Is schizophrenia the price we pay for an evolving brain?

Schizophrenia is pretty darned common, and it's a terrible disorder with clear inherited roots. So why is it so common?

Scientific American 9/6/07: It's No Delusion: Evolution May Favor Schizophrenia Genes

New research reveals that genes related to the debilitating disorder may also provide developmental advantages..

...Dorus co-authored a report, appearing in this week's Proceedings of the Royal Society B, about the evolution of genes linked to schizophrenia. After analyzing human DNA from several populations around the world and examining primate genomes dating back to the shared ancestor of both humans and chimpanzees, researchers reached a striking conclusion that several gene variants linked to schizophrenia were actually positively selected and remained largely unchanged over time, suggesting that there was some advantage to having them.

"Schizophrenia can be explained by a lot of individual alleles (variations of genes)," Dorus notes. "There are many different loci that impact the actual manifestation of the disease." Over the past decade, several dozen genes have been identified as potential culprits, and scientists believe that several genes cause disruptions in protein formations predisposing a person to schizophrenia.

...the team ... focused on 76 gene variations most strongly related to schizophrenia. By comparing these combinations with the evolution of other genes known to affect neuronal processes, the researchers determined that 28 of the schizophrenia-associated genes have been evolutionarily preferred in recent years by either Caucasian, Asian or African populations.

"Because it's a such a complex genetic trait … you actually expect there to be some variability from population to population, in terms of what genes are playing a role in the disorder," Dorus says. He notes that he was surprised that the study turned up a positive selection for some of the genes most closely associated to the disease, including DISC1 (disrupted in schizophrenia 1), which is involved in the transport of proteins along the relatively lengthy cell bodies of neurons, among them. "The most important thing is we don't really know what the basis of the selection has been," he says. "It could be due to an entire range of neurodevelopmental processes."

Co-author Crespi says that a number of theories have been floating around regarding the persistence of schizophrenia's genetic underpinnings. One holds that schizophrenia is a "disorder of language" and that the illness is an unfortunate consequence of the development of human speech, expression and creativity. "Whenever you get strong selection, it's like a big plus, and you can drag along a lot of minuses," he says. "You can think of schizophrenics as paying the price of all the cognitive and language skills that humans have—they have too many of the alleles that taken individually…might have positive effect, but together they are bad."

Dorus says the team will now home in on the 28 genes fingered in positive selection in the hope of finding new treatments for the mysterious disorder.

The explanation seems to be that it's very hard to construct a functioning human brain, and that the brain is still actively evolving. So in this case there's not necessarily an advantage to a schizophrenia gene, but rather that the diffuse set of disorders we label as "schizophrenia" arise because the human brain is very much a work in progress, one with a high defect rate ...

Update 7/2/2010: Structural variation in the human genome and its r... [Annu Rev Med. 2010]...

... The discovery of submicroscopic copy-number variations (CNVs) present in our genomes has changed dramatically our perspective on DNA structural variation and disease. ... CNVs, to a larger extent than SNPs, have been shown to be responsible for human evolution, genetic diversity between individuals, and a rapidly increasing number of traits or susceptibility to traits; such conditions have been referred to as genomic disorders. In addition to well-known sporadic chromosomal microdeletion syndromes and Mendelian diseases, many common complex traits including autism and schizophrenia can result from CNVs. Both recombination- and replication-based mechanisms for CNV formation have been described.