Exon repetition: a major pathway for processing mRNA of some genes is allele-specific

Abstract

Exon repetition describes the presence of tandemly repeated exons in mRNA in the absence of duplications in the genome. Its existence challenges our understanding of gene expression, because the linear organization of sequences in apparently normal genes must be subverted during RNA synthesis or processing. It is restricted to a small number of genes in some of which over half of the mRNA contains specific patterns of repetition. Although it is sometimes assumed to arise by trans-splicing, there is no evidence of this and the efficiency is very much higher than for examples of bona fide trans-splicing in mammals. Furthermore, a potentially ubiquitous reaction such as trans-splicing is not consistent with a phenomenon that involves such a high proportion of the products of so few genes. Instead, it seems more probable that exon repetition is caused by a specific trans-acting factor. We have tested this and demonstrate for the two best characterized examples that the property is restricted to specific alleles of the affected genes and is determined in cis. It is not determined by exonic splicing signals, as had been suggested previously. In heterozygotes, RNA transcribed from the two alleles of an affected gene can have fundamentally different fates.

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“…Additionally, the COT transcript bearing only the exon 2 repetition is out of frame. It was also observed that a construct bearing exon 2 repetition dropped the expression of the reporter gene, a fact that was interpreted by the authors as a detrimental effect of the exon repetition in natural COT expression (Rigatti et al 2004). On the other hand, a negative regulation could also be proposed to explain the biological meaning of this exon repetition.…”

“…The only putative product detected is the 80 kDa protein coded by exon1-exon2-exon3-exon2-exon3-exon4-exon5-exon6 COT mRNA. However, this protein is not essential, since exon repetition was not observed in all rat lines studied (Rigatti et al 2004). Additionally, the COT transcript bearing only the exon 2 repetition is out of frame.…”

“…The observed pattern was exon1-exon2-exon2-exon3-exon4-exon5-exon6 and exon1-exon2-exon3-exon4-exon2-exon3-exon4-exon5-exon6 . Remarkably, relative frequency of exon repeated transcripts is as abundant as the canonical ones showing an efficient production of the transspliced molecule (Rigatti et al 2004). The concomitant analysis of COT exon 2 nucleotide sequences from these two rat lines showed that both sequences were identical.…”

“…On the contrary, a hallmark of the transcripts bearing repeated exons, besides the low number of genes studied, is their high level of expression (Caudevilla et al 1998, Rigatti et al 2004, suggesting a limited but efficient process.…”

“…This factor and not by a ESE. However, segregation studies using SHR and WKY rats showed that exon repetition is restricted to specific alleles (Rigatti et al 2004), i.e. the determinant factor for COT transcript exon repetition is a cis-regulatory element, but not related to the proposed ESE sequence.…”