Evo Devo

Evolutionary development - at the biological interface between genetic regulatory mechanisms and biological evolution.

exon skipping

Exon skipping is the most frequent alternative splicing mechanism known in mammals, and as such is a major contributor to protein diversity in mammals. Exon skipping results in the loss of an exon in the alternatively spliced mRNA.

Alternative splicing can alter the mRNA product in several ways. At the simplest level, an exon can be removed (exon skip), lengthened or shortened (alternative 5' or 3' splicing). In addition, introns may be retained in a lengthened mRNA.

Many disease-associated mutations also affect pre-mRNA splicing, usually causing inappropriate exon skipping. SR proteins are essential splicing factors that recognize exonic splicing enhancers and drive exon inclusion. Alternative splicing is reported to regulate the sub-cellular localization of divalent metal transporter 1 isoforms and the NMDA R1 receptor gene.

Conserved sequence elements associated with exon skipping.
One of the major forms of alternative splicing, which generates multiple mRNA isoforms differing in the precise combinations of their exon sequences, is exon skipping. While in constitutive splicing all exons are included, in the skipped pattern(s) one or more exons are skipped. The regulation of this process is still not well understood; so far, cis- regulatory elements (such as exonic splicing enhancers) were identified in individual cases. We therefore set to investigate the possibility that exon skipping is controlled by sequences in the adjacent introns. We employed a computer analysis on 54 sequences documented as undergoing exon skipping, and identified two motifs both in the upstream and downstream introns of the skipped exons. One motif is highly enriched in pyrimidines (mostly C residues), and the other motif is highly enriched in purines (mostly G residues). The two motifs differ from the known cis-elements present at the 5' and 3' splice site. Interestingly, the two motifs are complementary, and their relative positional order is conserved in the flanking introns. These suggest that base pairing interactions can underlie a mechanism that involves secondary structure to regulate exon skipping. Remarkably, the two motifs are conserved in mouse orthologous genes that undergo exon skipping.
Miriami E, Margalit H, Sperling R. Conserved sequence elements associated with exon skipping. Nucleic Acids Res. 2003 Apr 1;31(7):1974-83. Free Full Text Article

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