It is widely accepted that at least 10% of all mutations causing human inherited disease disrupt splice-site consensus sequences. In contrast to splice-site mutations, the role of auxiliary cis-acting elements such as exonic splicing enhancers (ESE) and exonic splicing silencers (ESS) in human inherited disease is still poorly understood. Here we use a top-down approach to determine rates of loss or gain of known human exonic splicing regulatory (ESR) sequences associated with either disease-causing mutations or putatively neutral single nucleotide polymorphisms (SNPs). We observe significant enrichment toward loss of ESEs and gain of ESSs among inherited disease-causing variants relative to neutral polymorphisms, indicating that exon skipping may play a prominent role in aberrant gene regulation. Both computational and biochemical approaches underscore the relevance of exonic splicing enhancer loss and silencer gain in inherited disease. Additionally, we provide direct evidence that both SRp20 (SRSF3) and possibly PTB (PTBP1) are involved in the function of a splicing silencer that is created de novo by a total of 83 different inherited disease mutations in 67 different disease genes. Taken together, we find that ~25% (7154/27,681) of known mis-sense and nonsense disease-causing mutations alter functional splicing signals within exons, suggesting a much more widespread role for aberrant mRNA processing in causing human inherited disease than has hitherto been appreciated.
We had subjects view action sequence videos during neuroimaging (fMRI)
Sessions and identified lexical descriptions of those videos by decoding (SVM)
The brain representations based only on their fMRI activation patterns. As a
Precursor to this result, we had demonstrated that we could reliably and...
We show that networks of interbank exposures can however significantly
Amplify contagion due to overlapping portfolios. To illustrate this point, we
Consider the case of the Austrian interbank network and perform stress tests on
It according to different protocols. We consider in particular contagio...
We develop a dust efflux model of radiation pressure acting on dust grains
Which successfully reproduces the relation between stellar mass, dust opacity
And star formation rate observed in local star-forming galaxies. The dust
Content of local star-forming galaxies is set by the competition between...
Pubget Updates sends you emails when Pubget finds new papers that match your search. Use Pubget Updates to get the latest articles for your specialty, written by a colleague, or published by your favorite journals.