Clues to origins of bipolar and schizophrenia found in 'dark genome'

Illustration of DNA created from dark spots.
Could the ‘dark genome’ provide insight into schizophrenia? Yuichiro Chino/Getty Images
  • Evolutionary biologists have trouble explaining why schizophrenia and bipolar disorder — which are highly heritable conditions — persist in populations despite harming reproductive fitness.
  • Researchers may have found an explanation in recently evolved regions of the human genome that are not usually recognized as genes but can still code for proteins.
  • This “dark genome” may generate proteins that are vital for brain development but also increase a person’s risk of schizophrenia or bipolar disorder.
  • The proteins could be suitable targets for new drugs. They could also help diagnose the conditions or identify those at high risk of suicide.

Schizophrenia and bipolar disorder are severe and persistent mental illnesses that can have a profound effect on people’s lives.

Schizophrenia disrupts thinking and behavior and can cause psychosis, leading to hallucinations and delusions.

Bipolar disorder involves extreme swings of mood between depression and mania. The condition can also cause psychosis, making it difficult to distinguish from schizophrenia.

Both conditions are highly heritable. Studies of twins have found that genetics accounts for roughly 70% of a person’s tendency to develop bipolar disorder or schizophrenia. Environmental factors account for the remaining 30%.

This high degree of heritability presents biologists with a conundrum because the prevalence of these conditions remains steady at around 1% in populations around the world.

Usually, if a particular gene variant severely restricts the average number of viable offspring that individuals produce, known as reproductive fitness, natural selection will eventually eliminate that variant from the population.

One explanation for the persistence of schizophrenia and bipolar is that the genes that increase the risk of these illnesses may also increase reproductive fitness — for example, by boosting creativity — in people who carry the genes but don’t develop these conditions.

According to this hypothesis, genetic mutations that occurred relatively recently in human evolution allowed us to develop our species’s unique cognitive abilities, but at the price of increased vulnerability to psychosis.

However, genetic research to test this idea has produced inconclusive results.

The dark genome

Another puzzle is that all the gene variants that increase the risk of schizophrenia scientists have found so far account for only 7% of the total risk.

According to geneticists at the University of Cambridge in the United Kingdom, the problem is that we have been looking for disease-causing genes in the wrong place.

They believe that most of the genetic causes of psychosis may lie outside conventional genes — which comprise just 1–2% of the human genome — in what is known as the dark genome.

“The traditional definition of a gene is too conservative, and it has diverted scientists away from exploring the function of the rest of the genome,” says first author Chaitanya Erady, a Ph.D. student at the university.

Geneticists in Cambridge and elsewhere have recently discovered that there may be “hidden” genes that current sequencing technologies find difficult to read.

They call these hidden genes “novel open reading frames” or nORFs.

“When we look outside the regions of DNA classed as genes, we see that the entire human genome has the ability to make proteins, not just the genes,” says Erady.

“We’ve found new proteins that are involved in biological processes and are dysfunctional in disorders like schizophrenia and bipolar disorder,” she adds.

The researchers have published their latest findings in Molecular Psychiatry.

Newly evolved regions

Erady and her colleagues focused on regions of the genome that regulate human traits and, therefore, probably played an important role in our recent evolution.

They looked for differentially expressed nORFs, or hidden genes, within these regions that have different activity levels in people with schizophrenia or bipolar compared with control participants without these conditions.

The researchers mined a genome database called PsychENCODE to identify 56 nORFs associated with schizophrenia and 40 nORFs associated with bipolar disorder.

They report that some of these hidden genes produce proteins that could serve as drug targets for new treatments.

“This opens up huge potential for new druggable targets,” says Sudhakaran Prabakaran, Ph.D., who was based at the University of Cambridge when conducting the research and is senior author of the report.

“It’s really exciting because nobody has ever looked beyond [conventionally defined genes] for clues to understanding and treating these conditions before,” he adds.

Dr. Prabakaran left his post at the University of Cambridge in 2021 to create a company called NonExomics, which aims to develop and market new drugs and diagnostics based on these and other discoveries.

He told Micro B Life that further work is underway to determine the function of the newly identified proteins.

“We have predicted potential functions based on computational analysis and have shared those results in the paper, but for each of the nORFs specifically, we have to perform in-depth structure-function analysis, which we are doing now,” he said.

Other hidden genes that the team identified produce proteins that may help to differentiate between schizophrenia and bipolar disorder or estimate a person’s risk of suicide.

However, because of the limited data they had access to for the study, Dr. Prabakaran explained, they believe that they have identified only a small subset of nORFs involved in the two conditions.

Brain development

“We show in the paper that these nORFs are present in the recently evolved regions of the human genome that correlate with schizophrenia and bipolar disorder genetic susceptibility locations,” said Dr. Prabakaran.

The authors speculate that the hidden genes they have identified in these recently evolved parts of the human genome may play a vital role in the development of the brain.

They may be responsible for uniquely human cognitive abilities that enhance reproductive fitness.

However, unknown environmental factors may trigger schizophrenia or bipolar disorder in people who have particular variants of these hidden genes.

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