Alternative splicing

Alternative splicing is the process that occurs in eukaryotes in which the splicing process of a pre-mRNA transcribed from one gene can lead to different mature mRNA molecules and therefore to different proteins. Also viruses have adapted to this biochemical process when using the protein biosynthesis apparatus.

When the pre-mRNA has been transcribed from the DNA, it includes several introns and exons. In nematodes, the mean is 4-5 exons and introns; in the fruit fly Drosophila there can be more than 100 introns and exons in one transcribed pre-mRNA. But introns and exons are not yet determined at this stage. This decision is made during the splicing process. The regulation and selection of splice sites is done by Serine/Arginine-residue proteins, or SR proteins. The use of alternative splicing factors leads to a modification of the definition of a "gene". Some have proposed that a gene should be considered as a twofold information structure:

• A DNA sequence coding for the pre-mRNA
• An additional DNA code or other regulating process, which regulates the alternative splicing.

There are four known modes of alternative splicing:

• Alternative selection of promoters: this is the only method of splicing which can produce an alternative N-terminus domain in proteins. In this case, different sets of promoters can be spliced with certain sets of other exons.
• Alternative selection of cleavage/polyadenylation sites: this is the only method of splicing which can produce an alternative C-terminus domain in proteins. In this case, different sets of polyadenylation sites can be spliced with the other exons.
• Intron retaining mode: in this case, instead of splicing out an intron, the intron is retained in the mRNA transcript. However, the intron must be properly encoding for amino acids. The intron's code must be properly expressible, otherwise a stop codon or a shift in the reading frame will cause the protein to be non-functional.
• Exon cassette mode: in this case, certain exons are spliced out to alter the sequence of amino acids in the expressed protein.

Importance in molecular genetics

Alternative splicing is of great importance to genetics - it invalidates the old theory of one DNA sequence coding for one polypeptide (the "one-gene-one-protein" hypothesis). External information is needed in order to decide which polypeptide is produced, given a DNA sequence and pre-mRNA. (This does not necessarily negate the central dogma of molecular biology which is about the flow of information from genes to proteins). Since the methods of regulation are inherited, the interpretation of a mutation may be changed.

It has been proposed that for eukaryotes it was a very important step towards higher efficiency, because information can be stored much more economically. Several proteins can be encoded in a DNA sequence whose length would only be enough for two proteins in the prokaryote way of coding. Others have noted that it is unnecessary to change the DNA of a gene for the evolution of a new protein. Instead, a new way of regulation could lead to the same effect, but leaving the code for the established proteins unharmed.

Another speculation is that new proteins could be allowed to evolve much faster than in prokaryotes. Furthermore, they are based on hitherto functional amino acid subchains. This may allow for a higher probability for a functional new protein. Therefore the adaptation to new environments can be much faster - with fewer generations - than in prokaryotes. This might have been one very important step for multicellular organisms with a longer life cycle.

A common myth is that alternative splicing is responsible for humans supposedly being the most complex animals, saying that humans perform more alternative splicing than the other animals. However, this is not the case. A study conducted on the subject found that "the amount of alternative splicing is comparable, with no large differences between humans and other animals." The "record-holder" for alternative splicing is actually a Drosophila gene with 38 000 splice variants called Dscam.

External links

• HHMI article on alternative splicing
• Study on alternative splicing and complexity
• Stamms-lab.net: Research Group dealing with alternative Splicing issues and mis-splicing in human diseases
• Alternative Splicing of ion channels in the brain, connected to mental and neurological diseases