Characterization of intron loss events in mammals

Abstract

The exon/intron structure of eukaryotic genes differs extensively across species, but the mechanisms and relative rates of intron loss and gain are still poorly understood. Here, we used whole-genome sequence alignments of human, mouse, rat, and dog to perform a genome-wide analysis of intron loss and gain events in >17,000 mammalian genes. We found no evidence for intron gain and 122 cases of intron loss, most of which occurred within the rodent lineage. The majority (68%) of the deleted introns were extremely small (<150 bp), significantly smaller than average. The intron losses occurred almost exclusively within highly expressed, housekeeping genes, supporting the hypothesis that intron loss is mediated via germline recombination of genomic DNA with intronless cDNA. This study constitutes the largest scale analysis for intron dynamics in vertebrates to date and allows us to confirm and extend several hypotheses previously based on much smaller samples. Our results in mammals show that intron gain has not been a factor in the evolution of gene structure during the past 95 Myr and has likely been restricted to more ancient history.

Figure 1.

An example of intron loss in the mouse ortholog of the human DYNC1H1 gene, visualized in the UCSC Genome Browser display of multispecies alignments. Uppercase, boxed sequences correspond to exons. Note that the alignment is inexact at the splice sites, resulting in an artifactual 3-bp intron length in mouse, which necessitates an approximate search strategy (described in Methods), and realignment of sequences using an appropriate parameter choice in order to confirm all candidate intron deletions. Realigned sequences of the introns and neighboring exons for all 120 cases of intron loss are provided in Supplemental data.

Figure 2.

Log₂(size) distribution of all introns (black) versus deleted introns (gray). The deleted introns are unusually short and much shorter than the human genome average.

Figure 3.

The evolution of the intron–exon structure of the GAPDH gene throughout the vertebrate phylogeny. The numbers on the branches indicate the inferred deletion events. The introns are numbered according to their position within the coding sequence of the ancestral gene.