A naive view of schizophrenia might leave someone wondering why it persists in human populations. The disease has a strong genetic component, and it strikes individuals during their peak reproductive years, radically reducing their ability to function socially. Selective pressures would be expected to have reduced its incidence, yet it persists at a prevalence of nearly one percent in a broad range of societies. A new analysis in the Proceedings of the Royal Society B suggests that the disease may simply be a consequence of genetic features that are useful in building and maintaining a complex brain.

The clearest models for this sort of behavior are the mutations that affect the hemoglobin genes, such as the one that causes sickle cell disease. In these cases, mutations that can be debilitating persist because they provide a strong selective advantage—resistance to malaria. The researchers set out to find out whether some of the genes implicated in schizophrenia were also under positive selection by looking for evidence of both selective sweeps and positive selective pressure on protein sequences. The authors looked at a panel of 76 genes that have been linked to schizophrenia; a set of 300 neural genes acted as controls. They also looked broadly at primate evolution, comparing values across the human/chimp split, those two vs. other primates, and among primates in general.

Fourteen of those genes showed signs of having undergone a recent selective sweep; this was about double the rate of the control set of neural genes; a few others showed signs of more ancient sweeps that occurred prior to humans forming a distinct lineage. One gene, DISC1, also showed powerful evidence of positive selection at the protein level. Just this week, evidence was published that suggests that this gene helps new neurons integrate into the mature brain, something that might help make sense out of the adult onset of the symptoms.

Assuming these figures hold up as more information comes in, the lingering question is what positive things these genes are doing in healthy populations. The authors explicitly suggest that the schizophrenic mind is at the extreme end of a spectrum of increased creative thought; that schizophrenics are simply thinking too far outside the box. I don't find this entirely convincing, especially given the sickle cell model, where the feature under positive selection has nearly nothing to do with the actual disease state. I expect that each gene will have its own evolutionary story, with no general theme. Still, the data look good, and the general model makes a reasonable suggestion as to why the human population is burdened with a high rate of schizophrenia.

Proceedings of the Royal Society B, 2007. DOI: 10.1098/rspb.2007.0876