I love it when seemingly disparate concepts converge, shedding light on a medical mystery. Today, for example, developmental biologist David Kingsley, PhD, and his colleagues published a paper in the American Journal of Human Genetics connecting the dots between human evolution, brain development, and our risk of developing schizophrenia or bipolar disorder.
I've written here before about Kingsley's fascinating research into human evolution and the nitty gritty of how we developed some of our most defining traits. Intriguingly, many of our so-called 'advances' also have a dark side.
Now he, along with graduate student Janet Song and former postdoctoral scholar Craig Lowe, PhD, has uncovered a previously hidden stretch of DNA found only in humans that is linked to psychiatric disorders.
As I wrote in our article:
Song and Lowe didn’t start out intending to study psychiatric disorders. Instead, Kingsley and his colleagues have long been interested in identifying regions of the human genome that differ from those of our closest animal relatives such as primates. Studying these regions is a way to trace evolutionary changes that confer some of our uniquely human traits.
But many of these seeming advances, such as walking upright or changing jaws and teeth to accommodate different foods or larger brains, come at a cost. New styles of walking and new diets in humans have brought with them a high incidence of bad backs, sore knees, and impacted wisdom teeth. Some researchers have wondered whether the rapid evolution of our large, complex brains could also be the reason why humans suffer some psychiatric disorders that don’t appear to afflict members of other species.
In their quest to identify differences between the human genome and that of our closest animal kin, Kingsley and his colleagues discovered that humans have a DNA sequence of 30 nucleotides that is repeated from 100 to as many as 1000 times (think of the "All work and no play makes Jack a dull boy" scene in the movie "The Shining"). In contrast, chimpanzees sport only one repeat of the sequence.
Similar to the tiny differences introduced in each line of Jack Nicholson's typographical raving, the number and even the content of these sequences vary among individuals. But because repeated arrays such as these tend to form structures that are difficult to sequence, they had remained largely hidden from previous investigators.
The repeated sequences are found in the middle of a gene called CACNA1C previously shown to be associated with an increased risk for schizophrenia and bipolar disorder. But until now it's not been possible to pinpoint specific mutations that might be responsible. Kingsley and his colleagues found that some combinations of repeats appeared to protect against the development of the diseases, while others seemed to increase risk.
The finding is particularly exciting because the gene encodes a member of a family of proteins known as calcium channels. These calcium channels are responsible for many critical biological processes, and drugs modulating their function are widely used to treat high blood pressure and cancer.
As Kingsley explained:
Better classification of patients based on their repeat arrays in the CACNA1C gene may help identify the particular patient cohorts most likely to respond to existing calcium channel drugs. The best match between patients and drugs is not known right now, but we do hope that genotype-based drug targeting may lead to improved treatments in the future for these devastating diseases.
Image by Genome Research Limited