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Abstract

The ability to generate multiple RNA isoforms of transcripts from the same gene is a general phenomenon in eukaryotes. However, the complexity and diversity of alternative isoforms in natural populations remains largely unexplored. Using a newly developed full-length transcripts enrichment protocol, we sequenced full-length RNA transcripts of 48 individuals from outbred populations and subspecies of Mus musculus, as well as the closely-related sister species Mus spretus and Mus spicilegus as outgroups. This represents the largest full-length high-quality isoform catalog at the population level to date. In total, we reliably identify 117,728 distinct transcripts, of which only 51% were previously annotated. We show that the population-specific distribution pattern of isoforms is phylogenetically informative and reflects the segregating SNP diversity between the populations. We find that ancient house-keeping genes are the major source to the overall isoform diversity, and the recruiting of alternative first exon plays the dominant role in generating new isoforms. Given that our data allow to distinguish between population-specific isoforms and isoforms that are conserved across multiple populations, it is possible to refine the annotation of the reference mouse genome to a set of about 40,000 isoforms that should be most relevant for comparative functional analysis across species.