title: Genetic Architectures of Quantitative Variation in RNA Editing Pathways.
abstract: RNA editing refers to post-transcriptional processes that alter the base sequence of RNA. Recently, hundreds of new RNA editing targets have been reported. However, the mechanisms that determine the specificity and degree of editing are not well understood. We examined quantitative variation of site-specific editing in a genetically diverse multiparent population, Diversity Outbred mice, and mapped polymorphic loci that alter editing ratios globally for C-to-U editing and at specific sites for A-to-I editing. An allelic series in the C-to-U editing enzyme Apobec1 influences the editing efficiency of Apob and 58 additional C-to-U editing targets. We identified 49 A-to-I editing sites with polymorphisms in the edited transcript that alter editing efficiency. In contrast to the shared genetic control of C-to-U editing, most of the variable A-to-I editing sites were determined by local nucleotide polymorphisms in proximity to the editing site in the RNA secondary structure. Our results indicate that RNA editing is a quantitative trait subject to genetic variation and that evolutionary constraints have given rise to distinct genetic architectures in the two canonical types of RNA editing.
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine 04609.
authors.forename: Tongjun
authors.initials: T
authors.lastname: Gu
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine 04609.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Gatti
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine 04609.
authors.forename: Anuj
authors.initials: A
authors.lastname: Srivastava
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine 04609.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Snyder
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine 04609.
authors.forename: Narayanan
authors.initials: N
authors.lastname: Raghupathy
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine 04609.
authors.forename: Petr
authors.initials: P
authors.lastname: Simecek
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine 04609.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Svenson
authors.affiliation: Research Programme on Biomedical Informatics, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Hospital del Mar Medical Research Institute, Dr. Aiguader, 88 Barcelona, Spain The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06030.
authors.forename: Ivan
authors.initials: I
authors.lastname: Dotu
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06030.
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Chuang
authors.affiliation: Department of Biochemistry, University of Wisconsin, Madison, Wisconsin 53706-1544.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Keller
authors.affiliation: Department of Biochemistry, University of Wisconsin, Madison, Wisconsin 53706-1544.
authors.forename: Alan D
authors.initials: AD
authors.lastname: Attie
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine 04609 Bob.Braun@jax.org Gary.Churchill@jax.org.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Braun
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine 04609 Bob.Braun@jax.org Gary.Churchill@jax.org.
authors.forename: Gary A
authors.initials: GA
authors.lastname: Churchill
mesh_terms: D000071479:APOBEC-1 Deaminase; D000818:Animals; D002874:Chromosome Mapping; D003564:Cytidine Deaminase / Q000737:chemistry / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D014644:Genetic Variation; D016678:Genome; D008297:Male; D051379:Mice; D020412:Multifactorial Inheritance; D040641:Quantitative Trait Loci; D017393:RNA Editing
chemical_list: D000071479:APOBEC-1 Deaminase; D003564:Cytidine Deaminase
keywords: Apobec1; Diversity Outbred; MPP; Multiparent Advanced Generation Inter-Cross (MAGIC); RNA editing; genetics; multiparental populations; secondary structure