Vesalius. Source:
Vesalius. Source:
ScienceThe Loom

“The Dark Matter of Psychiatric Genetics”

The title of my blog post is provocative, I know, but I’m actually just lifting it from the title of a new commentary in the journal Molecular Psychiatry by Thomas Insel, the director of the National Institutes of Mental Health. In his piece, Insel expresses his excitement about a new way of thinking about how genes can contribute to our risk of psychiatric disorders such as schizophrenia. It’s based on an emerging understanding of the human genome that I explored in a recent story for the New York Times: each of us does not carry around a single personal genome, but many personal genomes.

When we start out as a single fertilized egg, we have a single genome. When the cell divides in two, there’s a tiny chance that any spot in the DNA will mutate. Over many divisions, the copies of that original genome accumulate mutations and become different from one another. Scientists only now have the tools to dig into this so-called mosaicism and see how different our genomes can become.

Scientists have long known that mosaicism can be important for cancer, but it’s only recently that experts on other diseases have thought about it. Insel clearly has turned his mind in its direction. As he notes in his commentary, a number of studies have implicated genes in the risk of conditions such as autism. But the picture is still murky, as reflected by the fact that among identical twins, it’s often the case that one sibling will develop a mental disorder and the other will not.

Part of the solution to this mystery, he suggests, is that the brain is a mosaic.

“The brain’s genome or more accurately genomes, may prove to be even stranger than we have imagined,” Insel writes.

What might be happening is this: when embryos are developing, the neurons of the brain are growing and dividing. A neuron may acquire a mutation, which it then passes down to daughter neurons. That new mutation alters how those neurons work and makes a person prone to developing a particular mental disorder. But you wouldn’t know that this mutation is playing a role if you just took a cheek swab from a patient and sequenced the DNA from the cells you retrieved. The mutation you need to see is locked away in the brain.

Scientists have already linked these late-arising mutations to a few brain disorders. One is hemimegalencephaly, in which one side of the brain becomes bigger than the other. Even though only a few percent of the neurons in the brain carry the mutation, they can still trigger large-scale changes to half of the brain. Some disorders seem to require a one-two punch, in which a child inherits a mutation from a parent, and then a new mutation arises on top of that in the brain.

Insel suspects that some mental disorders may have a similar origin. For example, males are more likely than females to develop most neurodevelopmental disorders. That may be because they’re especially vulnerable to late-arising mutations. While females have two X chromosomes, males have only one, the second X being replaced by a Y. If a mutation arises on the X chromosome as a male embryo develops, there isn’t a healthy back-up on another X chromosome to compensate.

As promising as this line of research may be, however, it won’t be easy to search for the brain’s mosaic. Cheek swabs won’t do. Scientists will need to look at individual neurons in the brain. As Insel notes, technology for probing single cells is improving enormously. But there’s still a needle-in-the-haystack quality to such a search. And the raw material for this kind of search is hard to come by. You can’t grab a few neurons from a living person with the ease that you can get cheek cells. You need autopsied brains donated to science.

So it’s unlikely that doctors would actually run a brain mutation test on patients to search for this mosaicism. Instead, understanding the mosaic brain could offer a more general insight: by identifying the late-arising mutations that lead to mental disorders, scientists will better understand their biology. And that knowledge could, some day, lead to better treatments.