Scientific article
Open access

Branch site haplotypes that control alternative splicing

Published inHuman Molecular Genetics, vol. 13, no. 24, p. 3189-3202
Publication date2004-12-15
First online date2004-10-20

We show that the allele-dependent expression of transcripts encoding soluble HLA-DQβ 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 DQβ, improve prediction of intronic point mutations and indicate how extraordinary, selection-driven DNA variability in HLA affects pre-mRNA splicing.

  • Alleles
  • Phenotype
  • Mutation
  • Alternative splicing
  • DNA
  • Exons
  • Haplotypes
  • Introns
  • Point mutation
  • RNA splicing
Citation (ISO format)
KRÁLOVIČOVÁ, Jana et al. Branch site haplotypes that control alternative splicing. In: Human Molecular Genetics, 2004, vol. 13, n° 24, p. 3189–3202. doi: 10.1093/hmg/ddh334
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Article (Published version)
ISSN of the journal0964-6906

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