Allele‐specific transcript isoforms in human

Abstract

Estimates of the number of human genes that produce more than one transcript isoform through alternative mRNA splicing depend on the assumption that the observation of multiple transcripts from a gene can be attributed entirely to alternative splicing. It is possible, however, that a substantial proportion of cases where multiple transcripts have been observed for a gene result from differences between alleles. Many examples of genes that are spliced differently from different alleles have been reported but no systematic estimate of the proportion of alternatively spliced genes that are affected by such polymorphisms has been carried out. We find that alternative transcript isoforms are non-randomly associated with closely linked nucleotide polymorphisms, based on an integrated analysis of the dbSNP, dbEST and ASAP databases. From the observed level of association between transcript isoforms and polymorphisms, we estimate that 21% of alternatively spliced genes are affected by polymorphisms that either completely determine which form of the transcript is observed or alter the relative abundances of some of the alternative isoforms. We provide a conservative lower bound of 6% on this estimate and point out that alternative splicing cannot be confirmed absolutely unless more than one transcript is observed from the same allele.

Current-generation high-throughput sequencing: deepening insights into mammalian transcriptomes

“…Previous studies based on exon tiling microarray experiments provided evidence that a subset of single-nucleotide polymorphisms (SNPs) located within exons or neighboring intronic sequences are associated with individual-specific variation in alternative splicing levels (Kwan et al 2008; for review, see Graveley 2008). Using RNA-Seq data from cerebellar cortex tissue samples from six individuals, Wang et al (2008) estimated that 10%-30% of alternative splicing events exhibited interindividual-specific variability, which is in agreement with a previous estimate of ;21% (Nembaware et al 2004). Moreover, it was estimated that individual-specific variation in alternative splicing is twofold to threefold less frequent than tissue-dependent variation in alternative splicing .…”

Systematic evaluation of the effect of common SNPs on pre-mRNA splicing

“…Thus, it is postulated here that allele-dependent splicing phenomenon is not uncommon in the human population, but it seems that splice SNPs exert their impact rather through complex effects. A recent survey showed association of 21% alternatively spliced genes with closely linked SNPs (Nembaware et al, 2004) and among these events, there is evidence of two different types of allelespecific splicing: 1) pure (complete) allele-dependent splicing, in which one allele gives rise to one isoform and another results in the alternative form (as detected in the present study). This type was later suggested to be less common (Nembaware et al, 2008).…”

Transposable elements in disease-associated cryptic exons

“…Deep sequencing of necroptic samples obtained from multiple tissues suggested that between *10 and 30% of alternative transcript events may show individual-specific variation ) and the existence of a considerable fraction of genome variability that influence pre-mRNA processing was supported by previous studies (Graveley 2008;Kralovicova et al 2004;Nembaware et al 2004;Pagani and Baralle 2004;Wang et al 2008). Therefore, it should be fruitful to employ mRef sequencing to identify disease susceptibility and protective haplotypes containing low-inclusion TE pseudoexons that may modulate expression of natural transcripts and disease risk.…”