Mehau Kulyk/SPL

Psychiatric disorders can be debilitating and often involve a genetic component, yet, evolution hasn’t weeded them out. Now, recent work is beginning to reveal the role of natural selection — offering a peek at how the genetic underpinnings of mental illness has changed over time.

Many psychiatric disorders are polygenic: they can involve hundreds or thousands of genes and DNA mutations. It can be difficult to track how so many genetic regions evolved, and such studies require large genome data sets. But the advent of massive human genome databases is enabling researchers to look for possible connections between mental illnesses and the environmental and societal conditions that might have driven their emergence and development. Others are looking to Neanderthal genetic sequences to help inform the picture of these disorders, as well as cognitive abilities, in humans. Several of these teams presented their findings at the American Society of Human Genetics (ASHG) meeting in Orlando, Florida, in late October.

One project found that evolution selected for DNA variants thought to protect against schizophrenia. The study, led by population geneticist Barbara Stranger of the University of Chicago in Illinois, looked at hundreds of thousands of human genomes using a statistical method that identified signals of selection over the past 2,000 years1. There were no signs of selection in genetic regions associated with any other mental illness.

Many of schizophrenia's symptoms, such as auditory hallucinations and jumbling sentences, involve brain regions tied to speech, says Bernard Crespi, an evolutionary biologist at Simon Fraser University in Burnaby, Canada. Over the course of hominid evolution, he says, the ability to speak could have outweighed the small, but unavoidable risk that the genes involved in language could malfunction and result in schizophrenia in a small percentage of the population.

A quest for context

Another team, lead by human geneticist Renato Polimanti at Yale University in New Haven, Connecticut, is trying to tease out links between environmental factors, mental illnesses and behavioural traits. Polimanti and his colleagues looked at 2,455 DNA samples from individuals at 23 sites across Europe and quantified each person’s overall genetic risk for mental disorders, such as autism, and personality traits, such as extraversion. They then calculated whether that risk was associated with certain environmental factors, such as rainfall, winter temperatures or the prevalence of infectious disease — exploring the idea that these factors might have been involved in selecting for the human traits.

People who live in European regions with relatively lower winter temperatures, they found, were slightly more genetically prone to schizophrenia. Polimanti suggests that if genes that helped people tolerate cold were located close to variants that promote schizophrenia in the genome, then the latter could have been inadvertently carried along during evolution as a “fellow traveller”.

“This was a nice first attempt to put some environmental context” on the polygenic variants associated with mental illness, says Tony Capra, an evolutionary geneticist at Vanderbilt University in Nashville, Tennessee. Polimanti now plans to repeat the study in other parts of the world.

For and against

Untangling the roles of genetics and the environment will be difficult, however, because unknown environmental conditions in the past could have selected for traits that were advantageous then, but considered negative today. And other evolutionary factors could contribute to mental illness indirectly. An overactive immune system is thought to be involved in many psychiatric disorders, such as depression2, but a stronger immune system would have made human ancestors more resistant to diseases, says Stranger.

Some researchers are exploring the evolution of mental illness through a different lens: by looking at possible differences in gene activity in tissues of Neanderthals and humans. A group lead by Capra and Vanderbilt human geneticist Laura Colbran used databases of modern human genomes to find DNA markers that suggest a gene is differently regulated in various tissues in the body. They then looked for these markers in two Neanderthal genomes. The team found that genes associated with neurological development were regulated differently in the Neanderthal brain compared with that of humans.

So while the DNA sequence of a gene such as FOXP2 — which is associated with language — is identical3 in humans and Neanderthals, human brains might have produced more of the associated protein, accounting for increased language ability. The results could eventually lead to a better understanding of how Neanderthal brains functioned, if they were similar to human brains and whether they might have suffered from similar psychiatric disorders.

Studying how mental illness evolved is still at an early stage, but the ability to use massive human genome databases is an exciting step forward, says Capra. He and his colleagues plan to take advantage of this with a survey of genetic areas that differ between Neanderthals and humans, searching for differences in how the genes are expressed.