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Ras/MAPK Modifier Loci Revealed by eQTL in Caenorhabditis elegans

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 b...

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Autores principales: Sterken, Mark G., van Bemmelen van der Plaat, Linda, Riksen, Joost A. G., Rodriguez, Miriam, Schmid, Tobias, Hajnal, Alex, Kammenga, Jan E., Snoek, Basten L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Genetics Society of America 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5592943/
https://www.ncbi.nlm.nih.gov/pubmed/28751501
http://dx.doi.org/10.1534/g3.117.1120
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author Sterken, Mark G.
van Bemmelen van der Plaat, Linda
Riksen, Joost A. G.
Rodriguez, Miriam
Schmid, Tobias
Hajnal, Alex
Kammenga, Jan E.
Snoek, Basten L.
author_facet Sterken, Mark G.
van Bemmelen van der Plaat, Linda
Riksen, Joost A. G.
Rodriguez, Miriam
Schmid, Tobias
Hajnal, Alex
Kammenga, Jan E.
Snoek, Basten L.
author_sort Sterken, Mark G.
collection PubMed
description 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 six eQTL trans-bands specific for the interaction between the genetic background and the mutation, one of which colocalized 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 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.
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spelling pubmed-55929432017-09-14 Ras/MAPK Modifier Loci Revealed by eQTL in Caenorhabditis elegans Sterken, Mark G. van Bemmelen van der Plaat, Linda Riksen, Joost A. G. Rodriguez, Miriam Schmid, Tobias Hajnal, Alex Kammenga, Jan E. Snoek, Basten L. G3 (Bethesda) Investigations 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 six eQTL trans-bands specific for the interaction between the genetic background and the mutation, one of which colocalized 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 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. Genetics Society of America 2017-07-27 /pmc/articles/PMC5592943/ /pubmed/28751501 http://dx.doi.org/10.1534/g3.117.1120 Text en Copyright © 2017 Sterken et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Investigations
Sterken, Mark G.
van Bemmelen van der Plaat, Linda
Riksen, Joost A. G.
Rodriguez, Miriam
Schmid, Tobias
Hajnal, Alex
Kammenga, Jan E.
Snoek, Basten L.
Ras/MAPK Modifier Loci Revealed by eQTL in Caenorhabditis elegans
title Ras/MAPK Modifier Loci Revealed by eQTL in Caenorhabditis elegans
title_full Ras/MAPK Modifier Loci Revealed by eQTL in Caenorhabditis elegans
title_fullStr Ras/MAPK Modifier Loci Revealed by eQTL in Caenorhabditis elegans
title_full_unstemmed Ras/MAPK Modifier Loci Revealed by eQTL in Caenorhabditis elegans
title_short Ras/MAPK Modifier Loci Revealed by eQTL in Caenorhabditis elegans
title_sort ras/mapk modifier loci revealed by eqtl in caenorhabditis elegans
topic Investigations
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5592943/
https://www.ncbi.nlm.nih.gov/pubmed/28751501
http://dx.doi.org/10.1534/g3.117.1120
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