Biological impact of mutually exclusive exon switching

Abstract

Alternative splicing can expand the diversity of proteomes. Homologous mutually exclusive exons (MXEs) originate from the same ancestral exon and result in polypeptides with similar structural properties but altered sequence. Why would some genes switch homologous exons and what are their biological impact? Here, we analyse the extent of sequence, structural and functional variability in MXEs and report the first large scale, structure-based analysis of the biological impact of MXE events from different genomes. MXE-specific residues tend to map to single domains, are highly enriched in surface exposed residues and cluster at or near protein functional sites. Thus, MXE events are likely to maintain the protein fold, but alter specificity and selectivity of protein function. This comprehensive resource of MXE events and their annotations is available at: http://gene3d.biochem.ucl.ac.uk/mxemod/. These findings highlight how small, but significant changes at critical positions on a protein surface are exploited in evolution to alter function.

The clinical importance of tandem exon duplication-derived substitutions

“…( 27 ), Lam et al. ( 30 ) analyses with the tandem exon duplication-derived substitutions annotated in GENCODE v33. The distribution of tandem exon duplication-derived substitutions is in bold.…”

“…Two more recent large-scale studies ( 27 , 30 ) concentrated on mutually exclusively spliced exons rather than events from tandem exon duplications. According to the strict definition of mutually exclusive splicing only one of each pair of exons can ever be spliced into the mature mRNA at any one time ( 16 ) and substitutions generated by alternative promoters and alternative poly(A) splicing events are excluded.…”

“…The Lam et al. study ( 30 ) analysed 143 homologous mutually exclusive splicing events in 125 genes from the Ensembl human reference set ( 31 ). This study included those isoforms produced from alternative promoter and alternative poly(A) usage, but homologous exons were not allowed to occur together in the same transcript.…”

“…Lam et al. ( 30 ) made a start on the functional characterisation of isoforms derived from tandem exon duplications, but we still have little idea of the functional role of most of the isoforms generated from these events. The high level of translation and the remarkable enrichment in pathogenic mutations in these ancient alternatively spliced exons demonstrates that tandem exon duplication-derived substitutions have important roles in the cell.…”

“…A recent study ( 30 ) of the functional properties of 143 homologous mutually exclusive spliced events in the human reference set ( 4 ) found that regions translated from these exons are enriched in surface-exposed residues and tend to cluster near protein functional sites. The authors suggest that these homologous substitution events may affect protein specificity and selectivity.…”