Debunking myths on genetics and DNA

Friday, July 29, 2011

The case of "junk DNA" and why it shouldn't be called junk: Epigenetics.

(This is part 3 of 4 in a series dedicated to "junk DNA". Links to the previous parts: Part 1, and Part 2.)

Last year I was diagnosed with thyroid disease. Despite feeling pretty crappy, I found the phenomenon extremely fascinating. Okay, I'll admit, I found it fascinating after my doc told me worst case scenario they'd remove the thyroid and I'd be as good as new (minus the thyroid, that is). Here's what happened: somehow, my immune system decided that my thyroid was some kind of foreign object that did not belong, and it started producing antibodies to destroy it. And I mean literally destroy it: left untreated, the antibodies will keep attacking the thyroid until it's gone.

How the immune systems knows "self" from "non-self" (and hence attacks foreign objects but, under normal conditions, not its own cells) is a fascinating topic and worth a post in itself (and I promise it'll come, just give me a few more weeks!).

For now, though, I want to focus on this: thyroid disease is a purely genetic disease. So, if it was encoded in my DNA, why did I end up getting it last year instead of having it since birth?

Epigenetics  holds the answer to my question (for the veterans in the field, please see my note below).

There was a nice article in the Time magazine a few months ago that described the concept really well: if you compare our body to a computer, genetics is the hardware and epigenetics is the software. Or, to use another analogy that my friend and fellow scientist/writer Ian Tregillis coined, if the genome is a four-note musical score, then the epigenome is the musician who interprets and executes the music.

"Epigenetics" is an umbrella term that encompasses all processes that regulate gene expression. In other words, what decides which genes are "turned on" and which are "turned off."

Think of en encrypted message. You don't know the meaning of the message until I give you the key. Depending on what key I give you, the message may change dramatically. DNA is the encrypted message. In order to "read" the message, i.e. the instructions on how to make proteins, we need a system capable of "translating" the message. It's a very delicate and complex system. And while our DNA is exactly the same in every cell of our body, the epigenetics is different.

Well, that's kind of obvious, isn't it? Think about it: how does a brain cell know to behave like a brain cell, and a skin cell to behave like a skin cell? After all, they have the same DNA. What differentiates them is the epigenetic processes that translate the DNA in each type of cell. The brain cell will have "brain genes" activated, and the skin cell will have the "skin genes" activated, while the others will be turned off.

So far so good. Still, how do you explain genetic diseases like diabetes showing up in adults rather than from birth? They are indeed encoded in the individual's DNA, but in a very subtle way. Mutations that sit there, waiting to go off. Waiting for the right change in the epigenetic process that will suddenly activate them.

Yes, that's exactly what happens: our DNA stays the same throughout our lifetime, but the way we express the genes can and does in fact change. Environmental stress is one of the major reasons affecting these changes [1]. Example: drought can cause certain plants to switch on pseudogenes regulating their capability of survival with less water [2]. The availability of food can induce analogous epigenetic changes in animals. Studies have shown that a pregnant woman's diet can activate pseudogenes not only on the baby, but the changes are actually inherited by the baby's babies as well [3]. Even though these are not genetic changes, hence they do not alter the DNA, still, they are in fact inheritable and it takes a few generations for the switches in gene expression to wear off [4].

So, think about it: (1) DNA doesn't quite dictate who or what we are. And (2) good ol' Lamarck was not so far from the truth after all, was he?

Back to my original question: thyroid disease was indeed "encoded" in my genome, but it was an epigenetic change in the way my genes were expressed that one day set my immune system off to an anti-thyroid mission.

What does this have to do with junk DNA?

Well, remember what junk DNA really is: it's non-coding DNA. Genes that are "turned off." But wait, we just learned that "turned off" or "turned off" is something that can change during one's lifespan. So, what we call "junk DNA" is something dynamical, something that when we look again tomorrow may have suddenly become functional because of the way DNA gets translated.

More and more studies are finding a link between cancer and mutations that sit in pseudogenes (non-functional genes that are part of the so-called junk DNA). At first this was quite surprising. If these genes aren't translated, how can they affect our body? Well, it turns out they are indeed expressed in cancer patients, giving origin to the term oncogene. In other words, the mutation is there, and it's not until an epigenetic change occurs and the pseudogene gets activated, that the disease takes off.

So, don't call non-coding DNA junk.

We need to study this part of our DNA, because it holds important information about our health. It also holds the key to our survival as a species by allowing us to adapt and change as the environment around us changes. And, finally, it holds our evolutionary history: we carry our ancestors, from viruses to bacteria to monkeys in our DNA.

Technical note: I am using the term "epigenetics" in a broad way, to include any of the following scenarios: post-replication DNA changes; post-transcription RNA changes; and, finally, changes in protein translation. The association between thyroid disease and epigenetics is purely my own, but an analogous conclusion has been reached for similar autoimmune disorders, where the immune systems fails to recognize self from non-self -- see this paper.   

[1] Inheritance of Stress-Induced, ATF-2-Dependent Epigenetic Change. Ki-Hyeon Seong, Dong Li, Hideyuki Shimizu, Ryoichi Nakamura, Shunsuke Ishii. Cell - 24 June 2011 (Vol. 145, Issue 7, pp. 1049-1061)

[2] Epigenetics in the extreme: prions and the inheritance of environmentally acquired traits. Halfmann R, and Lindquist S. Science. 2010 Oct 29;330(6004):629-32.

[3] Epigenomic disruption: the effects of early developmental exposures. Bernal AJ, Jirtle RL. Birth Defects Res A Clin Mol Teratol. 2010 Oct;88(10):938-44.

[4] Transgenerational Epigenetic Inheritance: Prevalence, Mechanisms, and Implications for the Study of Heredity and Evolution. Eva Jablonka and Gal Raz, The Quarterly Review of Biology. Vol. 84, No. 2 (June 2009), pp. 131-176

Picture: Rock. Canon 40D, focal length 85mm, exposure time 1/100.

Monday, July 25, 2011

The "eye test"

(Update: the next post in the "junk DNA" series will be up on Friday. Thanks to all of you who pitched in suggesting new topics, asking questions, and proposing guest blogs. We have a rich schedule coming up!)

Here's the checklist for a scientific paper:
  • you come up with a hypothesis; 
  • you design an experiment to test the hypothesis; 
  • you gather the data; 
  • you look at the data and decide whether or not your original hypothesis was correct.
No, wait, something's missing.

Oh, yeah. We forgot the analyst! Well, you're in luck, because that's exactly my job.

After they gather the data, the experimentalists show it to us, jumping up and down in excitement: "Look what we found!"
And we, the analysts, raise a brow, click our tongue, and reply: "Yeah, but can we prove it?"

So we design a new statistic, we write a code to implement it, we run, graph and debug until we've proven what the experimentalists saw in the first place. Or the opposite of that, it can go either way. Because the truth is, the human eye naturally looks for patterns. It's not objective. What you "see" is not always real. A good eye can help you make a conjecture, but then you have to prove your hypothesis. If you can't prove it, it's not real.

That's the core of scientific thinking.



So the other day we got the response on a paper we submitted for publication a few months ago. We had some data, which we summarized with a set of nice graphs, and then did some statistical analysis to prove the assert. The response? Rejected.

Turns out, the reviewer looked at our analysis, acknowledged the highly significant p-value (just so you know, a "highly significant p-value" means we proved our hypothesis), then stared at the data. He stared, stared, and stared and just couldn't see it. So he wrote: "The data doesn't pass the eye test."


May we suggest an eye doctor, kind Sir?

Picture: Ogunquit Beach, ME. Canon 40D, focal length 60mm, exposure time 1/800.

Friday, July 22, 2011

The case of "junk DNA" and why it shouldn't be called junk: Redundancy.

(This is part 2 of 4 in a series dedicated to the concept of "junk DNA". Part 1 is here.)

Carl Sagan used this beautiful video to illustrate evolution:

(And Vangelis's soundtrack is the cherry on top!)

You might think that the same happens to DNA: one mutation after the other, DNA branches out just like the organisms in the video. That is not quite the case. Most of the information is saved, not erased. Why? Because that is the smart thing to do.

Mutations typically occur as random errors when cells duplicate. This often results in a new, non-functional gene. The old gene is still functioning, and the new one has a mutation that may or may not be deleterious. As mutations accumulate, things shift. The new gene may end up being functional, and, if the new mutation doesn't alter the information (what we would call a "silent" mutation), it will perform the exact same function as the old gene. That's what we call "redundancy," in other words, two or more genes sharing the same functionality. This is advantageous because if one suddenly loses its functionality, the system can revert to the old one to restore the information. It's the same mechanism used in CDs and DVDs, for example, so that you can hand them off to your kids and, unless they decide to use them as frisbees, a few scratches won't ruin your music or favorite movies.

What if the mutation was not silent and it did change the functionality of the gene?

First of all, it takes many mutations and many generations for this to happen. Sagan's video summarizes million of years in just a few minutes. But when it does happen, the new gene takes over and becomes functional. And the old gene? Still there, stored away. If you compare genes to switches, whenever a "new" gene arises, the old one is turned off and a new switch is made and turned on.

The result?

We all share most of our DNA with monkeys, giraffes, elephants, mice. What changes is which genes are "on" and which are "off." The non-functional genes that we share with other organisms are called "pseudogenes," and they are non-coding. What this means is that when DNA is unfolded and prepared for the retrieval of information to make the proteins that keep us alive, all those pseudogenes are tossed away. And that's what led to the term "junk DNA." But you see, pseudogenes have a very important role in evolution.

Imagine to toss a ball onto a rugged landscape. There are infinitely many paths the ball can take. Evolution is a rugged landscape and organisms are balls competing for the equilibrium niches. In an ever-changing landscape, saving the information can be vital. How did mammals end up back in the ocean? Because it had become advantageous and the information was already there. A few pseudogenes became functional again and the switch happened.

Again, these changes don't happen overnight. We are talking about hundreds of generations. And there is no intention behind the changes, only pure randomness driven by selection pressure from the environment. We are changing our planet a little too fast for evolution to save us. But if we had enough time, eventually our body would adapt to a CO2 laden atmosphere as the first micro-organisms that populated the Earth.

That's because Mother Nature took care of everything.

Picture: Mirror installation at the Metropolitan Museum of Art, New York. Canon 40D, focal length 66mm, exposure time 0.3 seconds.

Tuesday, July 19, 2011

Photographic experiments...

Done with: Canon EOS 40D, ISO speed 400, focal length 85mm, exposure time 8 seconds. Oh, and a stroboscobic light. No Photoshop, no computer graphics, no editing!

Sunday, July 17, 2011

The case of "junk DNA" and why it shouldn't be called junk

Human DNA is made of roughly three billion pairs of nucleotides. In other words, each of our chromosomes contains a long string of A's, G's, T's and C's, and all together those strings form a word that's long three billion letters.
When the Human Genome Project started, scientists expected to find millions of coding genes. Coding genes are strings of DNA that contain the "instructions" on how to make proteins. When the project was completed, in 2003, they had found roughly twenty thousand coding genes. The surprise? Most of our DNA is not made of genes.

What is it made of, then?

It's been called many names: pseudogenes; junk DNA; non-coding DNA. Of all terms, "junk DNA" is the most unfortunate. Just because it doesn't have a function that we know of, it doesn't mean it's not important. And it doesn't mean it can't affect our lives.

In the next few weeks I'll make a case that "junk DNA" is indeed important.
It's part of our history, our heritage, and our future.
I will make my case using three concepts:
See you soon!

Picture: Lion's Mane Jellyfish, New England Aquarium, Boston. Canon 40D, exposure time 1/30, focal length 30mm.