Evolutionary conservation analysis increases the colocalization of predicted exonic splicing enhancers in the BRCA1 gene with missense sequence changes and in-frame deletions, but not polymorphisms
Identifieur interne : 00A171 ( Main/Exploration ); précédent : 00A170; suivant : 00A172Evolutionary conservation analysis increases the colocalization of predicted exonic splicing enhancers in the BRCA1 gene with missense sequence changes and in-frame deletions, but not polymorphisms
Auteurs : Christopher Pettigrew [Australie] ; Nicola Wayte [Australie] ; Paul K. Lovelock [Australie] ; Sean V. Tavtigian [France] ; Georgia Chenevix-Trench [Australie] ; Amanda B. Spurdle [Australie] ; Melissa A. Brown [Australie]Source :
- Breast Cancer Research [ 1465-5411 ] ; 2005.
Abstract
Aberrant pre-mRNA splicing can be more detrimental to the function of a gene than changes in the length or nature of the encoded amino acid sequence. Although predicting the effects of changes in consensus 5' and 3' splice sites near intron:exon boundaries is relatively straightforward, predicting the possible effects of changes in exonic splicing enhancers (ESEs) remains a challenge.
As an initial step toward determining which ESEs predicted by the web-based tool ESEfinder in the breast cancer susceptibility gene
Using the default settings of ESEfinder, we initially detected 669 potential ESEs in the coding region of the
In this report we show that evolutionary conservation analysis may be used to improve the specificity of an ESE prediction tool. This is the first report on the prediction of the frequency and distribution of ESEs in the
Url:
DOI: 10.1186/bcr1324
PubMed: 16280041
PubMed Central: 1410749
Affiliations:
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<series><title level="j">Breast Cancer Research</title>
<idno type="ISSN">1465-5411</idno>
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<front><div type="abstract" xml:lang="en"><sec><title>Introduction</title>
<p>Aberrant pre-mRNA splicing can be more detrimental to the function of a gene than changes in the length or nature of the encoded amino acid sequence. Although predicting the effects of changes in consensus 5' and 3' splice sites near intron:exon boundaries is relatively straightforward, predicting the possible effects of changes in exonic splicing enhancers (ESEs) remains a challenge.</p>
</sec>
<sec sec-type="methods"><title>Methods</title>
<p>As an initial step toward determining which ESEs predicted by the web-based tool ESEfinder in the breast cancer susceptibility gene <italic>BRCA1 </italic>
are likely to be functional, we have determined their evolutionary conservation and compared their location with known <italic>BRCA1 </italic>
sequence variants.</p>
</sec>
<sec><title>Results</title>
<p>Using the default settings of ESEfinder, we initially detected 669 potential ESEs in the coding region of the <italic>BRCA1 </italic>
gene. Increasing the threshold score reduced the total number to 464, while taking into consideration the proximity to splice donor and acceptor sites reduced the number to 211. Approximately 11% of these ESEs (23/211) either are identical at the nucleotide level in human, primates, mouse, cow, dog and opossum <italic>Brca1 </italic>
(conserved) or are detectable by ESEfinder in the same position in the <italic>Brca1 </italic>
sequence (shared). The frequency of conserved and shared predicted ESEs between human and mouse is higher in <italic>BRCA1 </italic>
exons (2.8 per 100 nucleotides) than in introns (0.6 per 100 nucleotides). Of conserved or shared putative ESEs, 61% (14/23) were predicted to be affected by sequence variants reported in the Breast Cancer Information Core database. Applying the filters described above increased the colocalization of predicted ESEs with missense changes, in-frame deletions and unclassified variants predicted to be deleterious to protein function, whereas they decreased the colocalization with known polymorphisms or unclassified variants predicted to be neutral.</p>
</sec>
<sec><title>Conclusion</title>
<p>In this report we show that evolutionary conservation analysis may be used to improve the specificity of an ESE prediction tool. This is the first report on the prediction of the frequency and distribution of ESEs in the <italic>BRCA1 </italic>
gene, and it is the first reported attempt to predict which ESEs are most likely to be functional and therefore which sequence variants in ESEs are most likely to be pathogenic.</p>
</sec>
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