What are examples of diseases caused by one gene?

Mutations. We know what they are.  Mutations change a gene, which can change the protein.  And this change in the protein can be either neutral, good or bad.  Let’s finally talk about how these mutations can be bad.

There are over 4,000 diseases that are caused by mutations in just one gene.  This means that if there is a mutation in one copy of the gene (if dominant) or both copies of the gene (if recessive), there is nearly 100% likelihood that you will get the disease.  Let’s look at some common examples.

Cystic Fibrosis

cfThis is a genetic disease of the lung that is caused by a recessive gene called the cystic fibrosis transmembrane conductance regulator (or CFTR for short). This gene makes a protein that transports chloride across the cell membrane.  The most common mutation in this gene is a deletion that causes a frameshift, which makes a much shorter protein.  This shorter protein doesn’t work properly at transporting chloride and results in fluid build up in the lungs and other organs that leads to cystic fibrosis (also known as CF).

Since this is a recessive disease, what this means is that you need TWO copies of the mutated CFTR gene to get cystic fibrosis. Remember those genetic squares we used to figure out what the possibility of a child inheriting a particular allele of a gene?  Let’s look at one for CFTR.  If you imagine that the normal CFTR gene (the one that isn’t mutated) is “C” (shown in blue) and the mutated CFTR gene is “c” (shown in orange).  If each parent has one copy of the non-mutated and one copy of the mutated CFTR gene Cc, then they have a 25% chance of having a child with CFTR.  Why?  Because only a child with two copies of the recessive trait (which in this case is the mutated CFTR gene) will have cystic fibrosis.

Huntington Disease

This is an example of a dominant mutation that causes a disease.  The huntingtin genehuntingtin
has a region that has lots of repeats of one codon CAG. Most people have less than 36 repeats of CAG.  However, if a person has more than 36 repeats, it creates a protein that is toxic to brain cells – exactly how and why it is toxic isn’t really well understood.  Since this is a dominant mutation, you only need one copy of this mutated gene to get Huntington’s disease.  So if you have one parent with the Huntingtin mutation (shown as H*), which means they have one copy of the Huntingtin gene with >36 CAGs, then a child has a 50% chance of also inheriting Huntington’s disease (HH*)

Now you may be wondering, how do we know if the mutation will be dominant or recessive?  That’s a complicated question.  In part, you may know if you look at the family history.  A disease caused by a dominant mutation will be inherited by more often by the children of an affected parent whereas a recessive mutation is less likely to be inherited because it is only inherited when both parents have one copy of the recessive gene.  Another option is to study the function of the mutation protein and see how the mutation in the gene affects the function of the protein.  Since there are two copies of every gene, if one copy is mutated, the second copy of the gene could compensate for this mutation (in the case of cystic fibrosis).  In other cases, the mutation could cause such dysfunction that even with the normal protein around, it still causes disease (like Huntingtin’s).

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.



How do genes affect traits? It’s just like “50 Shades of Grey”

In “50 Shades of Grey”, there isn’t any mention of molecular biology or genetics, but maybe there should be, because it’s a great example of how to explain how genes affect traits. And yes, I’m talking about dominance. Don’t get too excited – there won’t be any photos or explicit descriptions of sexy time (aka business time, if you’re  Flight of the Conchords fan).  We’re going to be talking about dominant and recessive genes.

You have two copies of each gene – one on each chromosome – and these are called alleles.  One allele is from your mother and one from your father, and these genes can be slightly different.  In some cases, the gene is dominant, which means that the variant of the trait that it is responsible for will take over – this would be represented by the dominatrix or Mr Grey.  Other genes are considered recessive – or the submissive, Anastasia Steele.  Christian Gray is the boss and what he says goes.  Only when the dominant person isn’t around does the submissive get to do what it wants.
dominant_and_recessiveAnother way to think of this is if you have a bully.  The dominant bully will take over whenever any other kids are around.  Only when the bully isn’t there, can the other kids do what they want.

What does this mean in genetics?  First, let’s get some terminology out of the way.  The dominant gene is usually represented in capital letters (for simplicity let’s call it gene “A”) and the recessive gene is in lowercase “a”.  Whenever the dominant trait, A, is present on one chromosome, that trait will be visible.  So if you have two As (AA) or one dominant and one recessive gene (Aa), you’ll only see the dominant trait.  Only when you have two recessive genes (aa) will you see the recessive trait.

punnetsquareLet’s give an example using eye color.  Let’s say that the dominant gene trait (A) is from brown eyes and the recessive trait (a) is for blue eyes.  With AA or Aa, you will have brown eyes, and with aa you will have blue eyes.  If you look at the image on the right, you may be having nightmares back to high school biology.  All this is representing are the possibilities of what trait a child might have depending on the parents genes.  If each of the parents has one copy of A and one copy of a, the child will randomly get either the A allele or the a allele from each parent. The boxes represent those possibilities.  From there you can ask and answer some really interesting questions – what’s the likelihood that with two Aa parents that the child will have blue eyes?  What do you think?  The answer is here.

What we have just discussed is what’s called “Mendelian Genetics” or “Mendelian Inheritance” named after the Monk Gregor Mendel who in the 1800s discovered these rules with dominant and recessive genes in pea plants.  What’s most interesting for us, besides being able to understand traits like eye color, is that over 4,000 diseases can be attributed to a single gene, either because it was inherited or by chance.


Is love part of your DNA?

Happy Valentine’s Day!  On a day where people are overdosing on chocolate and champagne and whispering sweet nothings into each others ears, I want to tell some stories.  Three short stories (well, two stories and a research paper) that have to do with love.  And maybe not exactly love, but attraction, sex and genetic compatibility.

The Three Fs

When I was in graduate school, the research faculty at my institution (which, by the way is 125 years old and has created an awesome video about the laboratory here) focused on a lot of different scientific topics ranging from understanding cancer better to figuring out how the brain works.  Each Friday, we held “In House”, which was a seminar that the entire institution attended and one faculty member spoke about their recently published research.  My favorite line of all time from one of these seminars was a neuroscientist discussing the “The 3 F’s” that drive all life:  Feeding, Fleeing, and Mate Selection.

Ba dum tsssh…

No Genetic Disappointments

Photo Feb 14, 10 16 17 AMI think that every person on the planet has had their fair share of dating duds. I was no exception, however my Mom’s method for handling these less than ideal suitors was at times hysterical.  Typically, when people think about compatibility they consider whether one person is a night owl and the other person likes to wake up early or if they both enjoy the same hobbies.  However, my Mom decided to appeal to my scientific side and focus on genetic compatibility.  In particular, we discussed how we wouldn’t want my future children to end up with less than desirable personality or character traits through combining their “loser” genes with mine!  Well, scientifically, it doesn’t exactly work that way, but it was an entertaining topic of conversation.  So much so that when I met the author Tom Wolfe and had the opportunity to chat with him over coffee and dinner when he was researching “I am Charlotte Simmons“, I discussed my Mom’s argument in detail. When he inscribed my first edition of his “Bonfire of the Vanities” book, it charmingly said “To Cathy: with fond hopes there will be no genetic disappointments”

And you thought he should do his laundry

One of my favorite experiments (and well covered in the press) studied attraction using sweaty T-shirts.  The researchers had men wear a T-shirt for 2 days, and then women were asked to smell the sweaty T-shirts and decide which she found most attractive.  The interesting result, published in 1995, showed that women were more attracted to the scent of men who were more different from 6555 010them genetically.  The researchers determined this genetic diversity by looking at a set of genes call the Major Hisocompatibility Complex (or MHC, for short).  This is a family of genes that make proteins that mediate immune response.  There are 10 different MHC genes in humans, and each of these 10 MHC genes are slightly different genetically in different people.  These differences are what, for example, result in rejection in organ transplants or skin grafts.   These differences, however, are also what the researchers in the sweaty T-shirt experiment found attracted people to one another. The more different the MHC of the T-shirt wearer was from the T-shirt smeller, the more attractive the smeller found it.

Why did the researchers think that these “opposites attract”?  Honestly, they weren’t entirely sure.  One of the hypotheses was that it could be a way to increase diversity of these important immunity genes to improve our defenses against disease.  But does it really matter?  Because now your significant other will have a reason not to do the laundry – to be more sexy in the name of genetic diversity!