Spooled DNA and Hidden Genes

The latest finding in how our DNA is organized and read

by Dr. Barry Starr, Stanford University

We all have 6 feet of DNA crammed into the nucleus of every cell. This is somewhere between 5 and 10 billion miles of the stuff in every one of us. So how does all that DNA fit into the average person?

By being wound up like threads on a spool. And then those spools are stacked and organized. And then all of that is organized again and again until we get to chromosomes.

This isn't a perfect analogy. Unlike thread, only about 1.65 turns of DNA get wrapped around nucleosomes (this is what the spools are called). This means there is lots of DNA not on these spools.

Now we knew all of this before. What is new is that scientists can predict what DNA is on the spool. In other words, we can look at a piece of DNA and predict where the spools will go.

How is this a new code? It is a code because where these spools are can control which genes get used in which cells. Other things do this too so the fanfare may be a bit much for these findings. But they are still very important to understanding how our DNA works.

The First Genetic Code

The genetic code revealed
the language of DNA

When the first genetic code was deciphered, it was a huge deal. We had found a Rosetta stone that let us read our own instructions.

The first genetic code was figuring out how the body knows how to make its specific proteins. Remember, proteins are the workers of the cell. If you need something done, chances are a protein does it.

They carry our oxygen, help digest our food, let us see, etc. They really are the peasants from Woody Allen's Love and Death—they do all the work!

So how does the body know how to make these proteins? From our DNA.

Contained in our DNA are segments called genes. Each gene is an instruction for making a protein.

These genes are written in a specific language. The alphabet is much simpler than English. Instead of 26 letters, there are only 4—A, G, T, and C.

What's more, there are only three letter words in this primitive language. If you put these two things together, you have a total of 64 words. That's it.

The difference between you and a cucumber is based largely on the instructions written with only 64 words. Now that is an amazing finding.

So we have the code. But this code is incomplete.

Not all of our DNA is genes. So how do our cells know where a gene starts and ends? Also, not every gene is read in every cell. So how does a cell know which genes to read and which to leave alone?

The findings we'll talk about shed light on the second issue. It isn't the only way cells find the right genes to make the right proteins in the right place at the right time. But it is part of one way they do it.

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The Second Genetic Code

So, genes make proteins according to a simple code. But as I said, not all proteins are made in every cell.

An eye cell doesn't need any breathing genes on. And so they are shut off in the eye. Seeing genes are also shut off in the lungs. This sort of thing goes on in all of our different cell types.

What we really have is another layer of coding—a code to tell a cell what to make when. Let's use a cookbook analogy to help us understand all of this better.

Finding a gene is alot
like finding a recipe

Think about all of our DNA as 46 big cook books. Each book has 1000's of recipes for proteins called genes. And each of these recipes is made up of 100's or 1000's of three letter words.

Now it isn't as simple as this. In between the recipes are millions and millions of letters that seem like gibberish. These letters don't form any of the three letter words.

Now imagine you want to make some spaghetti. If you have 6 billion letters all run together, how are you going to tell where the spaghetti recipe is? How do we do it in a real cookbook?

Well, first off there are clues that a recipe is starting and stopping. This punctuation includes things like a title to tell you that the recipe is starting and a period and blank space to tell you the recipe is done.

Our genes have similar sorts of things. There are certain strings of letters to start a gene and certain strings to end one.

OK, so now our cells can find genes. But how does the cell "know" which genes to read? And which ones to ignore? In other words, how does it know to make spaghetti for dinner on spaghetti night?

This is where the new finding comes in. Remember the spools we talked about earlier? Well, besides compacting the DNA, these nucleosomes can also hide genes from the cell.

We can think of them as paperclips that stick a bunch of our cookbook pages together. Now those recipes can't be read (unless you get rid of the paperclip).

We knew this stuff before. What was unclear is how the nucleosomes got there.

One idea was that proteins placed the nucleosomes in their correct places. Another idea was that the nucleosomes found their way there on their own.

The humble yeast showed us
where nucleosomes like to bind

Actually, scientists suspected that it was a combination of the two but the importance of each was unclear. This new research showed that the spools can find their way to the right places on DNA.

What the researchers did was look at the string of letters where some nucleosomes were in baker's yeast. From these letters, they were able to piece together a common string of letters that nucleosomes liked (called a consensus sequence).

When they went back and looked at all 12 million letters of yeast, they found that they could predict where around half of the nucleosomes were. This is really good.

This doesn't explain why nucleosomes are covering up a gene in one cell and not in another. But it is an important clue towards solving this mystery.

Of course this isn't the only way to hide genes from the cell. Sometimes chemical groups get stuck to the DNA and cover up the start. This "methylation" is more like putting a Post-it over the title. Sometimes a cell makes a protein that marks a lot of genes to be read. These "activators" are like putting tabs on all of your favorite recipes.

And there are lots of other ways besides. The new finding about where nucleosomes form on the DNA is an important piece of information that will help us better understand all of this. It isn't the whole answer, but it is a start.

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Content provided by the Department of Genetics, Stanford University.