Natural Selection May Have Purpose for Schizophrenia
One thing about diversity in natural species that is well understood by evolutionary biologists,” said Nobel Prize—winning mathematician John Nash, “is that the natural phenomenon of mutations serves to prepare a species for adaptation to changing conditions or for improved adaptation to an existing level of environmental circumstances.
“So a possible, but perhaps questionable, inference is that humans are notably subject to mental illness because there was a need for diversity in the patterns of human mental functions.”
Nash, who has schizophrenia, was speaking at APA's 2007 annual meeting in San Diego, where he presented the William C. Menninger MemorialLecture. The speech, delivered to a packed auditorium at the Convocation of Fellows, was a theoretical meditation on a paradox that has long intrigued schizophrenia researchers: though the disease negatively impacts reproductive capacity, it persists at a prevalence of about 1 percent in all human cultures.
Compounding the curiosity is the occasional nexus—of which Nash himself is a prime example—between psychosis and genius.
Applying his specialized understanding of “game theory” to an analysis of mental illness and his own experience with psychosis, Nash suggested during his address that severe mental illness exists in nature as a consequence of the diversification of species and that it may serve the needs of adaptation by its not infrequent association with genius.
Now, genetic researchers have published evidence that Nash's theory may be on the money. A study in the Proceedings of the Royal Society of Biological Sciences reports the results of two separate tests looking at the likelihood of evolutionary selection for 76 genes believed to be linked to schizophrenia. The study is currently posted online and will appear in print in the November 22 issue.
The researchers found that both tests showed that positive selection was evident using one or both methods for 28 of the 76 genes, including DISC1, DTNBP1, and NRG1, which exhibit especially strong and well-replicated functional and genetic links to schizophrenia.
The lead author of the study was Bernard Crespi, Ph.D., of Simon Fraser University in British Columbia.
Exactly why these genes—which carry a high risk for such a deleterious and maladaptive disease—should be naturally selected over generations is unclear. But Crespi and colleagues suggested that cognitive creativity—of the sort exhibited by John Nash—may be part of it.
“The mechanisms connecting schizotypal cognition and creativity with [natural selection] are unclear, but may include sexual selection, creative and artistic skills, or general benefits from insight problem solving,” they wrote. “These processes could potentially help to explain the paradoxical high heritability and persistence of schizophrenia....”
Ping-I Lin, M.D., Ph.D., a professor of genetics and genomic medicine at the Maryland Psychiatric Research Center, and Gunvant Thaker, M.D., chief of the Schizophrenia Related Disorders Program there, reviewed the report for Psychiatric News and said the authors have found evidence of positive selection for many of the genes that are thought to be associated with schizophrenia liability.
Lin explained that one of the tests involved examining relatively large blocks of DNA containing schizophrenia-associated genes in recent human evolution. Using this test, the researchers found that the schizophrenia genes are conserved and more frequently transmitted to succeeding generations than expected.
A second analysis was aimed at inferring the evidence for positive selection by comparing, in a human lineage, the ratio of DNA sequence changes that cause protein structural changes with DNA sequence changes that do not affect the protein structure.
“The higher the ratio is, the more likely that positive selection for protein-coding sequence changes may have occurred,” Lin explained.
The positive selection for DNA sequence changes causing protein structural changes in a number of schizophrenia-associated genes was found specific to the human lineage, he explained.
In primate evolution the authors also found accelerated DNA sequence changes in the protein coding regions in one of the genes (DISC1) that is implicated in schizophrenia.
“These tests suggest that during the recent evolution, certain variations in the genome were positively selected, and some of these overlap with the genes implicated in schizophrenia,” Lin said.
Thaker said the observations are not surprising since schizophrenia is such a uniquely human disease, and evolutionary forces that have endowed individuals with specialized cognitive and social skills may also make them vulnerable to insults that can result in maladaptive behaviors.
“The intriguing part of their findings is that the same genetic variations that lead to devastating illness such as schizophrenia, an illness with serious impairments in cognition and in social and motivational drive, may also provide some advantage,” Thaker told Psychiatric News.
“To understand this apparent contradiction, one needs to understand that schizophrenia is multifactorial, with several genes in various combinations interacting with the environment, resulting in the overt illness,” he said. “Certain patterns of allelic variations across a number of genes may be devastating, but variation in an individual gene by itself may provide advantage.”
Thaker noted that Andreas Meyer-Lindenberg, M.D., Ph.D., of the National Institute of Mental Health recently found that the same allelic variation in the DARPP-32 gene—which is associated with schizophrenia—is important for better cognitive performance.
“A larger proportion of relatives of schizophrenia patients are likely to have partial genetic loading than the general population, and schizotypal personality styles are common in this group that are associated with unique cognitive styles, some disadvantageous, but others leading to creativity,” Thaker added.
An abstract of “Adaptive Evolution of Genes Underlying Schizophrenia” is posted at<www.journals.royalsoc.ac.uk/content/6215831652282576>.▪
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Published online: 2 November 2007
Published in print: November 2, 2007
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“The mechanisms connecting schizotypal cognition and creativity with [natural selection] are unclear, but may include... creative and artistic skills or general benefits from insight problem solving.”
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