Allele-specific recognition of the 3' splice site of INS intron 1.

Human Genetics
Jana Kralovicova, Igor Vorechovsky

Abstract

Genetic predisposition to type 1 diabetes (T1D) has been associated with a chromosome 11 locus centered on the proinsulin gene (INS) and with differential steady-state levels of INS RNA from T1D-predisposing and -protective haplotypes. Here, we show that the haplotype-specific expression is determined by INS variants that control the splicing efficiency of intron 1. The adenine allele at IVS1-6 (rs689), which rapidly expanded in modern humans, renders the 3' splice site of this intron more dependent on the auxiliary factor of U2 small nuclear ribonucleoprotein (U2AF). This interaction required both zinc fingers of the 35-kD U2AF subunit (U2AF35) and was associated with repression of a competing 3' splice site in INS exon 2. Systematic mutagenesis of reporter constructs showed that intron 1 removal was facilitated by conserved guanosine-rich enhancers and identified additional splicing regulatory motifs in exon 2. Sequencing of intron 1 in primates revealed that relaxation of its 3' splice site in Hominidae coevolved with the introduction of a short upstream open reading frame, providing a more efficient coupled splicing and translation control. Depletion of SR proteins 9G8 and transformer-2 by RNA interference was associated wi...Continue Reading

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Citations

Dec 14, 2011·Nature Genetics·Timothy A GraubertMatthew J Walter
May 26, 2011·Nucleic Acids Research·Jana KralovicovaIgor Vorechovsky
Jun 20, 2014·Nucleic Acids Research·Jana KralovicovaIgor Vorechovsky
Mar 25, 2014·RNA Biology·Michela RaponiDiana Baralle
Aug 28, 2016·Nucleic Acids Research·Jana Kralovicova, Igor Vorechovsky
May 23, 2018·Nucleic Acids Research·Jana KrálovicováIgor Vorechovský
Feb 8, 2021·Nucleic Acids Research·Jana KrálovičováIgor Vořechovský

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Methods Mentioned

BETA
PCR
transfection

Software Mentioned

XLStat
Systat
SigmaStat
BLAST
ImageQuant TL
SDS

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