Nxf1 Natural Variant E610G Is a Semi-dominant Suppressor of IAP-Induced RNA Processing Defects

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. © 2015 concepcion et al.