This Is Your Brain on Sex (9 page)

So now there is a new neurobiological focus on the epigenome. The word comes from the Greek; the prefix
epi
means “over” or “above.” The epigenome is a mechanism of gene expression that lies above the genome itself. The study of these environmentally induced chemical changes to gene expression (which takes place without mutation or change to the nucleotide sequence of
DNA) is called epigenetics. It is a robust phenomenon; the epigenome is often passed down several generations along with the genes themselves. And it is turning out to be a great game changer for the neuroscience world in the understanding of learning, memory, and behavior.

Say What?

Take a good look at your computer. It is a physical object composed of hardware, such as a hard drive and a monitor. You probably also have some software on that computer: an operating system, a good word processing program, and, with luck, a good Solitaire or Tetris game to help you procrastinate. The hardware and software are separate elements, usually designed and built by different companies. To do something useful, say write a letter or beat your kid’s top score on the video game du jour, you need to have both working together. The software is basically directing your hardware’s action. To you, the user, this partnership is seamless. You do not think about your software being the program and your hardware running it. You don’t have to. You are simply using your computer. It is only when one of the two breaks, making it impossible for you to beat that stupid game that has been invading your dreams, that their separateness becomes apparent.

It is not so different in the field of epigenetics. “The genome is comparable to hardware. And the epigenome to the software,” says Randy Jirtle, director of the Epigenetics and Imprinting Laboratory at Duke University. “It’s a good analogy for understanding how it works.”

Simply stated, epigenetics is the way that life experiences, your parents’ or your own, can actually mark up your DNA. By leaving the biological equivalent of highlights, ticks, and margin notes on individual and group genes, epigenetics can change their expression. In fact those epigenetic changes can alter whether those genes are expressed at all—even for several generations. I think it is fair to say that some of these marks are made in pencil, easily erased by new experiences or direct treatment, while others remain present in a most durable ink, holding steadfast as those genes are passed down to subsequent generations of offspring.

If you have some recall of your
eighth-grade science class, you remember that DNA is a double helix, two polymer chains of simple nucleotides called adenine, cytosine, guanine, and thymine twisted together into base pairs. This particular molecular architecture provides the genetic code, the blueprint that will direct the construction and function of every cell in your body. But it does not act in isolation. Researchers have now discovered several ways different proteins can chemically adhere to DNA, or its messenger pal, ribonucleic acid (RNA), to alter not the genetic material itself but rather how that DNA is used by the cells to make all those different critical proteins.

The first and most stable of these molecular mechanisms is DNA methylation. Your experience in utero and in early life can result in an enzyme called DNA methyltransferase adding new molecules to the cytosine nucleotides in your DNA chain. This chemical change does not mutate the DNA itself. No, your genetic code remains fully intact, the order of nucleotides unchanged. Instead the methylation process adds a checkmark of sorts next to the genes it affects, typically resulting in the suppression or all-out removal of gene expression for the associated protein.

A second epigenetic phenomenon involves histone proteins and increased gene expression. In the cell DNA is wrapped around a core of alkaline proteins called histones, which have long tails that sometimes manage to stick out of their double-helix enclosure. In a process called acetylation, a different type of molecule, an acetyl group, attaches to that errant tail and creates more space between the proteins and the DNA. By doing so, it leads to a surge in gene expression. Similarly, deacetylation can occur here too. As you have likely guessed, an experience may start a chemical chain that ultimately releases an enzyme called histone deacetylase, removing those acetyl groups (and with them the space between the DNA and histone proteins), resulting in fewer proteins being made.

There is a third molecular mechanism studied in the epigenetics of behavior, one that involves microRNA. Back to eighth-grade science class: you probably have a vague recollection that messenger RNAs copy the genetic code from DNA and then travel into the cell nucleus so it can make the prescribed proteins. MicroRNAs are short RNA molecules that attach to that messenger chain and
change the message just a little bit, ultimately suppressing the expression of the gene.

If you glossed over the previous three paragraphs, I don’t blame you. I offered only the most basic information for a little background. For the purposes of this book, the exact molecular mechanisms underlying epigenetic changes to gene expression are of little consequence. The important take-home message is that life experience has the power to change your genetic material at the molecular level, not by mutating your genes, but by affecting the manner in which those genes express themselves—or, more specifically, by facilitating the production of more or fewer proteins by your cells. And as we learned in chapter 3, the number of those proteins can have grand consequences in how our brain cells communicate with one another, ultimately resulting in changes to our own behaviors. “This is evolution riding on the back of software,” Jirtle told me. “These changes happen rapidly. It’s easier to change the code in the software, or the epigenome, than to mutate the genes in the hardware. And these changes can have profound effects on our behaviors.”

It Starts with a Genetic Battle

Want to see epigenetics work its magic? Consider a newborn baby. He is the product of both his parents, both contributing their own DNA when the sperm fertilized the egg and the cells grew into a fetus. He has not had much experience in the world yet. He sleeps, he eats, and he dirties his diapers. Maybe he has worked up to a little cooing. But despite this lack of worldliness, his genome, made up of half his mother’s DNA and half his father’s, already shows some epigenetic markers from a phenomenon called genomic imprinting.

You inherit two copies of each gene from your respective parents. But in some cases, scientists were surprised to learn, one of those two copies is turned off. Take the gene for insulin growth factor 2 (IGF2), a hormone that plays a big role in gestational growth. Although you inherit a copy of this gene from each parent, only the copy from dear old Dad will be expressed. The maternally inherited allele is silenced. In contrast, cyclin-dependent kinase inhibitor 1C, a gene that is thought to suppress tumor growth, shows the opposite pattern of expression: Dad’s copy is turned off,
Mom’s is expressed. The cases, in which you see these parent-of-origin effects, in an estimated two to four hundred genes, are called “genomic imprinting.”

“The phenomenon is paradoxical,” explained Catherine Dulac, a Howard Hughes Medical Institute investigator studying genomic imprinting at Harvard University. “It’s a huge advantage to have two copies of each gene. But here you have something that shuts down one of the two copies of an essential gene. There must be some advantage.”

David Haig, an evolutionary geneticist at Harvard University, hypothesizes that genomic imprinting is simply an evolutionary battle for nutrients, that is, a genetic conflict between the two sexes that helps to determine the size and growth of offspring. Going back to that cute, cuddly newborn—his mom knew he was hers from the get-go. After all, she carried him in her belly for nine months and some change. Dad, however, has no real way of knowing, short of trust and a modern DNA test, that he is the father of that baby. Given this discrepancy of knowledge over the past few million years, Haig suggests, maternally expressed genes are working to make sure all of a mother’s various offspring get the resources they need for survival, while allowing the mother to remain healthy and whole enough to have more babies in the future. The paternally expressed genes, however, are not worried about Mom or the health of any other kids that may belong to different fathers. Instead they work to demand more nutrients for that single newborn from the mother in utero and beyond so it might have a leg up on its potentially unrelated siblings.

Take IGF2, the paternally expressed gestational growth gene I mentioned above. If the maternal copy of this gene was not silenced, moms would likely end up birthing some big ol’ babies—too big to successfully nourish without detriment to herself as well as to her other children. Haig hypothesizes that while the paternally expressed genes encourage the growth of offspring, the maternally expressed genes help keep growth to a manageable size. He calls this theory the “conflict hypothesis,” and some scientific work in animal models lends credence to the idea. “Genes of paternal origin make offspring grow larger and demand more resources from the mother,” Haig told me. “But the maternally expressed genes show preference
to the mother’s ability to reproduce in the future and help limit any one offspring from taking too much.”

Why did I lead you down this particular garden path? There has been no evidence that the baby or his parents did anything to change gene expression, and no evidence of life experiences adding methyl groups or throwing kinks into microRNAs with genomic imprinting. But this is a basic epigenetic result that can have profound impact on behavior. What’s more, it is an effect that is passed from one generation to the next. Without even taking a bite of cheeseburger, my parents were giving me an epigenome that made alterations to the way my genes expressed themselves and my subsequent behaviors through some of these imprinted genes. Because not only do they affect growth; imprinted genes also have a lot to say about brain development and function. “When scientists have genetically manipulated imprinted genes, the most frequent effect identified relates to embryonic growth,” said Dulac. “But the second most frequent phenotype identified involves cognitive function.”

In two papers published in an August 2010 issue of
Science
magazine, Dulac, Haig, and their colleagues reported their finding of differential expression of parent-of-origin genes in the mouse brain. They found 347 genes with sex-specific imprinting features that influenced the development of different areas of the cortex and, interestingly enough, that randy-dandy hypothalamus.
²
These findings suggest that imprinted genes are involved in feeding, mating, and social behaviors—like our old friends, sex and love.

Imprinting is not just a simple, static change made in the womb. No, these imprinted genes turn on and off over time, regulating the expression of genes at different points in the life span. What’s more, maternally expressed genes contribute most to the developing brain, while paternally expressed genes seem to do more work once the brain reaches adulthood. Why, exactly, is unknown.
³
“[Genomic imprinting] is a dynamic process,” said Dulac. “It’s not something fixed through the life of the organism. The neurons and neuronal precursors have a certain repertoire during development where maternal or paternal genes are preferentially expressed. Later in life, that pattern of expression is different. It’s a major mode of epigenetic regulation and a gold mine for the future understanding of how
our genes may control our behaviors.”

As I said, it is all my mother’s fault. It is possible that various traits and aspects of my behavior, including those involved in love and sex, can be traced back in part to the expression of Mom’s imprinted genes. But if I am to give credit where it is due, apparently my father had quite an influence. So I will let him share some of the blame too.

What about Those Cheeseburgers?

I can guess what you’re thinking: “Genomic imprinting is interesting and all, but can you really say it’s your mother’s or father’s fault? And what does that have to do with cheeseburgers, for that matter? Or love?” You are right. There I go talking about genes as if they are little General Pattons directing the troops. It’s a hard habit to break. But imprinting is important. It shows you how epigenetics can change the way your genome works before you even make the jump from embryo to fetus, not to mention from early childhood to adulthood. But the cheeseburgers may play a role too, if agouti mice have anything to say about it.

Agouti mice are a strain of laboratory mice often used as a model to study diseases like diabetes, obesity, and cancer. As such, it is probably no surprise that they are quite fat and susceptible to disease. They also happen to be a very distinct shade of yellow. (The color is quite reminiscent of first morning urine.) These mice are this way because they have a certain permutation of a gene called the agouti gene. And that particular permutation has proved to be quite resilient. When this strain of mice breed on their own, their offspring are also fat, yellow, and prone to health problems, propagating the same variation on the agouti gene from generation to generation. Jirtle and one of his postdoctoral fellows, Robert Waterland, wondered whether they could change the way the agouti gene expressed itself in these animals without genetic engineering or drug treatment. They opted to try changing a simple environmental factor: diet.
⁴

Jirtle and Waterland simply adjusted the feed of a group of agouti mice. Instead of the usual mice chow, they offered a diet rich in methyl donors like folic acid, vitamin B, and choline. As it so happens, you can find these methyl donors naturally
in victuals like onions and beets and in prenatal vitamins. Because we already know that methyl groups can bind to DNA and change it in an epigenetic manner, Jirtle and Waterland hoped they would see a change in agouti expression. They kept the mice on this diet and then allowed them to breed.