Nxf1 natural variant E610G is a semi-dominant suppressor of IAP-induced RNA processing defects.

• Main Authors: Dorothy Concepcion, Kevin D Ross, Kasey R Hutt, Gene W Yeo, Bruce A Hamilton
• Format: Article
• Language: English
• Published: Public Library of Science (PLoS) 2015-04-01
• Series: PLoS Genetics
• Online Access: http://europepmc.org/articles/PMC4383553?pdf=render

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.