Tuesday, November 21, 2006

Alternative splicing

Not so very long ago it used to be that molecular biologists thought that for every protein in the body there was a specific gene, and every gene contained the instructions for making just one protein. Then, when the human genome was completely mapped several years ago, it was found, to everyone's embarrassment, that there were a lot fewer than 25,000 different genes in the genome. This is in a genome of 3.12 billion base pairs. And the human genome is far from the largest. Ordinary corn has 5 billion base pairs and 50,000 genes. The trumpet lily plant (Lilium longiflorum) has 90 bilion base pairs in its genome, and the marbled lungfish (Protopterus aethiopicus) has 139 billion – but apparently nobody has had the patience to sit down and count their actual genes. (Reference; see also here.)

Anyhow, it's estimated that humans use at least 100,000 different proteins, maybe a lot more, so the point is that some genes must be capable of coding for a lot more than just one protein. It's now understood that this is accomplished by the process known as alternative splicing. As you know, genes are not simple, uninterrupted sequences of base pairs. They have within them several subsequences known as exons and introns. In a nutshell, the exons are eventually transcribed into messenger RNA, while the introns are discarded.

Except there's a little more to it than that. In order to produce different proteins, it's necessary to select a subset of exons to code for each particular protein. So how does this actually happen? Some new research has figured this out in one specific case:

RNA Map Provides First Comprehensive Understanding Of Alternative Splicing
It's biology's version of the director's cut. In much the same way that numerous films could be stitched together from a single reel of raw footage, a molecular process called alternative splicing enables a single gene to produce multiple proteins. Now a new RNA map, created by a team of researchers at Rockefeller University and the Howard Hughes Medical Institute and announced in the journal Nature, shows for the first time how the specific location of short snippets of RNA affects the way that alternative splicing is controlled in the brain.

Though scientists have begun to appreciate how alternative splicing adds a layer of complexity to brain processes that enable us to think and learn, exactly how alternative splicing is regulated during these processes -- and in some cases is uncontrolled (or dysregulated) to cause disease -- has remained elusive. The map provides the first comprehensive understanding of how alternative splicing works throughout the genome. The results have implications for a better understanding of such brain functions as learning and memory, neurological diseases and cancer biology.

To make a long story short, there is a brain protein called Nova that was known to be capable of binding to 50 different sequences of RNA. The study found that there were actually 30 different exons which contained those sequences, and whether or not a given sequence had been bound by Nova could cause the exon to be either included or excluded (depending on circumstances) from a final transcript.

This is of more than just theoretical interest. Errors in the transcription process can cause a variety of disease conditions:
By offering a global understanding of how alternative splicing works across the genome, the map has implications for the treatment of a growing list of human neurologic diseases in which RNA regulation, and particularly RNA splicing, has been implicated as the primary cause, including certain types of cancer and a number of brain and muscle disorders.

"Given that the complexity of the brain is orders and orders of magnitude more complex than the number of genes we have, one of the intriguing things about alternative splicing is that a relatively small number of regulatory splicing factors acting in concert on a single transcript can potentially generate a large number of different protein variants," says Darnell.

"There is a converging set of observations indicating that as neurologic diseases are better understood, alternative splicing is going to play an important role in generation of disease and therefore an important role in normal generation of cognitive function," he adds. "Our new work lays out an approach to developing a global understanding of how alternative splicing is regulated by one disease-associated protein, Nova, offering a route by which scientists may now be able to approach a number of diseases with a fresh start."

It's interesting, also, that this process is being observed in the brain. Because, as Antonio Damasio has just predicted for New Scientist as one of the most likely discoveries of the next 50 years, we should learn how relatively few genes can create such complexity in the brain:
Most of what I regard as exciting in recent neuroscience has concentrated on two broad areas: molecular neurobiology and an understanding of the systems related to cognition and behavior. The future will no doubt promote advances in those two areas. On the molecular side, it will be possible to know how so few genes (relatively speaking) create so much complexity in the human brain.

It would be a good guess that the use of alternative splicing is pretty common in brain tissue.

Update: And in fact, I wrote about this very topic a year ago: RNA splicing occurs in nerve-cell dendrites. The interesting thing is that in most cells, splicing is known to occur only in the nucleus. In neurons, however, it occurs in dendrites, the part of a neuron to which other neurons form connections.

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6 Comments:

Anonymous Jason Calacanis said...

Its a nice illustration of alternative splicing . There is much more to it that we discover every day. a constantly updated subject.

11/05/2007 10:05:00 PM  
Anonymous Anonymous said...

hi, nice article. i have a question on this part: what's the different between splice variants and isoforms? thanks

12/21/2007 07:09:00 AM  
Blogger Charles Daney said...

Splice variants are proteins that result from different ways the mRNA from the same gene can be spliced together. Usually the proteins differ in function.

Isoforms are proteins coming from different, but very similar, genes. They usually have the same function. The similar genes were probably copies of an original gene and have diverged slightly over time.

12/21/2007 08:31:00 PM  
Anonymous Anonymous said...

What is the purpose of alternative splicing in eukaryotes? thanks!

5/14/2008 11:29:00 PM  
Blogger Charles Daney said...

What is the purpose of alternative splicing in eukaryotes?

The purpose is to allow more than one distinct protein to be produced from a single gene.

This is useful, since different conditions inside or outside the cell can influence which of the alternative proteins is produced, according to the circumstances.

5/15/2008 11:59:00 AM  
Anonymous Subha Srinivasan said...

Jivan biologics Inc. is a Bay Area company providing complete solutions for studying alternative splicing in human diseases. Jonathan Bingham and I started Jivan in 2001, months after the shocking revelation from the completion of the human genome sequencing by both public and industrial efforts. Although, it is well established that alternative splicing mechanism is responsible for much of the protein diversity in metazoans, the market for Jivan's solutions has been slow to grow. The cause for market apathy in adopting high-throughput technologies for alternative splicing is unclear. However, it goes without saying that a full understanding of human biology will not be complete without fully understanding the role of alternative splicing in human biology and disease.

7/21/2008 01:18:00 PM  

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