Human Molecular Genetics Advance Access originally published online on October 20, 2004
Human Molecular Genetics 2004 13(24):3189-3202; doi:10.1093/hmg/ddh334
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Human Molecular Genetics, Vol. 13, No. 24 © Oxford University Press 2004; all rights reserved
Branch site haplotypes that control alternative splicing
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echovsk
1,*1University of Southampton School of Medicine, Division of Human Genetics, Southampton SO16 6YD, UK and 2University of Geneva, Department of Cell Biology, CH-1211 Geneva 4, Switzerland
Received August 25, 2004; Revised October 6, 2004; Accepted October 12, 2004
We show that the allele-dependent expression of transcripts encoding soluble HLA-DQß chains is determined by branchpoint sequence (BPS) haplotypes in DQB1 intron 3. BPS RNAs associated with low inclusion of the transmembrane exon in mature transcripts showed impaired binding to splicing factor 1 (SF1), indicating that alternative splicing of DQB1 is controlled by differential BPS recognition early during spliceosome assembly. We also demonstrate that naturally occurring human BPS point mutations that alter splicing and lead to recognizable phenotypes cluster in BP and in position –2 relative to BP, implicating impaired SF1–BPS interactions in disease-associated BPS substitutions. Coding DNA variants produced smaller fluctuations of exon inclusion levels than random exonic substitutions, consistent with a selection against coding mutations that alter their own exonization. Finally, proximal splicing in this multi-allelic reporter system was promoted by at least seven SR proteins and repressed by hnRNPs F, H and I, supporting an extensive antagonism of factors balancing the splice site selection. These results provide the molecular basis for the haplotype-specific expression of soluble DQß, improve prediction of intronic point mutations and indicate how extraordinary, selection-driven DNA variability in HLA affects pre-mRNA splicing.
* To whom correspondence should be addressed at: University of Southampton School of Medicine, Division of Human Genetics, Duthie Building, MP808, Southampton SO16 6YD, UK. Tel: +44 2380796425; Fax: +44 2380794264; Email: igvo{at}soton.ac.uk
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