How do mutations change proteins?

We’ve talked about mutations and how they can be good, bad or neutral, but how does that work exactly?  This is the nitty gritty. Remember back to how DNA is transcribed into messenger RNA which is then translated into the protein?  This is based on a three letter code – where each 3 letters of the RNA makes on amino acid. (If you’re interested in knowing how 4 nucleotides, which have 64 possible combinations makes only 20 amino acids, see my Answers page). If you change one of these amino acids a number of things can happen.

To make it easier, let’s pretend that these codons make the sentence “DNA HAS ALL YOU CAN ASK FOR” (see the picture below).  You may change one letter and it doesn’t change the meaning of the sentence (or the function of the protein) at all, making it a “silent” mutation. You may change one letter and it does change the meaning, but maybe not significantly – this is a missense mutation.  You may have a mutation that stops the sentence early – this would make a protein that is shorter than it’s supposed to be and probably will cause the protein to function improperly.  This is a nonsense mutation. Finally, you may add or remove one or many nucleotides which shifts the letter of the sentence so that they no longer make any sense.  These frameshift mutations also will affect the protein, and likely not in a good way.

protein_mutationsNow you can see how small changes may or may not affect the protein.    It’s interesting because it helps really explain how ONE nucleotide change can affect a protein and cause disease.  Also, if you think about the effect one nucelotide change can have, it helps us understand how finding and understanding these changes can be important for diagnosing disease.


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.