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Genes increasing risk for mental disorders should have been weeded out of the gene pool. Why haven’t they been?

Schizophrenia, bipolar disorder and other mental disorders usually appear by the time the sufferers are in their reproductive prime, and these people typically have fewer offspring (the currency of natural selection) than average.

Given that mental disorders are so heritable, evolutionary considerations would seem to suggest that these maladies should gradually diminish in frequency over time. But they are remarkably common (almost half of people will meet criteria for one or more mental disorder at some point in their lives).

Matthew Keller, an assistant professor of psychology and a fellow at the University of Colorado’s Institute for Behavioral Genetics, has spent years musing over these issues. The question of why some heritable disorders are so common has made him “puzzled, obsessed even.”

He believes that mental disorders may stem not from a single or even a few genes, but rather from huge numbers of “slightly deleterious” genetic mutations that exist, to different degrees, in everyone’s genome. This hypothesis can’t be proved or disproved now, but the technology to assess it is coming within the decade, he says.

Severe mental disorders, which are common, differ from severe physical disorders caused by mutations in a single gene, which appear very infrequently. Achondroplastic dwarfism, for instance, occurs in no more than 4 in 100,000 Americans. The fertility rate of these people is believed to be low.

On the other hand, severe mental disorders occur with much greater frequency. Bipolar disorder and schizophrenia affect 800 of every 100,000 Americans, and mental retardation affects 2,000 of every 100,000 Americans. The fertility estimates of people with these conditions ranges from 47 percent to 80 percent—lower than the norm.

“If it’s the case that these things harmed reproductive success over evolutionary time, then the alleles (variant forms of genes) that predispose to those disorders should have been wiped out many millennia ago,” Keller says. “So it’s really puzzling that you have this persistence of mental disorders. From an evolutionary perspective, it’s paradoxical.”

In the December issue of the journal Current Directions in Psychological Science, Keller discusses three different mechanisms grounded in modern evolutionary genetics, and weighs the evidence supporting their potential role in persistent forms of mental disorder.

The first mechanism, “balancing selection,” occurs when alleles are beneficial in some genetic or environmental backgrounds but harmful in others. Natural selection strives to maintain two or more equally fit alleles at a gene. If one allele “drifts to a lower frequency” than equilibrium, its fitness increases, which nudges it back toward equilibrium.

That balancing mechanism exists in some equatorial Africans who have heterozygous hemoglobin. They are protected against malaria, but if their children are homozygous, they would be vulnerable to malaria or suffer from sickle cell anemia. However, such homozygous offspring have lower reproductive success, so the heterozygous hemoglobin is favored over time.

Keller says there’s little evidence indicating that balancing selection helps explain the persistence of severe mental disorders.

A second explanation involves “evolutionary time lags,” in which genetic code that worked well for millennia are maladaptive now. Keller gives a hypothetical example:

Some people might carry alleles that predispose them to being shy. Eons ago, such people would spend their whole lives with a few well-known people. In such cases, the shyness alleles might have little or no effect.

In a modern anonymous environment, however, those alleles might predispose a person to loneliness and depression. The genes would not have been eradicated because their negative effects have manifested themselves only recently.

There is some evidence for such time lags: recent studies have found a handful of mental disorder risk alleles that were once beneficial but that are now headed toward extinction. However, Keller says that the sum total of such alleles explains only a tiny part of the overall risk.

While acknowledging that these mechanisms are not mutually exclusive, Keller says the best supported explanation for the persistence of severe mental disorder currently is the “mutation-selection” mechanism.

As he describes it, it reflects the fact that human beings are extraordinarily complex. When computer chips are manufactured, he says, the environment is tightly controlled to ensure that there is no dust. “The reason is that it’s so easy to screw up something so tightly coordinated.

“It’s very much the same thing that goes on in the most complex machinery known to humankind, the human brain.”

Any new generation could inherit one or two new genetic mutations, along with 500 to 1,000 “slightly deleterious” older mutations that exist now but are eventually destined for extinction, he says. People who have fewer of these mutations have better-functioning systems; people who have more of these mutations have less stable systems that may break down, leading perhaps to symptoms characteristic of the various mental disorders.

This hypothesis suggests that what psychiatrists call a “mental disorder” is not the expression of one or even a few genetic alterations, but perhaps a very large number of slightly deleterious mutations whose cumulative effect is nevertheless significant.

“If this is true, then everyone has a mental disorder—it’s just a matter of degree,” Keller says. Psychologists tend to use dichotomous labels; people either have a pathology or not. But under a mutation-selection model, psychological disorders such as major depression would not be a single thing, but rather a scaled manifestation of a large number of environmental and genetic causes.

“Dysfunction is not a binary, black-and-white thing,” Keller says, adding that he hopes such an understanding “would spur compassion for people who have psychiatric disorders.”

Theoretically, this explanation makes sense. But “the gold standard in science is to back it up with evidence,” he says.

Today, scientists cannot directly measure a person’s “mutation load.” But the technology is being developed.

“This isn’t just fodder for cocktail parties,” Keller says. “We are going to know an answer, and we’re going to know an answer within 10 years.”

“It’s a remarkably exciting time to be a researcher.”