Each cell in our body contains two meters of DNA that contains the six billion bits of DNA code necessary to create a healthy human body. This is known as the human genome. It is now accepted that what makes people different and contributes to their susceptibility to ill health are the 6-10 million differences in DNA in the human genome known to exist within the general population.
A surprising fact is that only 1.7% of these 6 billion bits of code represent genes that make proteins. Proteins are the physical components of our bodies and are essential to keep us healthy.
Although great strides have been made in mapping the DNA differences associated with mental health conditions such as depression, schizophrenia, and chronic anxiety thanks to sequencing of the human genome, what surprised many was the discovery that more than 98% of these DNA changes are found within the dark and mysterious rest of the human genome that did not produce proteins.
This part of the genome had been largely dismissed as the “junk” genome but, because of its health importance, is now known as “the non-coding genome”. Critically, we still don’t fully understand what kind of information is contained in the non-coding genome that is so essential to human health and how DNA differences change this information as a result of poor health.
Useful garbage
To understand how the non-coding genome supports health, it may be helpful to think of the human body as a vast and extremely complex community of different cells. Which means that the identity of a cell and its ability to communicate effectively with other cells is essential for normal human development and health.
Based on this assumption, many scientists have suggested that although genes contain the information to produce cells, the information required to allow these cells to communicate and organize in tissues resides in the non-coding genome. Incredibly, recent estimates suggest that the human non-coding genome contains more than five times more critical health information than is contained in genes.
We now know that much of the information in the non-coding genome is in the form of “gene shift” sequences (also known as promoters and enhancers) that control the levels that genes activate in specific cells and in response to specific signals. These switches, in responding to signals traveling between cells, are most likely responsible for coordinating the cell-to-cell interactions necessary to form the structure and function of organs such as the brain.
However, identifying these switches and their function in specific cells has been a challenge. Being able to easily identify and understand these genetic changes, and the effects of DNA differences that induce health problems on your activity, will be critical to fully understanding the genetic basis of mental health.
Alcohol and anxiety
Several genes have long been known to be responsible for regulating behaviors such as alcohol consumption and mood. Disappointingly, analysis of these genes in the human population has failed to identify changes in the DNA of these genes that were strongly associated with disorders such as alcohol abuse and chronic anxiety.
Working collaboratively with Andrew McIntosh at the University of Edinburgh, our research sought to determine what controlled the highly specific expression of neuropeptides (chemical signals) in parts of the brain where they are essential for controlling normal mood and alcohol intake.
We note that the specific cell types in which many of these genes were turned on were shared by many different species. For example, the gene that produces alcohol intake and galanin peptide to control mood was activated in very specific regions of the hypothalamus and amygdala, parts of the brain that control appetite and mood in mice, rats and human.
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We reasoned that the sequences of the gene switches that controlled this expression would also be very similar among these species. So we used powerful computers that aligned the DNA sequences of more than 100 vertebrate species and found that a DNA sequence that does not code for proteins, along with the galanin gene, had changed little through evolution, suggesting its importance for survival.
Using the CRISPR editing of the genome, a process that allows us to make specific deletions in the DNA of the mice, we removed this sequence from the mouse genome and discovered that the galanin gene was turned off in these mice. Surprisingly, we also found that mice lacking this switch drank less ethanol and that male mice had reduced fear. The most important observation was that the switch contained DNA differences in the human population that altered its activity.
Our research showed that one of the differences could be related to alcohol abuse and anxiety in men in the UK Biobank human genetic cohort, reflecting our observations in mice. This study was recently published in the academic journal Molecular Psychiatry.
We believe that our ability to quickly and accurately identify the functional components of the non-coding human genome, and how they can go wrong in contributing to susceptibility to mental health conditions, is just the tip of the iceberg in terms of human health. This means that the same principles used in our studies can be applied for other diseases such as cancer, cardiovascular diseases, type 2 diabetes and susceptibility to Covid-19.
There is even evidence that the activity of these genetic switches can be affected by life events, such as childhood deprivation known to affect susceptibility to the disease through an epigenetic process known as DNA methylation; Epigenetics is the study of biological mechanisms that turn genes on and off.
There’s never been a more exciting time to be in genetics, and exploring the “dark matter” of the non-coding genome is expected to bring tremendous benefits in terms of diagnosing susceptibilities to mental health disorders and other conditions. and help us develop new and more personalized treatments.
