Alternative splicing during mammalian organ development

Pavel V Mazin,Margarida Cardoso-Moreira,Philipp Khaitovich,Henrik Kaessmann

doi:10.1038/s41588-021-00851-w

Abstract

Alternative splicing (AS) is pervasive in mammalian genomes, yet cross-species comparisons have been largely restricted to adult tissues and the functionality of most AS events remains unclear. We assessed AS patterns across pre- and postnatal development of seven organs in six mammals and a bird. Our analyses revealed that developmentally dynamic AS events, which are especially prevalent in the brain, are substantially more conserved than nondynamic ones. Cassette exons with increasing inclusion frequencies during development show the strongest signals of conserved and regulated AS. Newly emerged cassette exons are typically incorporated late in testis development, but those retained during evolution are predominantly brain specific. Our work suggests that an intricate interplay of programs controlling gene expression levels and AS is fundamental to organ development, especially for the brain and heart. In these regulatory networks, AS affords substantial functional diversification of genes through the generation of tissue- and time-specific isoforms from broadly expressed genes.

Highlights

Alternative splicing (AS) is pervasive in mammalian genomes, yet cross-species comparisons have been largely restricted to adult tissues and the functionality of most AS events remains unclear
We find that very young cassette exons are predominantly incorporated into testis isoforms, as observed for adult testis[43], whereas new exons of greater age are predominantly used in the brain (Fig. 6c)
The extent of devAS and selection patterns differ across organs, developmental periods, exon usage patterns, exon ages and types of cassette exons

Summary

90 Percentage of exons Percentage of exons

Proportion of 3N exons m mr mrb hqmrb hqmrbo hqmrboc m mr mrb hqmrb hqmrbo hqmrboc. Previous work indicated that microexons are more conserved and functionally relevant than macroexons[37,38]. A nonsense mutation in this exon, which is predominantly included in early brain development (Extended Data Fig. 9), leads to severe impairments of human brain development[46] We investigated another evolutionary source of new alternative exons: constitutive exons. Consistent with the fact that alternified exons stem from functional constitutive exons, and contrary to new exons, most of them have coding capacity (Fig. 6g) and show a drop in mean PSI with increasing evolutionary age (Fig. 6e) These observations suggest that the more substantial and developmentally dynamic skipping of older alternification events is likely to be of functional relevance, whereas the nonfrequent exclusion of young (often frame-disrupting) exons might primarily reflect transcriptional noise. Deletions in this exon, which becomes progressively excluded during development in the brain (Extended Data Fig. 10), are associated with neurodegenerative motor neuron disease[48]

Discussion

Methods

Findings

Code availability