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Evolutionary DNA changes may alter neuropsychiatric disease risk

A study published in the American Journal of Human Genetics found that changes in the structure and sequence of nucleotide arrays of tandem repeats may have contributed to changes in the human calcium channel gene CACNA1C during human evolution and may modulate risk for schizophrenia, bipolar disorder and other neuropsychiatric diseases in modern populations.

“Both [bipolar disorder] and [schizophrenia] are highly heritable. While they are classified as different diseases based on their clinical symptoms, they share a similar set of genomic risk variants,” Janet HT Song, BA, graduate student at Stanford University, and colleagues wrote. “Genome-wide association studies for [bipolar disorder] and [schizophrenia] have consistently implicated risk variants in or near genes involved in calcium signaling. Some of the strongest and best-replicated associations for [bipolar disorder] and [schizophrenia] map within CACNA1C.”

In exploring the understudied regions of the human genome, researchers identified a large discrepancy between the standard human reference genome and levels of DNA sequence reads coming from the human calcium channel gene CACNA1C, which was previously tied to psychiatric disease. They carried out further research on 181 human cell lines and postmortem brain tissue samples, according to a press release.

The researchers found lengthy stretches of DNA, which were much longer and more complex than expected, that also contained many variant nucleotide base pairs embedded in a noncoding region of the CACNA1C gene, the press release said. According to the release, different versions of these highly repeated sequences demonstrated unique abilities to activate gene expression and were associated with genetic markers of bipolar disease and schizophrenia disease susceptibility in humans.

These variants may shed light on the risk for psychiatric disease among patients whose DNA profile is otherwise ordinary, senior author David M. Kingsley, PhD, professor of developmental biology at Stanford University, said in the release.

“Our research illustrates how characterizing hidden variation in the human genome can uncover variants associated with both human evolution and disease,” the authors wrote in the full study. “[Single-nucleotide polymorphisms] are still the most commonly studied type of variant in most genotyping and trait association studies. However, structural variants and repeat sequences make up a substantial fraction of the human genome, show abundant variation both within and between species, and may contribute to key phenotypic traits and disease susceptibilities in humans and other organisms.” – by Savannah Demko

Disclosure: The researchers report no relevant financial disclosures.