Alternative splicing and mRNA editing are known to contribute to transcriptome diversity. Although alternative splicing is pervasive and contributes to a variety of pathologies, including cancer, the genetic context for individual differences in isoform usage is still evolving. Similarly, although mRNA editing is ubiquitous and associated with important biological processes such as intracellular viral replication and cancer development, individual variations in mRNA editing and the genetic transmissibility of mRNA editing are equivocal. Here, we have used linkage analysis to show that both mRNA editing and alternative splicing are regulated by the macrophage genetic background and environmental cues. We show that distinct loci, potentially harboring variable splice factors, regulate the splicing of multiple transcripts. Additionally, we show that individual genetic variability at the Apobec1 locus results in differential rates of C-to-U(T) editing in murine macrophages; with mouse strains expressing mostly a truncated alternative transcript isoform of Apobec1 exhibiting lower rates of editing. As a proof of concept, we have used linkage analysis to identify 36 high-confidence novel edited sites. These results provide a novel and complementary method that can be used to identify C-to-U editing sites in individuals segregating at specific loci and show that, beyond DNA sequence and structural changes, differential isoform usage and mRNA editing can contribute to intra-species genomic and phenotypic diversity.
[Supplemental material is available for this article.]Splicing is an obligatory step in the processing of both coding and noncoding RNA precursors (pre-RNA) to mature RNA, and is executed by a ribonucleoprotein megaparticle known as the spliceosome. Even though the sequential assembly of the spliceosome (Kornblihtt et al. 2013) can occur around any splice site that consists of consensus sequences recognized by the spliceosomal components, splice sites that conform better to a consensus sequence are strongly recognized and favored by the spliceosome complex. Besides the consensus sequences, the selection of optimal splice sites is regulated, in part, by a minimal set of conserved cis-acting GU and AG sequences at the 59 and 39 splice sites, respectively , and sequence elements known as intronic/exonic splicing enhancers and silencers