schmid, T. ; Hajnal, A. ; Kammenga, J.E. ; Snoek, L.B. - \ 2014
Scientific Reports 4 (2014). - ISSN 2045-2322 - 7 p.
natural variation data - c-elegans - signaling components - neuroblast migration - negative regulator - vulval development - gene-expression - cell-migration - proteins - endoderm
C. elegans is extensively used to study the Wnt-pathway and most of the core-signalling components are known. Four beta-catenins are important gene expression regulators in Wnt-signalling. One of these, bar-1, is part of the canonical Wnt-pathway. Together with Wnt effector pop-1, bar-1 forms a transcription activation complex which regulates the transcription of downstream genes. The effects of bar-1 loss-of-function mutations on many phenotypes have been studied well. However, the effects on global gene expression are unknown. Here we report the effects of a loss-of-function mutation bar-1(ga80). By analysing the transcriptome and developmental phenotyping we show that bar-1(ga80) impairs developmental timing. This developmental difference confounds the comparison of the gene expression profile between the mutant and the reference strain. When corrected for this difference it was possible to identify genes that were directly affected by the bar-1 mutation. We show that the Wnt-pathway itself is activated, as well as transcription factors elt-3, pqm-1, mdl-1 and pha-4 and their associated genes. The outcomes imply that this response compensates for the loss of functional bar-1. Altogether we show that bar-1 loss-of function leads to delayed development possibly caused by an induction of a stress response, reflected by daf-16 activated genes.
|Uncovering hidden Wnt/beta-catenin enhancer in Caenorhabditis elegans
Rodriguez, M. ; Snoek, L.B. ; Schmid, T. ; Riksen, J.A.G. ; Samadi, N. ; Bent, L. van der; Grolleman, J. ; Hajnal, A. ; Kammenga, J.E. - \ 2013
In: Proceedings of 1st Annual Meeting, COST FA 1208, 09-11 October 2013, Birnam, Scotland. - - p. 55 - 55.
Background: Wnt/ß-catenin pathway is well conserved along metazoans and plays an essential role in important cellular functions such as specialization, migration, adhesion and development. Mutant analyses in C. elegans strain Bristol N2 have been widely studied. However mutations in a single genetic background do not reveal genome-wide allelic effects in natural populations and they are of limited value in the approach of complex human disease pathways, for which C. elegans is an important model species. Observations: Mutations in natural variants may revealed hidden polymorphic regulators, thus we investigated the phenotypic effects of bar-1(ga80) in a population of different C. elegans genotypes. Each genotype carries the bar-1 mutation in a genetic mosaic background resulting from the recombination of two of the most divergent C. elegans strains genotypes: Bristol N2 and Hawaii CB4856. We quantified genome-wide gene expression and measured the vulval development index (determined by the number of vulval precursor cells that undergo vulval development cell fate) and gonad migration across all genotypes. Quantitative genetics analysis identified loci on chromosome I and II which are associated to vulval development and gonad migration phenotypes. The two loci spanned regions of 300 Kbp on chromosome I harbouring 100 genes and 55 Kbp containing 15 genes on chromosome II. Experiments will be presented to reveal the candidate gene that plays the causal modifier role. Continue Conclusions: By applying forward genetics in different genotypes we have revealed hidden genetic modifiers affecting Wnt signalling pathway. We show that natural genetic variation provides a powerful means to study the cryptic variation harbouring new players in Wnt/ ß-catenin signalling.
|Natural variation in Monoamine Oxidase A modulates RAS/MAPK pathway activity during C. elegans vulval development
Schmid, T. ; Snoek, L.B. ; Rodriguez, M. ; Bent, L. van der; Despot Slade, E. ; Kammenga, J.E. ; Hajnal, A. - \ 2013
In: Proceedings of the 5th EMBO meeting, 21-24 September 2013, Amsterdam, the Netherlands. - - p. 49 - 49.
Background: The genetic background has a strong influence on the pathogenesis of many complex, polygenic human diseases. Therefore, detailed genetic studies are needed to decipher the underlying genetic risk factors in human diseases. We use the Nematode C. elegans as a model to study the interplay between cancer-related signaling pathways and genetic background. We focus on the RAS, Notch and WNT pathway genes, whose human orthologues have been shown to be involved in several complex diseases. Obervations: We are addressing the question of how the genetic background influences the output of these signaling networks. For this purpose, we crossed mutants in the RAS pathway originally isolated in the N2 Bristol background into the CB4856 strain isolated in Hawaii and established mutation included recombinant inbred lines (MIRILs). We then measured pathway activity of RAS of each RIL by scoring the number of differentiated vulval cells. A RIL sets containing a mutation in the RAS homologue let-60(gf) in a mixed Hawaii/Bristol background show strong variation in the penetrance and expressivity of the phenotype when compared to the mutant let-60(n1046) in the “pure” Bristol background. This indicates the presence of polymorphic modifiers affecting RAS signaling. Subsequently, we have identified by QTL mapping several genomic regions that contain those modifiers. Using RNAi knockdown and transgenesis, we could identify amx-2, homologous to human MAOA, as being important for suppression of RAS pathway activity. We are now further evaluating the link between the metabolism of biogenic amines such as Serotonin and Dopamine and their role in cancer signaling. Conclusions: By using a quantitative genetics approach, combined with classical genetics we identified amx-2/MAOA as a polymorphic modifier of RAS signaling during C. elegans vulval development.
|Uncovering genotype variation of Wnt signaling in C. elegans
Rodriguez, M. ; Snoek, L.B. ; Schmid, T. ; Samadi, N. ; Bent, L. van der; Hajnal, A. ; Kammenga, J.E. - \ 2013
In: Proceedings of the 19th International C.elegans Meeting, 26-30 June 2013, Los Angeles, California, USA. - - p. 330 - 331.
WormQTL—public archive and analysis web portal for natural variation data in Caenorhabditis spp
Snoek, L.B. ; Velde, K.J. van der; Arends, D. ; Li, Y. ; Beyer, A. ; Elvin, M. ; Fisher, J. ; Hajnal, A. ; Hengartner, M. ; Poulin, G. ; Rodriguez Sanchez, M. ; Schmid, T. ; Schrimpf, S. ; Xue, F. ; Jansen, R.C. ; Kammenga, J.E. ; Swertz, M.A. - \ 2013
Nucleic acids research 41 (2013)D1. - ISSN 0305-1048 - p. D738 - D743.
life-history traits - c. elegans - systems biology - qtl - polymorphism - genotype - environment - plasticity - platform - genome
Here, we present WormQTL (http://www.wormqtl.org), an easily accessible database enabling search, comparative analysis and meta-analysis of all data on variation in Caenorhabditis spp. Over the past decade, Caenorhabditis elegans has become instrumental for molecular quantitative genetics and the systems biology of natural variation. These efforts have resulted in a valuable amount of phenotypic, high-throughput molecular and genotypic data across different developmental worm stages and environments in hundreds of C. elegans strains. WormQTL provides a workbench of analysis tools for genotype–phenotype linkage and association mapping based on but not limited to R/qtl (http://www.rqtl.org). All data can be uploaded and downloaded using simple delimited text or Excel formats and are accessible via a public web user interface for biologists and R statistic and web service interfaces for bioinformaticians, based on open source MOLGENIS and xQTL workbench software. WormQTL welcomes data submissions from other worm researchers.
|Identification of polymorphic modifiers of ras and wnt signaling in C. elegans
Schmid, T. ; Largey, F. ; Rodriguez Sanchez, M. ; Snoek, L.B. ; Kammenga, J.E. ; Hajnal, A. - \ 2012
In: 4th International conference on Quantitative Genetics: Understanding Variation in Complex Traits, Edinburgh, Scotland, 17-22 June, 2012. - Edinburgh, Scotland : ICQG2012 - p. 224 - 224.
|Combining natural genetic variation and vulval development mutants in Caenorhabditis elegans to understand complex human disease pathways
Rodriguez Sanchez, M. ; Snoek, L.B. ; Schmid, T. ; Hajnal, A. ; Kammenga, J.E. - \ 2012
In: Model Organisms to Human Biology: Cancer Genetics, Washington, USA, 17-20 June, 2012. - Washington, USA : The Genetics Society of America - p. 89 - 90.
|“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.
|WormQTL – Public archive and analysis web portal for C. elegans natural variation data
Snoek, L.B. ; Li, Y. ; Velde, J.K. van der; Arends, D. ; Beyer, A. ; Elvin, M. ; Fisher, J. ; Hajnal, A. ; Hengartner, M. ; Poulin, G. ; Rodriguez Sanchez, M. ; Schmid, T. ; Schrimpf, S. ; Xue, F. ; Zheng, X. ; Jansen, R.C. ; Kammenga, J.E. ; Swertz, M.A. - \ 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. 48 - 48.
WormQTL – Public archive and analysis web portal for C. elegans natural variation data Basten L Snoek¹, Yang Li², Joeri K van der Velde², Danny Arends², Antje Beyer³, Mark Elvin 4, Jasmin Fisher³, Alex Hajnal5, Michael Hengartner5, Gino B Poulin4, Miriam Rodriguez¹,Tobias Schmid5, Sabine Schrimpf5, Feng Xue4, Xue Zheng5 , Ritsert C Jansen², Jan E Kammenga¹, Morris A Swertz2,6 1Wageningen University, Nematology, Wageningen, 7608PB, Netherlands, ²University of Groningen, Bioinformatics Centre, Groningen, 9747AG, Netherlands, ³Microsoft Research, Programming Principles and Tools, Cambridge, CB3 0FB, United Kingdom, 4 University of Manchester, Life Sciences, Manchester, M13 9PT, United Kingdom, 5University of Zurich, Molecular Life Sciences, Zurich, CH-8057, Switzerland, 6University Medical Centre, Genomics Coordination, Groningen, 9700RB, Netherlands Over the past decade increased efforts have been made to explore the model species C. elegans as a platform for molecular quantitative genetics and the systems biology of natural variation. These efforts have resulted in a huge amount of phenotypic and genotypic data across developmental worm stages and environments. To facilitate the accessibility, comparative analysis and meta-analysis of all these data we present WormQTL, a public web portal for the management of all these new data and for integrated development of suitable analysis tools. The web server provides a rich set of data and analysis tools available for direct use, based on R/qtl software. But users can also upload and share new scripts as ‘plugin’ for colleagues in the community. Furthermore, new data can be uploaded and downloaded using XGAP, which is an extensible text format for genotypes and phenotypes (Swertz et al. 2010a). All data and tools can be accessed via web user interfaces and programming interfaces. Large consortia as well as individual researchers can make use of a private area that is under embargo for publication. All software is free for download as MOLGENIS ‘app’ (Swertz et al. 2010b). WormQTL is freely accessible without registration and is hosted on a large computational cluster enabling high throughput analyses. We present WormQTL as an online scalable system for QTL exploration to service the worm community. WormQTL provides many publicly available datasets and welcomes submissions from other worm researchers. Funding: The Centre for BioSystems Genomics (CBSG) and the Netherlands Consortium of Systems Biology (NCSB), both of which are part of the Netherlands Genomics Initiative / Netherlands Organisation for Scientific Research and the EU 7th Framework Programme under the Research Project PANACEA, contract nr 222936.
|Combining Genetic Variation with Targeted Knock-downs to Construct Gene Networks of Complex Human Diseases in C. elegans
Kammenga, J.E. ; Fisher, J. ; Li, Y. ; Swertz, M.A. ; Elvin, M. ; Poulin, G. ; Snoek, L.B. ; Rodriguez Sanchez, M. ; Beyer, A. ; Schrimpf, S. ; Velde, J. van de; Escobar, J. ; Schmid, T. ; Zheng, C. ; Hajnal, A. ; Hengartner, M. ; Jansen, R. - \ 2011
In: Abstract Book of the 12th International Conference on Systems Biology, Heidelberg/Mannheim, Germany, 28 August - 1 September 2011. - Heidelberg : IBM System Storage Solutions - p. 116 - 116.
The nematode worm C. elegans has intensively been studied for complex human disease pathways. Within the EU FP7 funded PANACEA consortium we perform a quantitative pathway analysis of natural variation in complex disease signalling in C. elegans. Here, we present a robust approach for selecting candidate genes associated with the Notch, Wnt and RAS pathway using a combination of recombinant inbred lines (RILs), derived from a cross of the wildtypes N2 and CB4856, and RNAi. The consortium focuses on the transcriptome, proteome and cellular development. We tested 180 different RNAi’s targeted against genes within these three pathways in a set of 50 RILs. We highlight a case of this cryptic genetic variation in genome wide gene expression levels underlying a gld-1 knock-down (a gene involved in germline development) This revealed new candidate regulators of gld-1 affected gene expression. Furthermore we will show how mutations of the RAS pathway in different genetic backgrounds lead to the discovery of hidden modifiers affecting vulva-development, an important readout of cancer signalling pathways. All this (transcriptomics, proteomics and phenotypic) data will feed into a predictive model of vulva development which can be used to investigate the relative contributions of various recombinants.
Trouwen in Nederland : een historisch - demografische studie van de 19e en vroeg - 20e eeuw
Poppel, F.W.A. van - \ 1992
Agricultural University. Promotor(en): A.M. van der Woude. - S.l. : Van Poppel - 654
huwelijk - gezinsleven - gezinnen - ethiek - demografie - statistiek - echtscheiding - recht - geschiedenis - gebruiken - samenwoning - Nederland - cum laude - marriage - family life - families - ethics - demography - statistics - divorce - law - history - customs - cohabitation - Netherlands
This study deals with the development of marriage, marital dissolution, and remarriage in the Netherlands in the period 1815-1930. It consists of two parts, the first dealing with first marriages, the second with marital dissolution and remarriage.
Although this study is a demographic one, it clearly distinguishes itself from previous demographic studies. This relates not only to the fact that earlier studies were based mainly or solely on published, statistical data, and could, as a consequence, give only a vague and incomplete picture of the social and regional variation in marriage patterns. It also has to do with the fact that these studies seldom paid attention to the cultural ideas which regulated the entry into and the dissolution of marriage and that they neglected marital dissolution and remarriage, which were important phenomena during most of the period. These shortcomings are discussed in Chapter I and the main principles and topics of our research are introduced.
Chapter II analyzes the overall trends in age at first marriage and marriage frequency in the Netherlands during the 19th and 20th century. In this period, the marriage frequency clearly increased while age at first marriage decreased, particularly between 1860 and the end of the 19th century.
Chapter III pays attention to the cultural ideas that guided the marriage decisions of 19th century men and women. It is based on an extensive analysis of 19th and 20th century statistical, sociological, historical, legal, economic, and ethnographic sources. Inasmuch as these opinions were recorded, they were fairly biased with respect to the origin of those involved; in the majority of cases this was males from higher social classes. From this analysis it appeared that, during the period studied, there were definite ideas on the age at which males and females ought to get married. Too 'early' marriages were considered detrimental to the health of the husband, wife, and children, while too 'late' marriages were considered unnatural or indecent. It was expected of individuals who wished to marry that they were economically, physically, and socially mature, but obviously these criteria varied per social group.
A popular complaint was that males from the working class entered marriage rashly, without considering whether they were able to support themselves and a family. One way to reduce these careless marriages was to teach the lower social classes to take responsibility for their own actions. Others did not support this and were advocates of state interference in the freedom to get married. However, another group, in defense of the behaviour of the lower classes, pointed out the hopelessness of their situation and that hope of improvement was in vain. This group realized that the age-dependent nature of the wage level actually made early marriages worthwhile.
As the 20th century approached, the disapproving attitudes became less voluble. The neo-malthusians considered the psychological and physical health problems, related to sexual abstinence, as a justification for marriages at a young age, and felt that the use of contraceptives could solve the problems related to the declining age at marriage. The organized labour movement also generally understood the need for labourers to marry at a young age, just like some progressive physicians. Abstinence was considered too difficult and, from a societal viewpoint, this was also seen as an injustice to a group that was already so deprived. Those opposed to prostitution felt this could be best combatted by resolving the issue of marriage at a young age.
The high age at marriage of the higher classes was intended to set an example for the working class, but was negatively judged by many as well. From a eugenistic viewpoint, it was considered disadvantageous that the most valuable social group married so late. The fact that many women from the higher social classes could not find a marriage partner, or not until they were older, stimulated the discussion on issues such as the improvement in women's education and the extension of vocational possibilities for women and was considered a factor which stimulated or even caused the growth of the feminist movement.
Chapter IV contains a general overview of existing theories on the development of the European and Dutch marriage pattern, an overview in which Hajnal's thesis and a theory developed by the Dutch sociologist Hofstee are predominant. In both theories, as well as in the opinions of 19th century observers, class differences in age at marriage were the central issue.
In chapter V, the differences in age at marriage between the social classes in the 19th century are examined. Data on age at marriage and occupation of bride and bridegroom for more then 63,000 marriages during the period 1812-1912 in a number of Dutch municipalities, indicate that there were large differences in age at marriage between the various social classes. Among males, it was indeed the upper class and the farmers who married later than others, while the working classes got married a few years sooner. Among females, the differences between social classes was less than for males, with the highest ages at marriage among females who married casual and unskilled labourers.
The age at marriage for males and females only dropped after 1860-70, and it did so particularly rapidly among casual and unskilled labourers, and among craftsmen in small businesses, in industries and the building industry, and among agricultural labourers. However, the age at marriage also declined among the lower level professionals and lower civil servants and supervising occupations. Among the upper class, only males showed a decline, while the development among farmers varied greatly per region. The age at marriage among farmers and shopkeepers, small entrepreneurs and merchants, and self-employed artisans did not drop until after 1890. It seems plausible that the increase in the standard of living, an increase not restricted to one social class, was the cause of the decline in age at marriage. From the 1860s, there was definite economic growth in trade and agriculture, and the marriage conditions could be more easily met due to rising wages and more stable employment. After 1880, in the cities, industrialization led to an increase in the number of jobs providing a stable income and relatively secure employment.
The continuous reproaches against the lower classes, who carelessly got married at a young age and thus caused the group of impoverished to increase, seem to be rather exaggerated when looking at our data. Craftsmen in small businesses, industrial craftsmen, building craftsmen, and casual and unskilled labourers did get married relatively younger than the farmers, the upper class, lower level professionals, and lower civil servants, but the differences were not as great as is often suggested. And although contemporary observers considered it a fact that males and females from the last mentioned groups got married less often and at increasingly higher ages, we did not find an increase in the age at marriage among these groups during the 19th century. During the second half of the 19th century, the marriage frequency of upper class males was above the Dutch average and did not show a decline. Among females, however, there were signs that the upper class was not included in the general declining trend in age at marriage.
A striking fact was that there was a very high regional variation in age at marriage within the various social groups: for almost a century, marrying late and not very frequently remained a phenomenon that was characteristic of the rural areas of North Brabant, Limburg, and Gelderland and for the cities in Brabant, while the highest marriage frequencies and the lowest ages at marriage were found in the cities in the West and in the rural areas of North Holland, Friesland, Groningen, and Drenthe. In chapter VI, this regional variation for the years 1850, 1890, and 1930 is subjected to multivariate analysis, using published statistical data for 27 regions.
It appeared that in 1850 and 1890, three variables - the availability of mates (the sex ratio), the feasibility of marriage (measured by the income level), and the social desirability of marriage (indicated by the percentage of Catholics) - together explained about 75% of the regional variance in the age at marriage and the marriage frequency for males. Female surpluses and low percentages of Catholics were associated in each period with relatively many and relatively young marriages. Contrary to expectations, as income rose, the marriage frequency of males dropped. This was the result of the strong negative relation between income level and the sex ratio. Income level remained highest in groups where the male surplus was the lowest: females mainly departed for areas where earnings were higher, that is, where job opportunities in domestic service were highest.
Part II of our study deals with marital dissolution and remarriage. Chapter VII first describes the global development. The frequency of marital dissolution due to the death of husband or wife especially decreased between 1870 and 1930. Nearly at the same time, around the 1860s, an increase began in the divorce frequency. Increasingly fewer males and females remarried, while the age at remarriage rose.
The overwhelming majority of marriages that were dissolved in the 19th century were dissolved by the death of one of the partners. Dissolution of marriage seriously affected the position of the remaining man or woman, of the children, and also the socio-economic basis of the family, partly due to the limited public aid available. In these situations, remarriage was very significant: it could provide a solution for the economic, care, and emotional problems confronting the family and the community. However, remarriage also caused new problems for those involved. Thus the decision to remarry or to contemplate other living arrangements had to be carefully considered. Chapter VIII discusses the international literature on widowhood and remarriage, analyzes the existing Dutch data on widowhood and remarriage, and traces the position of the widow and widower in 19th century Dutch society, using a variety of qualitative sources.
The Dutch remarriage pattern is examined in more detail in chapter IX, using data from the vital registration system (marriages, births, and deaths) and the population register, in the period 1850-90 for the cities of Breda (South Netherlands) and Gouda (West Netherlands). A group of 6,500 widows and widowers was followed from the moment they became a widow(er) to the time of remarriage or death as a widow (er). Migrating widow (er) s were also followed to their new destinations.
Proportional hazards models were used in the analysis. It appeared that age at widowhood was most indicative of the probability of remarriage. In addition, males had a much higher probability of remarriage than females. This was partly ascribed to the large female surpluses in cities, but mainly to the negative societal attitudes towards remarriage of a widow and the fact that widowhood was relatively easier to bear for females than for males. Children could not be considered an advantage: men and women with children had a much lower probability of remarriage than childless couples, and if there was a child, it had to be young to be successful in finding a new partner. Thus remarriage mainly occurred for widow (er) s whose situation was as close as possible to that of a normal marriage: the partner had to be relatively young and childless or have children who were still young. Neither the occupation nor the religion of the widow (er) were very significant, and changes in remarriage probabilities were not found in the period studied. Finally, it was striking, but fitted the general idea that existed on the differences between the West of the Netherlands on the one hand, and the South on the other hand, that in Gouda the probability of remarriage was generally much higher: family ties were much looser in the West and attitudes toward remarriage of widows and widowers were less negative than in the South. The restrictions on age at marriage and marriage frequency that were characteristic for the South thus also applied to the marriages of widows and widowers.
As was already stated, the divorce rate in the Netherlands rose considerably between 1865 and 1915. In this same period, lively debates were held on the legal procedure for divorce and on the grounds for receiving a divorce. Chapter X gives an overview of this discussion, starting around 1870.
Many arguments were raised, in the beginning mainly by liberal jurists, later also by socialists, feminists, and the sexual reform movement - although these groups did not have similar views - favouring the liberalization of divorce laws. It was pointed out that the indissolubility of marriage caused persons to be very hesitant when deciding to get married, thus going against the natural law which dictated early marriage. Freedom to get a divorce was also beneficial for the children because divorce could take place sooner in marriage, namely at a time when the family was not yet so large, and it would help to stop prostitution which had been induced by the enforced union of couples who no longer loved each other. If marriage could be dissolved, then persons would more often marry for love because otherwise there could be grave consequences. The propagated increase in opportunities for marriage dissolution was therefore particularly inspired by the conviction that marriage was of fundamental importance for the wellbeing of society.
However, opponents of greater freedom to divorce pointed out the dangers related to liberalization. If divorce would be easier, then marriages would be taken even less seriously than was already the case. Uncertainty as to whether or not the couple would stay together would unfavourably influence the partner relationship and could affect the attempts to adjust to each other's character. Children would no longer be able to be raised harmoniously. The financial status of the family would also be affected so that care of the children would be more difficult.
In 1886, a State Commission introduced a moderate reform proposal for new divorce legislation. In the decade that followed, a conservative, mainly religious, opposition gradually arose against this proposal; for them, divorce was equivalent to undermining the foundation of State and society. When a few years later thanks to the extension of the right to vote, the majority of the population, who clung to the old-fashioned sexual morals, achieved greater political power, the Catholic and Protestant views on divorce started to determine the tone of the debate. For both groups marriage, once entered, achieved a Godly status and could therefore not be broken by man. However, there was no agreement on the specific grounds for allowing divorce, so the strengthening of Catholic and Protestant views did not lead to changes in existing legislation but only to a long-lasting halt in liberalization.
Chapter XI contains an empirical study of divorce and remarriage in the second half of the 19th century. The study was conducted in The Hague, using a case-control research design. The social characteristics of all 546 marriages in the period 1850-82, which ended in divorce, were compared with those of a random sample from the circa 25,000 marriages which ended in widowhood. A total of circa 2,300 marriages was included in the study. This group was followed from marriage till dissolution of marriage (by death or divorce), and after dissolution, the surviving persons and the divorced men and women were followed till remarriage or death. Again, all migrants were followed in their new place of residence, making use of the population register and the vital registration system.
At the beginning of the 1850s, the marriage cohort only had a 1 % divorce rate. By the end of the 1870s and the beginning of the 1880s, this had risen to 4%. In the course of time, divorce took place somewhat earlier in the marriage.
Multivariate analysis (proportional hazard models) showed that the highest probability of divorce occurred among persons who had already gone through a divorce before. High mobility was also related to higher risks of divorce. Young age at marriage and large age differences between husband and wife were also relatively important. The effects of the husband's occupation were slight but clear: the higher social classes had distinctly higher risks than the working classes. Women who worked had relatively high divorce rates. The probability of divorce in religiously-mixed marriages was much higher than in religiously-homogeneous marriages.
Compared to the dissolution of marriage by the death of one of the partners, divorce occurred much more often when husband and wife were relatively young, and as a consequence, the remarriage probabilities of divorce(e)s were much higher than those of widow(er)s. Males had a much higher probability of remarriage than females; a lower age at marriage dissolution was often associated with remarriage as well. Remarriage was more usual among males and females of the lower classes than among
Many of the factors that positively influenced the probability of divorce for 19th century marriages were indicative of, or the cause of, a fundamental contradiction between the expectations of one or both spouses regarding Marriage, and the actual marital situation. It was this contradiction that resulted in failed marriages and divorce. The expectations varied by social class, by gender, and by time period.
The growth in the divorce rate from the second half of the 19th century was related on the one hand to an increase in the expectations regarding marriage, and on the other hand to a loosening of the ties by which men and women were bound to the marital state. Opting for divorce rather than continuing an unsatisfactory relationship became easier over time: improvements took place with respect to the division of goods and to the right to alimony and the opportunities for custody of the children, which made divorce a more tempting alternative for women with children.
Chapter XI I summarizes the conclusions of the book and identifies some areas for future research.