When a Gene Is Not Enough

Ways to beat Mendel

by Dr. Barry Starr, Stanford University

Genetics can be tricky but the basics really boil down to a couple of simple points. We have two copies of most of our genes—one from our mom and one from our dad. And genes can come in different versions.

The trait you end up with depends on these different versions. Look at curly and straight hair as an example.

If you have two curly gene versions, you have curly hair. And if you have two straight hair gene versions, you have straight hair. And what if you have one of each? Then you have wavy hair.

Except when you don't. Just as we're getting a grasp on the basics of genes and genetics, some weird things begin to pop up. Sometimes an animal "remembers" a gene from a few generations back and ends up with that trait instead of the ones their genes tell them to have. This is called paramutation.

And sometimes what mom eats affects what color your hair ends up even if your genes tell you something different (at least if you're a mouse). This is called epigenetics.

Don't let the awful words scientists give to these things scare you off. This stuff is fascinating. And it is important for understanding why we are the way we are.

Remembering Our Genetic Past

As we talked about earlier, having one straight hair gene version and one curly one means you have wavy hair. But what if your cells remembered that your grandfather had straight hair? And that memory overrode your genes and gave you straight hair?

Sounds weird but something like this does happen in nature. It was given a name apparently designed to bore people, paramutation.

Paramutation was first noted in corn. Sometimes the purple color found in some corn followed the rules of genetics. And sometimes it didn't.

The KK mouse should have
a solid colored tail

A recent article describes something similar that happens with the color on the tip of a mouse's tail. Sometimes a tail keeps a white tip even when a mouse's genes tell it not to.

There is a gene called kit that, among other things, affects the color at the end of a mouse's tail. Kit comes in at least two versions that we'll call K and k.

If a mouse has two K versions, it has a solid colored tail. If it has a K and a k, then it has a white spot at the end of its tail. And if it has two k versions, it dies shortly after birth.

So, if you mate a white-tipped mouse with a solid colored one, you'd expect half of the mice to have a solid colored tail. But this isn't what happened. Nearly all of the mice ended up with a white tipped tail, both the Kk and the KK mice.

In other words, some of the mice overcame their genes and ended up with a trait not dictated by their genes. This is paramutation.

How do mouse cells "remember" that one parent had a white tipped tail? The researchers found out that it might have something to do with RNA.

To understand RNA, let's dig a bit deeper into genes. A gene is really just a recipe for a specific protein. For example, the kit gene is a recipe for the kit protein.

Small RNAs can shut off the kit gene
leading to a white tipped tail

Before the information in a gene is used to make a protein, the DNA sequence is first copied into RNA. This is why RNA is usually thought of as an annoying intermediate between DNA and proteins. But RNA can do a lot more.

Some very small RNAs can actually control whether a gene is on or off. The way these small RNAs do this is by having a gene's RNA destroyed before the cell can read it. A gene that makes no useable RNA is like a gene that isn't there.

What does this have to do with white tipped tails? Well, the k version of the kit gene makes no useable RNA. So a mouse with a solid colored tail has twice as much kit RNA as one with a white tipped tail.

If there were some way to decrease the amount of RNA in a KK mouse, then it might end up with a white tipped tail. And this is what the researchers think is happening.

The thought is that the sperm or egg from mice with white tips on their tails has small RNAs that get rid of some of the kit RNA. The mice that result from this sperm and egg would make less kit RNA no matter their DNA. And they would have white tips on their tails.

The trait also passed through at least another generation. In other words, the KK mouse with the white tipped tail had pups with a white tipped tail.

This is interesting because for the most part, RNAs are thought to be pretty unstable. It seems very unlikely that whatever RNA is involved hangs around for a whole mouse generation. Maybe whatever makes the RNA is continuing to happen in the mice pups. This will be the next question to be solved

In any event, this is one of the ways the body can overcome the genes it is given. And this isn't just some sort of academic exercise.

Some researchers think that some forms of diabetes and infertility might be related to a similar phenomenon. Perhaps by understanding these mice, we'll get a better handle on these problems as well. And maybe find better ways to treat or even prevent these conditions.

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You are what your mom eats

Same genes, different colors.
Blame it on what mom ate
while pregnant

As we talked about in our example of the mice with white tails, a shut off gene is like one that isn't there. Even though the mouse has the genes for a solid colored tail, something else is keeping the genes from being all the way on. The result is a white tipped tail.

There is another striking hair color example in mice. Scientists found that if you fed a pregnant mom one kind of food, she had yellow pups. A different kind of food resulted in black pups. And these pups all had the same genes!

The researchers discovered that this worked through a process called methylation. In methylation, little chemical groups get stuck to the DNA and hide the gene from the cell. To the cell, the gene isn't there anymore.

A cell reads a gene using certain proteins that copy genetic information from the DNA into RNA. There is lots of DNA in the cell that has nothing to do with genes. You wouldn't want the proteins that make RNA (called RNA polymerases) to turn all of our DNA into RNA. This would be a waste and probably muck things up.

No, you want the cell to be able to recognize genes and only see them (for the purposes of making RNA from genes). So at the start of each gene are certain DNA sequences that tell the cell to start here. Sort of like capitalizing the first word of a sentence.

What methylation does is uncapitalize that letter. Now we don't know where the sentence starts. And the cell doesn't know where the gene starts.

If the machinery doesn't see a start point, it ignores the gene for the most part. Now even though the mouse has a gene that says to give it black hair, the particular food that mom ate resulted in that gene getting methylated. Now the cell can't see the gene and you end up with a yellow mouse.

Just like the paramutation, this trait can be passed on down the generations. Once DNA is methylated, the body tends to keep it methylated with, you guessed it, special methylating proteins.

This sort of phenomenon is one of the ways the environment can affect who we are. For example, as identical twins get older, they become less and less alike. Part of this has to do with the sorts of changes that made a mouse destined to be black become yellow.

Paramutation and epigenetic changes are not just weird exceptions. They help determine who we are and whether or not we will get sick. There is a lot more to genetics than what Mendel found with his peas!

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Content provided by the Department of Genetics, Stanford University.