![]() The contribution of heritable variation to the observed diversity of mRNA splice isoforms is well established. However, if the gene is alternatively spliced to begin with, then sequence variants that affect sites that are involved in controlling isoform abundance may be affected, causing allelic differences in the regulation of alternative splicing, with potentially important biological consequences. In some cases, such sequence variants disrupt normal gene splicing, causing aberrant splicing of either a proportion, or all of the transcripts produced. A much larger proportion of variants are likely to occur at sites where the effect on splicing is less obvious, for example at less conserved sites close to intron/exon boundaries, close to the intronic branch-point, or within intronic or exonic splicing enhancer or suppressor sequences. Polymorphisms that occur at the highly conserved donor and acceptor di-nucleotides are an obvious case in which we expect an effect on splicing and these genomic variants, when they occur close to verified exon boundaries, tend be annotated in databases of sequence polymorphisms, such as dbSNP. Sequence variants found on the pre-mRNA can affect a number of different, and in some cases imperfectly characterized, cis-acting sequences that control splicing. Indeed, point mutations leading to aberrant splicing are thought to be among the most important contributors to human genetic diseases. ![]() The medical and biological significance of such variants is evident from the large and rapidly increasing volume of literature reporting examples of aberrant mRNA splicing associated with human cancers and genetic diseases. Mutations or polymorphisms that affect mRNA splicing can have a profound effect on the function of the spliced product, but these effects are often difficult to predict from the primary genomic sequence. However, the mechanisms through which genetic variants at many disease-associated loci affect disease susceptibility remain to be determined. The development of high throughput genotyping technologies and the use of these technologies in large-scale studies has enabled the identification of increasing numbers of human loci that are associated with common genetic disorders (e.g.). One of the key tasks of the post-genome era is to determine the functional implications of genomic variants. ![]() ![]() We also present a set of novel allele-specific splicing candidates and discuss the strengths and weaknesses of alternative technologies for inferring the effect of sequence variants on mRNA splicing. We report a set of genes showing evidence of allele-specific splicing from an integrated analysis of genomic polymorphisms, EST data and exon array data, including several examples for which there is experimental evidence of polymorphisms affecting splicing in the literature. Our results provide an extensive resource that can be used to assess the possible effect on splicing of human polymorphisms in putative splice-regulatory sites. We have also estimated heritability of splicing and report that a greater proportion of genes show evidence of splicing heritability than show heritability of overall gene expression level. The method uses SNPs and alternative mRNA isoforms mapped to EST sequences and models both regulated alternative splicing as well as allele-specific splicing. We developed a novel probabilistic method to infer allele-specific splicing from EST data. ![]() For 1,185 candidate splicing polymorphisms the difference in splicing between alternative alleles was corroborated by publicly available exon array data from 166 lymphoblastoid cell lines. The genome-wide scan uses published tools and identified 30,977 SNPs located within donor and acceptor splice sites, branch points and exonic splicing enhancer elements. We have combined a genome-wide scan for sequence polymorphisms likely to affect mRNA splicing with analysis of publicly available Expressed Sequence Tag (EST) and exon array data. However, because the effect of a mutation on the efficiency of mRNA splicing is often difficult to predict, many mutations that cause disease through an effect on splicing are likely to remain undiscovered. Many examples of mutations within human splice regulatory regions that alter splicing qualitatively or quantitatively have been reported and allelic differences in mRNA splicing are likely to be a common and important source of phenotypic diversity at the molecular level, in addition to their contribution to genetic disease susceptibility. Accurate mRNA splicing depends on multiple regulatory signals encoded in the transcribed RNA sequence. ![]()
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