The ‘dark genome’ offers insight into bipolar and schizophrenia

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Could the “black genome” provide insight into schizophrenia? Yuichiro Chino / Getty Images
  • Evolutionary biologists find it difficult to explain why schizophrenia and bipolar disorder – which are highly inherited conditions – persist in populations despite a degradation in reproductive capacity.
  • The researchers may have found an explanation in recently evolved regions of the human genome that are not generally recognized as genes but can still code for proteins.
  • This “black genome” can generate proteins vital for brain development, but also increase the risk of schizophrenia or bipolar disorder.
  • Proteins could be suitable targets for new drugs. They could also help diagnose conditions or identify people 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 disease can also cause psychosis, which makes it difficult to distinguish from schizophrenia.

Both conditions are highly hereditary. Studies of twins discovered that genetics make up about 70% a person’s tendency to develop bipolar disorder or schizophrenia. Environmental factors represent the remaining 30%.

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

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

One explanation for the persistence of schizophrenia and bipolar disorder is that genes that increase the risk of these diseases may also increase reproductive capacity – for example, by stimulating creativity – in people who carry the genes but do not develop. These conditions.

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

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

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

The problem, according to geneticists at Cambridge University in the UK, is that we looked for pathogenic genes in the wrong place.

They believe that most of the genetic causes of psychosis may lie outside of conventional genes – which make up only 1 to 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 distracted scientists from exploring the function of the rest of the genome,” says lead author Chaitanya Erady, a Ph.D. student at the university.

Geneticists at Cambridge and elsewhere recently discovered that there may be “hidden” genes that current sequencing technologies are finding. difficult to read.

They call these hidden genes “new open reading frames” or nORF.

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

“We have discovered new proteins involved in biological and dysfunctional processes in disorders like schizophrenia and bipolar disorder,” she adds.

The researchers published their latest findings in Molecular Psychiatry.

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

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

The researchers tapped into 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 drug targets,” says Sudhakaran Prabakaran, Ph.D., who was based at the University of Cambridge when the research was conducted and is the lead author of the report.

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

Dr Prabakaran left his post at Cambridge University in 2021 to start a company called NonExomics, which aims to develop and commercialize new drugs and diagnostics based on these and other findings.

He said Medical News Today that further work is underway to determine the function of the newly identified proteins.

“We predicted potential functions based on computational analysis and shared these results in the document, but for each of the nORFs in particular, we need to do a deep structure-function analysis, which we are doing now,” a he declared.

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

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

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

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

They may be responsible for human-specific cognitive abilities that improve reproductive capacity.

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

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