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Genome-wide survey of allele-specific splicing in humans.

ABSTRACT: BACKGROUND: Accurate mRNA splicing depends on multiple regulatory signals encoded in the transcribed RNA sequence. 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. 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. RESULTS: 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. 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. 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. We developed a novel probabilistic method to infer allele-specific splicing from EST data. 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 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. 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. CONCLUSION: 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. 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.

SUBMITTER: Nembaware V

PROVIDER: S-EPMC2427040 | biostudies-literature | 2008

REPOSITORIES: biostudies-literature

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Genome-wide survey of allele-specific splicing in humans.

Nembaware Victoria V Lupindo Bukiwe B Schouest Katherine K Spillane Charles C Scheffler Konrad K Seoighe Cathal C

BMC genomics 20080602

<h4>Background</h4>Accurate mRNA splicing depends on multiple regulatory signals encoded in the transcribed RNA sequence. 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. However, because the effect of a mut ...[more]

PMID: 18518984

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Project description:BackgroundMyxozoa represents a diverse group of microscopic endoparasites whose life cycle involves two hosts: a vertebrate (usually a fish) and an invertebrate (usually an annelid worm). Despite lacking nearly all distinguishing animal characteristics, given that each life cycle stage consists of no more than a few cells, molecular phylogenetic studies have revealed that myxozoans belong to the phylum Cnidaria, which includes corals, sea anemones, and jellyfish. Myxozoa, however, do possess a polar capsule; an organelle that is homologous to the stinging structure unique to Cnidaria: the nematocyst. Previous studies have identified in Myxozoa a number of protein-coding genes that are specific to nematocytes (the cells producing nematocysts) and thus restricted to Cnidaria. Determining which other genes are also homologous with the myxozoan polar capsule genes could provide insight into both the conservation and changes that occurred during nematocyst evolution in the transition to endoparasitism.ResultsPrevious studies have examined the phylogeny of two cnidarian-restricted gene families: minicollagens and nematogalectins. Here we identify and characterize seven additional cnidarian-restricted genes in myxozoan genomes using a phylogenetic approach. Four of the seven had never previously been identified as cnidarian-specific and none have been studied in a phylogenetic context. A majority of the proteins appear to be involved in the structure of the nematocyst capsule and tubule. No venom proteins were identified among the cnidarian-restricted genes shared by myxozoans.ConclusionsGiven the highly divergent forms that comprise Cnidaria, obtaining insight into the processes underlying their ancient diversification remains challenging. In their evolutionary transition to microscopic endoparasites, myxozoans lost nearly all traces of their cnidarian ancestry, with the one prominent exception being their nematocysts (or polar capsules). Thus nematocysts, and the genes that code for their structure, serve as rich sources of information to support the cnidarian origin of Myxozoa.

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Genome-wide survey of allele-specific splicing in humans.

Publications

Genome-wide survey of allele-specific splicing in humans.

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