Summary: Researchers propose that some neuropsychiatric disorders, including bipolar disorder and schizophrenia, may be unintended byproducts of recent human evolution.
Source: Cell Press.
Recent evolutionary changes that gave humans distinctive brains may also have created long, noncoding stretches of DNA that increase susceptibility to schizophrenia, bipolar disorder, and other neuropsychiatric conditions.
A study published on August 9 in the American Journal of Human Genetics reports the discovery of an unusually long tandem repeat that appears only in the human version of a gene responsible for calcium transport in the brain, CACNA1C. The research suggests that structural changes in these repeated DNA sequences could have altered CACNA1C function during human evolution and that those changes may influence modern risk for psychiatric illness.
David Kingsley, senior author and professor of developmental biology at Stanford University, explains that evolutionary trade-offs are common: just as upright walking and shrinking jaws introduced physical vulnerabilities such as back pain and impacted wisdom teeth, shifts in genes shaping brain size, connectivity, and function may have produced genetic features that now contribute to psychiatric disease risk.
Bipolar disorder and schizophrenia together affect more than 3 percent of people worldwide, and both conditions have strong heritable components. Genome-wide association studies have repeatedly linked genetic risk for these disorders to a roughly 100 kb interval within the third intron of the CACNA1C gene, but until now the specific causal variant has been unclear.
Missing, complex DNA regions revealed
Tandem repeats are sequences in which short DNA units are repeated in direct succession. These repeats can occur inside or outside genes and have been proposed to act as “tuning knobs” that modulate gene expression and contribute to individual differences in complex neurological traits. Because they are long, highly repetitive, and variable between individuals, such regions are difficult to sequence, assemble, and study using standard methods, and many remain understudied in the human reference genome.
After detecting a discrepancy between the standard human reference sequence and DNA reads mapping to the CACNA1C locus, Kingsley and his colleagues Janet Song and Craig Lowe examined 181 human cell lines and postmortem brain tissue samples. They identified extended arrays of tandem repeats within a noncoding section of CACNA1C that were ten to one hundred times longer and more complex than expected, containing numerous variant base pairs.
Different repeat variants showed distinct effects on gene regulation when tested in laboratory assays. The arrays acted as enhancers in a human neural progenitor cell line, increasing reporter gene expression to varying degrees depending on the specific repeat sequence. Notably, the 30-base-pair repeat units associated with higher psychiatric disease risk were linked to reduced enhancer activity in these assays.
Because these repeated arrays lie outside the protein-coding portion of CACNA1C, they could influence disease risk without altering the gene’s coding sequence. The researchers describe them as “hidden variants” that might explain vulnerability in patients whose standard DNA profiles otherwise appear normal.
Kingsley, who is also an investigator with the Howard Hughes Medical Institute, notes that classifying patients by their CACNA1C repeat arrays could eventually help predict who will benefit from calcium channel–targeting drugs. Existing medications that affect calcium channels have produced mixed clinical results, and further work is needed to determine whether risk-associated repeat variants increase or decrease channel activity in human neurons. The authors suggest that genotype-guided treatment strategies could improve therapeutic outcomes if such relationships are clarified.
Human-specific changes and future directions
The extensive repeat arrays identified in CACNA1C appear to be unique to humans, prompting questions about whether this expansion conferred an evolutionary advantage despite increasing vulnerability to psychiatric disorders. To explore functional consequences, the research team plans experiments that add or remove entire repeat arrays in animal models and cultured cells to observe effects on neural differentiation, cellular excitability, and the formation of brain circuits.
Funding: This work was supported by the National Institutes of Health.
Source: Carly Britton, Cell Press.
Publisher: Organized by NeuroscienceNews.com.
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Original research: Open access research article “Characterization of a Human-Specific Tandem Repeat Associated with Bipolar Disorder and Schizophrenia” by Janet H.T. Song, Craig B. Lowe, and David M. Kingsley in the American Journal of Human Genetics (published August 9, 2019).
DOI: 10.1016/j.ajhg.2018.07.011
Abstract
Characterization of a Human-Specific Tandem Repeat Associated with Bipolar Disorder and Schizophrenia
Bipolar disorder and schizophrenia are highly heritable neuropsychiatric disorders that together affect more than 3% of people worldwide. Genome-wide association studies have repeatedly linked risk for both disorders to a 100 kb interval in the third intron of the human calcium channel gene CACNA1C, but the causal mutation has not been identified. The authors report a human-specific tandem repeat in this region composed of 30-base-pair units that can be repeated hundreds of times. This large repeat is unstable using standard PCR and bacterial cloning methods and may be misrepresented in the human reference genome. In human populations the 30-mer repeat region is polymorphic in size and sequence. Specific sequence variants of the 30-mer are associated with risk status at nearby single-nucleotide polymorphisms previously linked to bipolar disorder and schizophrenia. Functionally, the tandem repeat arrays act as enhancers in a human neural progenitor cell line, and different human arrays vary in enhancer strength. Arrays associated with increased psychiatric disease risk exhibit decreased enhancer activity. The authors conclude that changes in the structure and sequence of these arrays likely contributed to altered CACNA1C function during human evolution and may influence neuropsychiatric disease risk in modern populations.