In a recent study, researchers found that schizophrenia and bipolar disorder may be caused by human brain revolution.
They found that the same aspects of relatively recent evolutionary changes that make us prone to bad backs and impacted third molars may have generated long, noncoding stretches of DNA that predispose individuals to schizophrenia, bipolar disorder, and other neuropsychiatric diseases.
The study identifies an unusually lengthy array of tandem repeats found only within the human version of a gene governing calcium transport in the brain.
Previous research has shown that common ailments such as lower back, knee, and foot problems are likely due to the transition to walking upright; impacted wisdom teeth may be tied to humans’ smaller jaws and recent changes in diet.
The team hypothesizes that the prevalence of neurological diseases in modern humans may stem from recent evolutionary changes in genes controlling brain size, connectivity, and function.
Bipolar disorder and schizophrenia affect more than 3% of the population worldwide.
Tandem repeats are repeated lengths of DNA occurring either inside or outside a gene’s coding sequence.
They have been hypothesized to explain individual-to-individual variations in complex neurological functions and may act as “tuning knobs” for modulating gene expression.
The tandem repeats may affect CACNA1C function—even when the coding region of the gene itself is free of mutations.
Most genetic studies focus on how simple letter substitutions in the DNA code cause disease.
Yet 15 years after the human genome was mapped, regions of the human genome are still largely unexplored, missing, or understudied.
In particular, large regions of a repeated sequence can be difficult to propagate in bacteria and to assemble correctly.
Many of these regions also vary substantially between individuals and may contribute to key phenotypic traits and disease susceptibilities in humans and other organisms.
The team identified a large discrepancy between the standard human reference genome and levels of DNA sequence reads coming from a key calcium channel gene previously linked to psychiatric diseases.
Then they carried out further studies of 181 human cell lines and postmortem brain tissue samples.
They found long stretches of DNA—ten to a hundred times longer and more complex than expected—containing many variant nucleotide base pairs embedded in a noncoding region of the CACNA1C gene.
Different versions of the highly repeated sequences showed different abilities to activate gene expression and were tightly linked to genetic markers of bipolar disease and schizophrenia disease susceptibility in humans.
Such “hidden variants” may illuminate the risk of psychiatric disease among patients whose DNA profile is otherwise unremarkable.
The team says classifying patients based on their repeat arrays may help identify those most likely to respond to existing calcium channel drugs.
These medications have produced mixed results to date, he notes, and further study is needed to clarify whether patients with a genetic variation of CACNA1C have too much or too little calcium channel activity.
The large structural arrays found in the CACNA1C gene are unique to humans, raising the question of whether we derived an evolutionary advantage from this expanded genetic sequence—even though it apparently increased our susceptibility to neuropsychiatric disease.
The team plans to study the effects on neural differentiation, cell excitability, and brain circuit formation of adding and removing entire repeat arrays from CACNA1C in animal models and cultured cells.
The senior author David Kingsley is a professor of developmental biology at Stanford University.
The study is published in the American Journal of Human Genetics.
Source: American Journal of Human Genetics.