Disease gene linked to evolution

Approximately two percent of Caucasians have a gene segment variation that can cause a certain form of schizophrenia. Most people with the variation, known as a polymorphism, do not have the disease. A University of Iowa, Iowa City, study reveals a good prognosis for those who do have this form of schizophrenia. The researchers also found that this polymorphism is associated with overall benefits for human survival, and the initial mutation occurred in a single common ancestor about 100,000 years ago.

This has implications for finding better ways to treat this particular type of schizophrenia and possibly augmenting the positive influences of the polymorphism on human survival, as well as studying other gene defects.

"While this polymorphism [known as HOPA12pb] makes us more vulnerable to a certain illness, in this case schizophrenia, overall it is evolutionarily beneficial," notes Robert Philibert, associate professor of psychiatry in the Roy J. and Lucille A. Carver College of Medicine and the study's principal investigator.

"Traditionally, genes that are selected for human evolution affect two things--resistance to infection and infant survival. This gene may be involved in both of these positive features."

While nearly one in 50 individuals of European extraction has the HOPA (Human Opposite Paired Element) polymorphism, only a small minority with the variant gene sequence actually have schizophrenia. About one in 30 men with HOPA has the condition. Men are more likely than women to have this form of schizophrenia because the gene is X-chromosome linked. Those with HOPA-linked schizophrenia may have hallucinations. However, they do not have the negative symptoms found with most other forms of schizophrenia, such as compromised thinking, decreased attention, and loss of emotion.

"We knew the gene causes a specific form of schizophrenia, but we didn't know that the type was associated with a good prognosis and marked by absence of negative symptoms," Philibert explains. "Most individuals with this positive symptom schizophrenia are able to function in society and hold down jobs."

He adds that the gene cannot by itself cause schizophrenia but must interact with other genes and environmental factors to result in illness. In addition to sometimes leading to schizophrenia, it can cause hypothyroidism or obesity. "It is critical to understand those interactions. If we can modulate them, we may be able to block the ill effects of this gene and keep the beneficial aspects."

The type of evolutionary advantage-resistance to disease--that the researchers noted in the HOPA polymorphism can be seen in a polymorphism linked to sickle cell anemia as well.

In that condition, one copy of the polymorphism causes mild cell abnormalities, yet provides resistance to malaria and thus promotes human survival. However, two copies of the variant gene result in the debilitating disease.

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