Introduction to Alternative Splicing: The "Street Gene"

Welcome! Real quick:

“Central Dogma”

— DNA---to---> RNA -----to---> Proteins.

Like we talked about:

• DNA = The Master Copy Recipe Book of you; whoever you are.
• RNA/ Genes = "Hand copied" individual recipes from the Master Copy Recipe Book/ DNA on how to make your body parts.
• Proteins = What your body parts are made up of.

Here's a pro-tip: If you find yourself in a situation where the light at the end of a long tunnel is your motivation, make it a point to get at least one good laugh a day. The goal is to stay "light," and laughter is a natural supplement for "lightness." My man T.J., the only other black dude in my cohort, comes right on time with my meds. Prime example: the other day in the lab we had a discussion about what he called the "street gene."

What if "hood/ street", the adjective, was a genetic trait? Meaning, is there some GENE in certain individuals that when turned on, the individual turns "street", in spite of wearing a tie or pastel colored polo and boat shoes? I said to him that it would have to be a single alternatively spliced gene as opposed to different "alleles," like the ones that make eye color because he and I obviously know how to cut it off, but can still "set it off" when provoked.  Ha! Since were talking genetics and gene expression, lets define the PHENOTYPES: The Wayne Brady phenotype and the Deebo phenotype as shown below.

Phenotypes of the Public Display gene

Before we break this thing down, learn this word/ concept:

“Alternative Splicing”

— One GENE can be the recipe for two different proteins, depending on how its presented or 'spliced'

And one more. For this one look at how the word "transcript" is used in the first picture and understand that the first picture is an example of CENTRAL DOGMA.

“Splicing Factor”

— Something that binds to DNA and changes the product; the transcript..

Back to our hypothetical discussion. Unprovoked and under normal conditions, Wayne Brady is a kind and charismatic guy; expressing the "Wayne Brady phenotype."

Exons (colored boxes) are joined together after the removal of certain Introns (black lines) to produce a Transcript. In this case Transcript A. Transcript A, containing exons A, B & C, is then translated to produce a distinct protein; producing the Wayne Brady phenotype.

However, when provoked by a statement on national television that "white people love Wayne Brady because he makes Bryant Gumbel look like Malcom X," he became uncharacteristically "street" and began to express the "Deebo phenotype." Wayne's ancestors must have passed down a genetic tool to make alternative splicing of the public display gene possible.

Under stressful conditions, the same public display gene produces a different transcript; Transcript B. Transcript B, containing only exons A & C, makes a distinct protein; producing the Deebo phenotype.

This is what we mean by alternative splicing of a gene. One gene, depending on which portions of it are presented or SPLICED can produce different traits and phenotypes.

Alternatively spliced public display gene.

Everyone has the public display gene but, not everybody has the ability to express the "Deebo phenotype." They can only express their own version of the "Wayne Brady phenotype." Why? Because they can only produce the "Transcript A" Why? Because they haven't evolved or devolved (depending on how you look at it) the Splicing Factor responsible for "splicing out" the yellow B exon to produce "Transcript B." As you know, only Transcript B produces the deebo phenotype!

Alternative splicing is a hallmark of complex eukaryotes such as insects, humans, reptiles, etc. The ability to diversify the number of proteins produced from a single gene has contributed to the complexity and diversity of our human bodies as well as the bodies of other animals such as flies. The fruit fly, Drosophila melanogaster produces over 30,000 transcripts from only 17,000 genes! This is similar to "multi-dresses;" where one dress can be over six different dresses depending on how you wear it.  How is this possible? A strategy employed in the animal kingdom is to evolve a new splicing factor to produce a new transcript and feature/phenotype(ABC = wayne brady; AC= Deebo). The splicing factor LS2 in the fruit fly Drosophila is a great example.

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Multi-dress: One dress, six distinct styles.

In a relatively short time Drosophila, the group of flies we talked about, made a new and distinct splicing factor by first copying, then modifying an old reliable splicing factor. Imagine you have some ideas that might make your vehicle quieter and get better gas mileage. You wouldn't want to test your theory on the car that your lifestyle depends on. You would do these things on a second car or a copy so that you could still maintain your lifestyle should the new prototype fail. This concept of evolution by gene duplication was introduced by Susumo Ohno in the 70's and is central to the story of the Large Subunit 2 (LS2) protein in Drosophila.

LS2 is an example of a protein that functions as a splicing factor. And, this splicing factor is a highly modified duplicate of U2AF50 that only exists in Drosophila. My masters thesis will provide snapshots of its development; from a redundant duplicate of the parent splicing factor U2AF50, to an evolved and distinct splicing factor protein, promoting novel alternative splicing patterns only in Drosophila, the fruit fly.

http://www.ted.com We have no ways to directly observe molecules and what they do -- Drew Berry wants to change that. At TEDxSydney he shows his scientifically accurate (and entertaining!) animations that help researchers see unseeable processes within our own cells.