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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 (2017). Ras/MAPK Modifier Loci Revealed by eQTL in Caenorhabditis elegans. G3 : Genes, Genomes, Genetics, 7(9):3185-3193.

Abstract

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.

Abstract

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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Additional indexing

Item Type:Journal Article, not_refereed, original work
Communities & Collections:07 Faculty of Science > Institute of Molecular Life Sciences
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:7 September 2017
Deposited On:12 Sep 2017 15:03
Last Modified:19 Feb 2018 08:38
Publisher:Genetics Society of America
ISSN:2160-1836
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1534/g3.117.1120
PubMed ID:28751501

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