A Journey from Ancient Infections to Modern Mental Health
The notion that 8% of our genome is derived from ancient viruses sounds like a plot twist from a science fiction movie, but it is true. Hidden within our DNA are sequences that originated hundreds of thousands, or even millions, of years ago from infections with retroviruses — viruses that can invade our cells and insert their genetic material into our DNA to replicate.
I am a Senior Lecturer in Translational Genetics & Neuroscience at King’s College London. My research group uses a combination of large genetic datasets and wet lab experiments to explore the biological mechanisms underlying psychiatric disorders. Recently, my lab became fascinated by the notion that ancient viral sequences in the human genome might play a role in the brain and affect susceptibility to mental health conditions, like schizophrenia and major depression.
Integration into Our Genome
During our evolutionary past, retroviruses inserted their genetic material within the DNA of our sex cells (the cells which go on to produce our children). Through a ‘copy and paste’ mechanism, genetic material was copied from retroviruses and pasted multiple times into our sex cells, generating offspring that then contained these DNA sequences within all their cells. Over many generations, these viral DNA sequences became fixed features in the human genome. We refer to these ancient viral sequences as human endogenous retroviruses, or HERVs.
The Enigmatic Role of HERVs
We know very little about what HERVs do. They were initially dismissed as inert "junk DNA", with limited biological importance, particularly as existing HERVs are no longer capable of adding more of their DNA into the genome.
Despite this, as research advanced, we realised there were special cases in which HERVs had been co-opted for specialised biological functions. For instance, syncytin 1 and 2 are genes which are derived from HERVs and are essential for the development of the human placenta. More recently, a myriad of HERV-derived sequences within the human genome have been recognised as having the potential to produce viral-like proteins and regulate cellular processes. Furthermore, there is evidence that some of these HERVs could be implicated in disease states.
Exploring HERVs and Psychiatric Disorders
During discussions with Prof. Douglas Nixon, a HERV specialist and immunologist at Northwell Health in New York, I became fascinated by the potential role HERVs could play in the brain. In collaboration with Dr. Rodrigo Duarte at King’s College London, we sought to determine whether HERVs are expressed at the RNA level in the brain — RNA being a molecule that carries instructions from DNA to make proteins — and if their expression is associated with a higher susceptibility to psychiatric disorders.
Using advanced analytical tools and data from nearly 800 autopsy brain samples, we explored the role HERVs might play in psychiatric disorders with greater precision than ever before. To our surprise, we discovered that over 4,500 HERVs are expressed at the RNA level in the human brain, supporting growing evidence that HERVs have more biological significance than previously expected.
To understand the role genetics might play in regulating the expression of HERVs, we considered the effects of common genetic variation. Within the population, individuals contain differences in their DNA sequences known as genetic variants. While most of these variants are harmless and contribute to diversity among humans, some can influence an individual’s risk of developing certain health conditions or disorders. In our study, we found that some common genetic variants associated with susceptibility to psychiatric disorders were also associated with specific profiles of HERV expression in the brain. Specifically, the genetic variants regulating the expression of four HERVs, were also associated with genetic susceptibility to major psychiatric disorders. Two HERVs were associated with schizophrenia, one HERV with both schizophrenia and bipolar disorder, and one with major depression.
What Do Our Findings Mean?
Our findings suggest that HERVs are regularly expressed in the adult brain and that their expression is influenced by genetic variants. In some instances, these genetic variants also correspond to risk factors for psychiatric disorders. This suggests that genetic susceptibility to psychiatric disorders might impart some of its effects through modulating the expression of particular HERVs in the brain. It also suggests that ancient viral DNA in the human genome is connected to brain function and psychiatric disorder susceptibility.
Do Ancient Viruses Cause Psychiatric Disorders?
Ancient viruses do not directly cause psychiatric disorders. The causes of these disorders are multifaceted, involving complex interactions between genetic and environmental factors. In addition to genetic risk factors affecting hundreds of known protein-coding genes, our findings suggest some HERVs are also affected.
The results shed light on new mechanisms that might increase susceptibility to psychiatric disorders. It adds to a growing body of knowledge about the risk factors for psychiatric disorders and their origins, which we hope one day will reveal better interventions and treatments. For instance, it might be that a subset of patients could benefit from treatment that targets HERVs in the brain, but we won’t know this until we test it.
What’s Next?
We have recently been awarded a Psychiatry Research Trust grant, enabling us to expand our approach and investigate the potential importance of HERVs in neurodegenerative conditions as well. Our findings so far demonstrate that HERVs are also linked to the causes of multiple sclerosis and amyotrophic lateral sclerosis, suggesting an even broader role for HERVs in the brain. Ultimately, we hope this line of research will provide new insights into the role of HERVs in the brain and their importance for mental health and neurodegenerative conditions.