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Branch site haplotypes that control alternative splicing

Branch site haplotypes that control alternative splicing
Branch site haplotypes that control alternative splicing
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.
3189-3202
Kralovicova, J.
b3e0c1e7-05ed-445d-b3d9-ace11e3b4878
Houngninou-Molango, S.
b758a529-cfbe-441b-8ddc-8916b64d6d1d
Kramer, A.
c454bc3c-ae04-4197-9cba-9c7360178cc0
Vorechovsky, I.
7245de2f-8c9b-4034-8935-9a451d9b682e
Kralovicova, J.
b3e0c1e7-05ed-445d-b3d9-ace11e3b4878
Houngninou-Molango, S.
b758a529-cfbe-441b-8ddc-8916b64d6d1d
Kramer, A.
c454bc3c-ae04-4197-9cba-9c7360178cc0
Vorechovsky, I.
7245de2f-8c9b-4034-8935-9a451d9b682e

Kralovicova, J., Houngninou-Molango, S., Kramer, A. and Vorechovsky, I. (2004) Branch site haplotypes that control alternative splicing. Human Molecular Genetics, 13 (24), 3189-3202. (doi:10.1093/hmg/ddh334).

Record type: Article

Abstract

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.

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More information

Published date: 2004
Additional Information: Human Molecular Genetics advance access originally published online on October 20, 2004

Identifiers

Local EPrints ID: 24812
URI: http://eprints.soton.ac.uk/id/eprint/24812
PURE UUID: 1caa66e8-5e0f-4777-a854-116d7c2c685b
ORCID for I. Vorechovsky: ORCID iD orcid.org/0000-0002-6740-6502

Catalogue record

Date deposited: 04 Apr 2006
Last modified: 16 Mar 2024 03:32

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Contributors

Author: J. Kralovicova
Author: S. Houngninou-Molango
Author: A. Kramer
Author: I. Vorechovsky ORCID iD

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