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anomalies of alternative splicing

Sunday 8 July 2007

Human genes contain a dense array of diverse cis-acting elements that make up a code required for the expression of correctly spliced mRNAs. Alternative splicing generates a highly dynamic human proteome through networks of coordinated splicing events.

Cis- and trans-acting mutations that disrupt the splicing code or the machinery required for splicing and its regulation have roles in various diseases, and recent studies have provided new insights into the mechanisms by which these effects occur.

An unexpectedly large fraction of exonic mutations exhibit a primary pathogenic effect on splicing. Furthermore, normal genetic variation significantly contributes to disease severity and susceptibility by affecting splicing efficiency.

Genetic diseases

Numerous inherited human genetic disorders are caused by defects in pre-mRNA splicing.

There is a link between genetic variation and pre-mRNA splicing by identifying SNPs that correlate with heritable changes in alternative splicing but do not cause disease. This suggests that allele-specific alternative splicing is a mechanism that accounts for individual variation in the human population.


Computational and experimental evidence has revealed that cancerous cells express transcript variants that are abnormally spliced, suggesting that mRNAs are more frequently alternatively spliced in cancerous tissues than in normal ones.

Cancerous tissues exhibit lower levels of alternative splicing than do normal tissues. Moreover, we found that the distribution of types of alternative splicing differs between cancerous and normal tissues.

The lower levels of alternative splicing in cancerous tissues might be a result of disruption of splicing regulatory proteins.


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