What happens when chromosomes rearrange? Sometimes cancer.

There are so many different kinds of genetic mutations.  So far, we’ve only discussed small single nucleotide changes and insertions and deletions.  But entire pieces of chromosomes can also be rearranged in what’s called a translocation. The prefix “trans” shows up a lot in science.  It comes from Latin and means “across” or “on the opposite side”.  “location” is physically talking about the chromosomal location.  So “translocation” mean s pieces of chromosomes moving to another location.

translocation

You can think of it as two different pieces of DNA that aren’t usually right next to each other, being put next to each other. Kind of like a centaur – the top of a human attached to the bottom of the horse – a human/horse translocation.  Of course, in the case of chromosome, genes or regulatory pieces of DNA are moved next to each other, and although it may not seem nearly as dramatic as a centaur, the effects can be just as surprising.

philadelphia chromosomeOne example of a translocation that has dramatic consequences is the translocation that causes the blood cancer Chronic Myelogenous Leukemia (abbreviated as CML).  In this case, part of Chromosome 9 and part of Chromosome 22 break off and swap.  So now, Chromosome 9 has part of chromosome 22 attached, and vice versa.  The part of chromosome 22 and the broken off part of chromosome 9 are called the Philadelphia chromosome, and this is what causes the leukemia.

But how?  We  imagine that Chromosome 9 and Chromosome 22 are both train tracks.  On those train tracks are trains that can either be going or not going depending on the upstream signals.  On Chromosome 22 there is a green signal that is stuck at green so the train is always going.  On Chromosome 9, there is a more sensitive signal – some times it’s green, but most of the time it’s red so the train isn’t going.

train_anaolgy

What happens now is that there is a switch (or a translocation) that attaches the Chromosome 9 and 22 train tracks together.   But when it does this, the green signal from Chromosome track 22 is telling the train on the chromosome 9 track to go – even though it usually doesn’t always go.  This is nearly exactly what happens in the case of the Philadelphia chromosome, except the trains are genes that are making protein (if the signal is green) or are not made into protein (if the signal is red). The signals are parts of DNA that regulate the “expression” of the gene (in other words, whether or not the gene makes the protein).

train_analogy_switch

In the case of the translocation in CML, what happens is a gene of Chromosome 22, called BCR is attached to part of the Abl gene on chromosome 9.  In this configuration, the BCR-Abl fusion gene makes a protein that is always “on”.   What does this protein do?  Essentially, it tells the blood cells to keep growing and dividing.  This makes too many blood cells and causes leukemia.

There are many different chromosomal translocations that cause a number of different diseases, but what they have in common is either creating a protein that is always on or changing the upstream signal that tells a gene to make more protein.  Most of the time, this results in signalling the cell to keep growing and dividing, which is why translocations are often associated as a cause of cancer.

What is a mutation?

X-Men are mutants.  So is Dr. David Banner, who turns into the Incredible Hulk.  And the Joker in Batman is a mutant (along with most of the other villains in Batman).  So many superheros and supervillains are considered mutants that the word MUTANT has come to mean something a little terrifying.

Before we start talking about diseases that are caused by gene mutations, it’s important to really understand what a mutation is and how it’s not necessarily terrifying, and won’t turn you into Wolverine or The Hulk.

A mutation is a change in the DNA.  Change is such a broad term, but it’s broad because the DNA can change in a lot of different ways.  One nucleotide of DNA could be replaced with a different nucleotide, a nucleotide or several nucelotides or big long stretches of nucleotides could be removed or added (this is called a deletion or insertion), pieces of chromosomes could be moved from one place to another (or switched, which is called a translocation), or pieces of DNA can be duplicated (this includes whole genes being copied, which is called an amplification).

MutationsWhat actually happens when there is a mutation in your DNA? Let’s first remind ourselves of what DNA does – about 2% of the DNA codes for proteins and the other 98% either does nothing (that we know of) or regulates the DNA.  So when there is a mutation, the mutation may be in a gene or it may not.  And it may affect the protein or not. So in terms of changing a trait or causing a diseases, sometimes it may do this and sometimes not.

So let’s talk about when mutations are good.  Mutations that happen by chance are what’s responsible for evolution.  For example, without genetic changes, humans wouldn’t be able to drink milk.  We’d still all be lactose intolerant since a mutation in the gene that allows us to metabolize milk allows us to process milk as adults.

There are also mutations that are neutral or have no noticeable affect.  These could be in places in the genome that don’t contain genes or regulate gene expression.  They could also be mutations that don’t change the 3D shape or function of a protein.  So even though the DNA is different, the protein isn’t affected.

But what about when the protein is affected?  Mutations can decrease the activity of a protein, increase the activity of a protein, change the amount of protein (making too much or too little), change the function of a protein, or remove a protein altogether.

As an example, let’s think about what would happen if we changed the function of a protein that was responsible for telling cells to grow and divide.  Usually, the protein would be turned on only if it received the proper signal, and then it would grow and divide.  If there was a mutation that make this protein always on, then the cell would grow and divide uncontrollably – like having a broken copy machine that keeps copying even though you didn’t want it to.  Sound familiar?  This is one of the ways that mutations can cause cancer, by turning proteins on that make the cells copy themselves when they shouldn’t forming a tumor.

protein_mt_analogy