title: Nxf1 natural variant E610G is a semi-dominant suppressor of IAP-induced RNA processing defects.
abstract: Endogenous retroviruses and retrotransposons contribute functional genetic variation in animal genomes. In mice, Intracisternal A Particles (IAPs) are a frequent source of both new mutations and polymorphism across laboratory strains. Intronic IAPs can induce alternative RNA processing choices, including alternative splicing. We previously showed IAP I∆1 subfamily insertional mutations are suppressed by a wild-derived allele of the major mRNA export factor, Nxf1. Here we show that a wider diversity of IAP insertions present in the mouse reference sequence induce insertion-dependent alternative processing that is suppressed by Nxf1CAST alleles. These insertions typically show more modest gene expression changes than de novo mutations, suggesting selection or attenuation. Genome-wide splicing-sensitive microarrays and gene-focused assays confirm specificity of Nxf1 genetic modifier activity for IAP insertion alleles. Strikingly, CRISPR/Cas9-mediated genome editing demonstrates that a single amino acid substitution in Nxf1, E610G, is sufficient to recreate a quantitative genetic modifier in a co-isogenic background.
authors.affiliation: Department of Cellular and Molecular Medicine, Moores UCSD Cancer Center and Institute for Genomic Medicine, University of California, San Diego School of Medicine, La Jolla, California, United States of America; Department of Medicine, University of California, San Diego School of Medicine, La Jolla, California, United States of America.
authors.forename: Dorothy
authors.initials: D
authors.lastname: Concepcion
authors.affiliation: Biomedical Sciences Graduate Program, University of California, San Diego School of Medicine, La Jolla, California, United States of America.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Ross
authors.affiliation: Department of Cellular and Molecular Medicine, Moores UCSD Cancer Center and Institute for Genomic Medicine, University of California, San Diego School of Medicine, La Jolla, California, United States of America.
authors.forename: Kasey R
authors.initials: KR
authors.lastname: Hutt
authors.affiliation: Department of Cellular and Molecular Medicine, Moores UCSD Cancer Center and Institute for Genomic Medicine, University of California, San Diego School of Medicine, La Jolla, California, United States of America; Biomedical Sciences Graduate Program, University of California, San Diego School of Medicine, La Jolla, California, United States of America; Stem Cell Program, University of California, San Diego School of Medicine, La Jolla, California, United States of America.
authors.forename: Gene W
authors.initials: GW
authors.lastname: Yeo
authors.affiliation: Department of Cellular and Molecular Medicine, Moores UCSD Cancer Center and Institute for Genomic Medicine, University of California, San Diego School of Medicine, La Jolla, California, United States of America; Department of Medicine, University of California, San Diego School of Medicine, La Jolla, California, United States of America; Biomedical Sciences Graduate Program, University of California, San Diego School of Medicine, La Jolla, California, United States of America.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Hamilton
mesh_terms: D000818:Animals; D005799:Genes, Dominant; D007426:Genes, Intracisternal A-Particle; D016153:Genes, Suppressor; D051379:Mice; D008810:Mice, Inbred C57BL; D020125:Mutation, Missense; D029543:Nucleocytoplasmic Transport Proteins / Q000235:genetics / Q000378:metabolism*; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*
chemical_list: C569386:NXF1 protein, mouse; D029543:Nucleocytoplasmic Transport Proteins; D012333:RNA, Messenger
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