Maybe It Isn't All In Your Genes

Joseph Nadeau is trying to find the missing link between heritability and genetics. What? You thought Gregor Mendel had it all figured out in the 19th Century? Well he did. But then DNA sequencing came along and upset the apple cart.

What we know about the fundamental laws of inheritance began to take shape in a monastery garden in Moravia in the middle of the 19th century, when Gregor Mendel patiently cross-bred pea plants over the course of several years, separated the progeny according to their distinct traits, and figured out the mathematical foundations of modern genetics. Since the rediscovery of Mendel's work a century ago, the vocabulary of Mendelian inheritance—dominant genes, recessive genes, and ultimately our own era's notion of disease genes—has colored every biological conversation about genetics. The message boils down to a single premise: your unique mix of physiological traits and disease risks (collectively known as your phenotype) can be read in the precise sequence of chemical bases, or letters, in your DNA (your genotype).

But what if—except in the cases of some rare single-gene disorders like Tay-Sachs disease—the premise ignores a significant portion of inheritance? What if the DNA sequence of an individual explains only part of the story of his or her inherited diseases and traits, and we need to know the DNA sequences of parents and perhaps even grandparents to understand what is truly going on?

The news for the "genes are destiny" folks are grim. Reality is more complicated than previously imagined. This will probably put the kibosh on full blown genetic engineering - at least for a time.

Large-scale genomic studies over the past five years or so have mainly failed to turn up common genes that play a major role in complex human maladies. More than three dozen specific genetic variants have been associated with type 2 diabetes, for example, but together, they have been found to explain about 10 percent of the disease's heritability—the proportion of variation in any given trait that can be explained by genetics rather than by environmental influences. Results have been similar for heart disease, schizophrenia, high blood pressure, and other common maladies: the mystery has become known as the "missing heritability" problem. Francis Collins, director of the National Institutes of Health, has sometimes made grudging reference to the "dark matter of the genome"—an analogy to the vast quantities of invisible mass in the universe that astrophysicists have inferred but have struggled for decades to find.

Joseph H. Nadeau has been on a quest to uncover mechanisms that might account for the missing components of heritability. And he is finding previously unsuspected modes of inheritance almost everywhere he looks.

Nadeau, who until recently was chair of genetics at Case Western Reserve University in Cleveland and is now director of research and academic affairs at the Institute for Systems Biology in Seattle, has done studies showing that certain traits in mice are influenced by specific stretches of variant DNA that appeared on their parents' or grandparents' chromosomes but do not appear on their own. "Transgenerational" genetics, as he calls these unusual patterns of inheritance, fit partly under the umbrella of traditional epigenetics—the idea that chemical changes wrought by environmental exposures and experiences can modify DNA in ways that either muffle a normally vocal gene or restore the voice of a gene that had been silenced. Researchers have begun to find that these changes are heritable even though they alter only the pattern of gene expression, not the actual genetic code. Yet it's both more disconcerting and more profound to suggest, as he does, that genes an ancestor carried but didn't pass down can influence traits and diseases in subsequent generations.

There are studies confirming this. One of them has to do with the heritability of PTSD.

An article in the UK Telegraph discusses this in relation to the 7 July terrorist attacks in Britain.

It is often said of a particularly dramatic event – such as the September 11 attacks or the July 7 bombings – that its consequences will "reverberate for generations". It can seem like hyperbole, yet new evidence suggests that traumatic events can affect the genes, and lives, of children as yet unborn. Take the July 7 London bombings. As the harrowing evidence continues to emerge, the psychological impact on the survivors has been all too clear.

As many as 30 per cent of those directly caught up in the atrocities have gone on to develop full post-traumatic stress disorder (PTSD). This is in line with similar incidents: after the Oklahoma City bombing in 1995, 41 per cent of survivors were diagnosed with PTSD after six months, and 26 per cent were still suffering after seven years. Among soldiers returning from Iraq and Afghanistan, the British Armed Forces reckon that 10 per cent develop PTSD. However, an American study gave a figure as high as 30 per cent.

Yet new evidence suggests that the trauma is not just psychological, but biological and even heritable. By altering the chemical mechanisms regulating gene expression, these modifications may become embedded in the male germ line, and can be passed down to the victim's children.

"The sins of the fathers are visited on the sons..." is more than a social construct evidently.

Embedded within the DNA sequence are epigenetic regulators, chemical marks that control which genes are expressed and which are not. This is a crucial function, given that every cell in our bodies contains our entire lexicon of DNA. It is the regulators that selectively silence some genes so that particular cells become, say, skin or brain cells, and stay like that when they divide.

The heretical proposition here is that these epigenetic marks can be transmitted along with the DNA. It is the result of intensive research into how these mechanisms work. The best understood is DNA methylation, in which methyl molecules latch on to some areas of the DNA strand and act as switches that render a gene active or inactive.

Too much or too little methylation, and a host of problems occur, from fragile X syndrome to a variety of cancers. The latest findings, however, indicate that psychological conditions, such as trauma and stress, also leave an epigenetic mark. Professor David Sweatt and his colleagues at the University of Alabama have found that maltreating rat pups for just one week is enough to trigger epigenetic changes that deactivate the gene for a protein important in memory formation and emotional balance. This same agent – brain-derived neurotrophic factor – is often abnormally low in schizophrenics and those with bipolar disorder.

In a similar experiment, Professor Eric Richards at Washington University, St Louis, showed that the way rats are nurtured affects the methylation of a crucial receptor in the hippocampus. After a positive nurturing experience, the appropriate gene gets turned on at a vital early stage; after a bad one, the gene remains unused. The same is found in humans. A study of women in Holland who were pregnant during a prolonged famine after the Second World War found that their daughters had twice the normal risk of developing schizophrenia.

Hmmmm schizophrenia. A lot in the news these days.

In his 1997 article Addiction Is A Brain Disease And It Matters [pdf] the Director of the National Institute on Drug Abuse (NIDA) from 1994-2001 Alan Leshner says:

The bad news is the dramatic lag between these advances in science and their appreciation by the general public or their application in either practice or public policy settings. There is a wide gap between scientific facts and public perceptions about drug abuse and addiction. For example, many, perhaps most, people see drug abuse and addiction as social problems, to be handled only with social solutions, particularly through the criminal justice system. On the other hand, science has taught that drug abuse and addiction are as much health problems as they are social problems. The consequence of the gap is a significant delay in gaining control over drug abuse problems.

From twin studies about alcohol we find that the heritability of addiction propensities runs about 50% to 60%. What accounts for the other 40% to 50%? My article, Heroin, provides a clue. And the clue points to trauma. There are more clues in my article PTSD and the Endocannabinoid System.

So does that mean that a DNA study would find the same level of heritability as twin studies? Given what we now know I think that is doubtful. But we also now know that DNA is not the only path to heritability.

What does all this mean for policy? I don't think putting a government gun to people's heads is going to fix a brain disease. Unless of course the people promoting that idea contemplate pulling the trigger. Every time.

Cross Posted at Classical Values