This relatively high level of splicing errors explains why most splice variants are rapidly degraded by nonsense-mediated decay.The presence of sloppy binding sites within genes causes splicing errors and it may seem strange that these sites havent been eliminated by natural selection. The argument for their persistence is similar to the argument for junk DNA. Although mutations which create or disrupt binding sites may be slightly deleterious, the large number of possible such mutations makes it inevitable that some will reach fixation in a population. This is particularly relevant in species, such as humans, with relatively small long-term effective population sizes. It is plausible, then, that the human genome carries a substantial load of suboptimal sequences which cause the generation of aberrant transcript isoforms. In this study, we present direct evidence that this is indeed the case. While the catalytic reaction may be accurate enough for effective processing most of the time, the overall error rate may be partly limited by the fidelity of transcription because transcription errors will introduce mutations that create cryptic splice sites. In addition, the transcription error rate of 10−5 - 10−6 is high enough that one in every 25,000 transcribed exons will have an incorporation error in one of the splice sites leading to a skipped intron or a skipped exon.
Almost all multi-exon genes will produce incorrectly spliced transcripts but the frequency of this background noise will depend on the size of the genes, the number of introns, and the quality of the splice site sequences.In some cases, splice variants will be produced by mutations in the gene (DNA). These can be SNP polymorphisms that create a cryptic splice site or mutate a functional site. They can also be somatic cell mutations that affect splicing in a particular tissue or a cell line. When the mutant allele is in a heterozygous state this will result in production of two abundant splice variants; one functional and one non-functional. In the homozygous state the mutant alleles may cause a genetic disease such as the hemophilia found in descendants of Queen Victoria where a mutation in one of the introns in a blood clotting factor gene creates a cryptic 3 splice site resulting in aberrant splicing. A significant fraction of human deaths by disease may be caused by mutations that interfere with normal splicing; mostly by creating cryptic splice sites.Incorrectly spliced transcripts can easily be detected and their sequences entered into the online databases. They are usually described as "alternatively spliced" transcripts, which can be confusing because the term does not distinguish between real, biologically relevant, alternative splicing and processing noise due to splicing errors. One of the central issues in the field of alternative splicing is working out the differences between these two possibilities.