Identifying modifiers of Wnt and EGFR/RAS/MAPK signaling through quantitative C. elegans genetics

S. Maxeiner, T. Schmid, L.B. Snoek, M. Rodriguez Sanchez, F. Largey, L. van der Bent, J.E. Kammenga, A.F. Hajnal

Research output: Chapter in Book/Report/Conference proceedingAbstract

Abstract

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.
Original languageEnglish
Title of host publicationProceedings of the FEBS-EMBO 2014
Pages474-474
Volume281
Publication statusPublished - 2014
EventFEBS-EMBO 2014 Congress, Paris, France -
Duration: 30 Aug 20144 Sep 2014

Conference

ConferenceFEBS-EMBO 2014 Congress, Paris, France
Period30/08/144/09/14

Fingerprint

Mutation
Modifier Genes
Gene Knockdown Techniques
Catenins
Vulva
RNA Interference
Chromosomes
Genome
Phenotype
Population
Neoplasms
Genetic Background

Cite this

Maxeiner, S., Schmid, T., Snoek, L. B., Rodriguez Sanchez, M., Largey, F., van der Bent, L., ... Hajnal, A. F. (2014). Identifying modifiers of Wnt and EGFR/RAS/MAPK signaling through quantitative C. elegans genetics. In Proceedings of the FEBS-EMBO 2014 (Vol. 281, pp. 474-474)
Maxeiner, S. ; Schmid, T. ; Snoek, L.B. ; Rodriguez Sanchez, M. ; Largey, F. ; van der Bent, L. ; Kammenga, J.E. ; Hajnal, A.F. / Identifying modifiers of Wnt and EGFR/RAS/MAPK signaling through quantitative C. elegans genetics. Proceedings of the FEBS-EMBO 2014. Vol. 281 2014. pp. 474-474
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abstract = "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.",
author = "S. Maxeiner and T. Schmid and L.B. Snoek and {Rodriguez Sanchez}, M. and F. Largey and {van der Bent}, L. and J.E. Kammenga and A.F. Hajnal",
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Maxeiner, S, Schmid, T, Snoek, LB, Rodriguez Sanchez, M, Largey, F, van der Bent, L, Kammenga, JE & Hajnal, AF 2014, Identifying modifiers of Wnt and EGFR/RAS/MAPK signaling through quantitative C. elegans genetics. in Proceedings of the FEBS-EMBO 2014. vol. 281, pp. 474-474, FEBS-EMBO 2014 Congress, Paris, France, 30/08/14.

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.; van der Bent, L.; Kammenga, J.E.; Hajnal, A.F.

Proceedings of the FEBS-EMBO 2014. Vol. 281 2014. p. 474-474.

Research output: Chapter in Book/Report/Conference proceedingAbstract

TY - CHAP

T1 - Identifying modifiers of Wnt and EGFR/RAS/MAPK signaling through quantitative C. elegans genetics

AU - Maxeiner, S.

AU - Schmid, T.

AU - Snoek, L.B.

AU - Rodriguez Sanchez, M.

AU - Largey, F.

AU - van der Bent, L.

AU - Kammenga, J.E.

AU - Hajnal, A.F.

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

M3 - Abstract

VL - 281

SP - 474

EP - 474

BT - Proceedings of the FEBS-EMBO 2014

ER -

Maxeiner S, Schmid T, Snoek LB, Rodriguez Sanchez M, Largey F, van der Bent L et al. Identifying modifiers of Wnt and EGFR/RAS/MAPK signaling through quantitative C. elegans genetics. In Proceedings of the FEBS-EMBO 2014. Vol. 281. 2014. p. 474-474