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Exonization of AluYa5 in the human ACE gene requires mutations in both 3' and 5' splice sites and is facilitated by a conserved splicing enhancer

Exonization of AluYa5 in the human ACE gene requires mutations in both 3' and 5' splice sites and is facilitated by a conserved splicing enhancer
Exonization of AluYa5 in the human ACE gene requires mutations in both 3' and 5' splice sites and is facilitated by a conserved splicing enhancer
Ancient Alu elements have been shown to be included in mature transcripts by point mutations that improve their 5' or 3' splice sites. We have examined requirements for exonization of a younger, disease-associated AluYa5 in intron 16 of the human ACE gene. A single G>C transversion in position –3 of the new Alu exon was insufficient for Alu exonization and a significant inclusion in mRNA was only observed when improving several potential splice donor sites in the presence of 3' CAG. Since complete Alu exonization was not achieved by optimizing traditional splicing signals, including the branch site, we tested whether auxiliary elements in AluYa5 were required for constitutive inclusion. Exonization was promoted by a SELEX-predicted heptamer in Alu consensus sequence 222–228 and point mutations in highly conserved nucleotides of this heptamer decreased Alu inclusion. In addition, we show that Alu exonization was facilitated by a subset of serine/arginine-rich (SR) proteins through activation of the optimized 3' splice site. Finally, the haplotype- and allele-specific ACE minigenes generated similar splicing patterns in both ACE-expressing and non-expressing cells, suggesting that previously reported allelic association with plasma ACE activity and cardiovascular disease is not attributable to differential splicing of introns 16 and 17.
0305-1048
3897-3906
Lei, Haixin
24595b39-a4e6-4cfc-9354-5001b7f70d5a
Day, Ian N.M.
b749b30a-1f4c-40eb-af0e-a50427388b39
Vořechovský, Igor
7245de2f-8c9b-4034-8935-9a451d9b682e
Lei, Haixin
24595b39-a4e6-4cfc-9354-5001b7f70d5a
Day, Ian N.M.
b749b30a-1f4c-40eb-af0e-a50427388b39
Vořechovský, Igor
7245de2f-8c9b-4034-8935-9a451d9b682e

Lei, Haixin, Day, Ian N.M. and Vořechovský, Igor (2005) Exonization of AluYa5 in the human ACE gene requires mutations in both 3' and 5' splice sites and is facilitated by a conserved splicing enhancer. Nucleic Acids Research, 33 (12), 3897-3906. (doi:10.1093/nar/gki707).

Record type: Article

Abstract

Ancient Alu elements have been shown to be included in mature transcripts by point mutations that improve their 5' or 3' splice sites. We have examined requirements for exonization of a younger, disease-associated AluYa5 in intron 16 of the human ACE gene. A single G>C transversion in position –3 of the new Alu exon was insufficient for Alu exonization and a significant inclusion in mRNA was only observed when improving several potential splice donor sites in the presence of 3' CAG. Since complete Alu exonization was not achieved by optimizing traditional splicing signals, including the branch site, we tested whether auxiliary elements in AluYa5 were required for constitutive inclusion. Exonization was promoted by a SELEX-predicted heptamer in Alu consensus sequence 222–228 and point mutations in highly conserved nucleotides of this heptamer decreased Alu inclusion. In addition, we show that Alu exonization was facilitated by a subset of serine/arginine-rich (SR) proteins through activation of the optimized 3' splice site. Finally, the haplotype- and allele-specific ACE minigenes generated similar splicing patterns in both ACE-expressing and non-expressing cells, suggesting that previously reported allelic association with plasma ACE activity and cardiovascular disease is not attributable to differential splicing of introns 16 and 17.

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Published date: 2005

Identifiers

Local EPrints ID: 24831
URI: http://eprints.soton.ac.uk/id/eprint/24831
ISSN: 0305-1048
PURE UUID: 96aee906-644e-49b9-b0cc-c1dc6b948d81
ORCID for Igor Vořechovský: ORCID iD orcid.org/0000-0002-6740-6502

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

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Author: Haixin Lei
Author: Ian N.M. Day

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