An elegant example of simple rules for complex results – Dscam mRNA alternative splicing

If you took any biology class in highschool that included a little bit of cell biology, it’s very likely that you know the central dogma of molecular biology. That is the information flow from our genes in DNA to RNA through transcription and to Proteins through translation. This has been considered the central dogma since every organism based on DNA uses this flow. Even though we’ve seen in Gene linkage as a tool to detect positive selection on genes and What’s in your genome? posts that an enzime called reverse transcriptase can do the opposite, the central dogma is arguably one of the biggest discoveries in the molecular biology era.

What you probably also remember from bio class is something called RNA splicing. The process through which RNA is processed before transcription and through which non-coding parts are eliminated. Instead of explaining all the details I’ll leave a scheme here:

rna_splicing1317107503447
RNA “alternative” splicing: Introns are “non-interesting” parts that are cut out, while Exons are the coding segments responsible for producing the protein during translation. The term alternative refers to alternative spliced RNA that can be produced after the process.

Splicing is an essential process that every mRNA goes through, especially in higher vetebrates where introns are very common. The fact that through alternative splicing we can have different variants of proteins from the same gene, is a clever stocking idea to have more information in a contained space in the DNA. If you have different RNAs from a single gene, you don’t have to have a different gene for every protein so you save space in your chromosomes. Having RNA splicing allow for many combination in a second level.

So with alternative splicing we can have different RNA that will produce different proteins. What’s amazing about this is exactly how many variants we can have. Most genes have only few variants but some of them are strikingly diverse! The example I want to give is the Dscam gene.

Dscam has 115 exons that can be joined together in different combinations. Through alternative splicing the fruit fly (who has this gene) can produce up to 38,016 different proteins!!! This is an unbelievable number of variants for a single gene!!! But why would you need so many isoforms (variants) of a gene? Considering that they come from the same gene, they will all have approximately the same function.

Well, that’s even more fascinating. Let me context the function. Do you remember neurons from biology class?? They are the typical cells making up our nervous system and they look like this:

173_neurons
Not necessarily an accurate depiction of real neurons but the point is that they are realloy branched and that they connect in super complex networks to one another.

Neurons create amazing networks connecting their branches (dendrites and axons) to other neurons and other cells. But every connection has a purpose, no connection is randomly assigned. Every branch leave the body of the cell looking for its target between millions of destinations. Branches follow gradients of molecules that are produced by their target. Is like a dog following an odour, he’s led by it to the source of the smell. But branches don’t only have to find their target but they also have to avoid each other and avoid wrong connections. Imagine the complexity and the chaos of the above picture, a growing branch that’s travelling toward its target has to avoid any collision with other branches, especially the ones from the same cell. Infact if branches from the same cells would connect, they would create shorcircuit and it would probably highly compromise neuronal function: clearly a big problem.

And we come back to our Dscam gene. Every neuron produce a different variant of the gene and the neurons follow a simple rule: branches can’t connect with protrusions with the same variants. Simple right? Having many thousands variations of the protein allow branches from neuronal cells to avoid shortcircuits, pretty clever I’d say!

The complexity we can observe at the molecular level is really impressive, and this is only a banal example! Simple rules for amazingly elaborated effects make up nature and the world. It’s all up to us being smart enough to understand them. And while we figure them out, let me tell you another story..

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