‘Dark genome’ provides insight into bipolar and schizophrenia

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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 inherited conditions – persist in populations despite harming reproductive condition.
  • Researchers may have found an explanation in newly developed areas of the human genome that are not normally recognized as genes, but which can still encode proteins.
  • This “dark genome” can generate proteins that are essential 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 can also help diagnose the conditions or identify those at high risk for suicide.

Schizophrenia and bipolar disorder are serious 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 mood swings between depression and mania. The condition can also cause psychosis, making it difficult to distinguish from schizophrenia.

Both conditions are very hereditary. Studies of twins have found that genetics stands 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 heredity confronts biologists with an enigma because the incidence of these conditions remains stable at approx. 1% in populations around the world.

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

One explanation for persistent schizophrenia and bipolar is that the genes that increase the risk of these diseases can also increase reproductive fitness – for example, by increasing creativity – in people who carry the genes but do not develop these conditions.

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

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

Another puzzle is that all the gene variants that increase the risk of schizophrenia that researchers have found so far make up only 7% of the total risk.

According to geneticists at the University of Cambridge in the UK, 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 make up only 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 lead author Chaitanya Erady, a Ph.D. students at the university.

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

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

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

“We have found new proteins that are involved in biological processes and are dysfunctional in disorders such as schizophrenia and bipolar disorder,” she adds.

The researchers have published their latest results in Molecular psychiatry.

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

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

The researchers excavated 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 can serve as drug targets for new treatments.

“This opens up a huge potential for new medical goals,” said Sudhakaran Prabakaran, Ph.D., who was based at the University of Cambridge when he conducted the research and is the senior author of the report.

“It’s really exciting because no one has ever looked beyond [conventionally defined genes] for clues to understand and treat these conditions before, ”he adds.

Dr. Prabakaran left his position 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 Medical news today that further work is being done to determine the function of the newly identified proteins.

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

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

However, due to the limited data they had access to for the study, Dr. Prabakaran, they believe they have identified only a small subgroup of nORFs involved in the two matters.

“We show in the paper that these nORFs are present in the newly developed areas of the human genome that correlate with schizophrenia and bipolar disorder genetic susceptibility sites,” said Dr. Prabakaran.

The authors speculate that the hidden genes they have identified in these newly developed parts of the human genome may play a crucial role in the development of the brain.

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

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

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