Alternative Splicing Modes

Alternative splicing, also referred to as differential splicing, is a process where the RNA exons of the RNA that is produced by transcription of a gene are reconnected in several different ways during RNA splicing. The different mRNAs that are created, may be translated, via transcription, into different protein isoforms, resulting in just one gene that may code for several proteins. This is a normal phenomenon in eukaryotes, where it significantly increases protein diversity that can then be encoded by the genome. Over 80 percent of genes in humans are alternatively spliced. There are several different alternative splicing modes that occur, and there are five basic modes that are most often recognized.

Exon Skipping

Also referred to as cassette exon, this mode involves an exon that may be retained or spliced out of the primary transcript. In pre-mRNAs, this is the most common mammalian mode.

Alternative Donor Site

In this mode, a donor site, an alternative 5′ splice junction, is used. This changes the 3′ boundary of the upstream exon.

Mutually Exclusive Exons

In mRNAs after splicing, one of two exons is retained, but not both.

Alternative Acceptor Site

An acceptor site, alternative 3′ splice junction is used. This changes the 5′ boundary of the downstream exon.

Intron Retention

In this alternative splicing mode, a sequence may be simply retained or spliced out as an intron. This differs from the exon skipping mode due to the sequence that is retained not being flanked by introns. If the intron that is retained is located within the coding region, the intron has to encode amino acids in frame with the exons that are neighboring, or a shift or stop codon in the reading frame will cause a non-functional protein. This mode is the rarest in mammals.

Other Mechanisms

In addition to the modes discussed above, there are two additional main mechanisms in which mRNAs may be produced from a single gene. These are known as multiple polyadenylation and multiple promoter sites. Using multiple promoters, when described properly, is not alternative splicing, but a transcriptional regulation mechanism. Both of these mechanisms give more variety in the mRNAs derived from a gene, and are found in combination with alternative splicing.

Association with Disease

When RNA processing machinery changes occur, disease may result. A high proportion of cancerous cells have abnormally spliced mRNAs found in them. When compared to normal cells, it has been found that in cancerous cells there is a reduction of alternative splicing, and the types of splicing differ.


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