Scientists have uncovered a link between ancient viral elements embedded in human DNA and the genetic risk for two major neurodegenerative diseases: multiple sclerosis and amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease or motor neuron disease. By analyzing genetic and brain tissue data, researchers identified specific viral sequences that may influence disease development, offering a new perspective on the role of dormant viral DNA in the human genome.
The findings have been published in Brain, Behavior, and Immunity.
The human genome contains remnants of ancient retroviruses, called human endogenous retroviruses (HERVs), which make up about 8% of our DNA. These sequences entered our ancestors’ genomes through infections millions of years ago. While most HERVs are inactive, some retain the ability to influence genetic activity and immune responses.
Past studies have suggested that abnormal HERV activity may be linked to diseases like Alzheimer’s, multiple sclerosis, amyotrophic lateral sclerosis, and Parkinson’s. However, these studies struggled to distinguish whether HERVs play a causal role in disease or simply react to disease-related processes.
The new study sought to clarify the potential role of HERVs in disease development by using a cutting-edge approach called retrotranscriptome-wide association studies (rTWAS). This method integrates genetic risk data with HERV activity in brain tissue, allowing researchers to investigate whether HERVs contribute to the genetic basis of neurodegenerative diseases.
“A large portion of our genome—about 8%—is made up of ancient viral DNA sequences, which research suggests may influence human health and disease. Over the past decade, there has been a surge in the development of specialized tools to study their expression with precision. Our group is using these tools to understand how these elements contribute to complex medical conditions,” said study author Rodrigo Duarte, a research fellow at King’s College London.
The researchers conducted the study using data from large-scale genome-wide association studies (GWAS) for four major neurodegenerative diseases: Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis, and Parkinson’s disease. These datasets contained genetic information from tens of thousands of participants, primarily of European ancestry, with a smaller subset of data from individuals of African and East Asian ancestry. The researchers integrated these genetic data with information about gene expression in brain tissue, obtained from the CommonMind Consortium, a resource that includes genetic and gene expression data from postmortem human brain samples.
“Using large genetic datasets and a new analysis pipeline, this study is well equipped at pinpointing which specific HERVs are important in increasing susceptibility for neurodegenerative diseases,” explained co-author Timothy Powell, a senior lecturer at King’s College London.
The researchers identified 12 HERV sequences associated with genetic risk for neurodegenerative diseases. Among these, two sequences stood out for their strong and independent links to specific conditions. A HERV located on chromosome 12 showed reduced expression in individuals with a higher genetic risk for amyotrophic lateral sclerosis.
Another HERV on chromosome 1 was associated with multiple sclerosis, also showing decreased activity in individuals with greater genetic susceptibility. These findings suggest that genetic risk factors for these diseases may exert their effects, at least in part, by influencing the activity of these specific HERVs.
“We were surprised to discover that genetic risk for motor neuron disease and multiple sclerosis is linked to the decreased expression of two HERVs, suggesting these elements might play a protective role in brain function,” Duarte told PsyPost. “This raises important questions about the potential benefits of HERVs in fundamental processes like cell adhesion. While future studies may also identify HERVs with negative effects on neurobiology, more research is ultimately needed to confirm their function.”
Preliminary analyses suggested that the HERVs identified in the study might influence biological processes such as cell adhesion, a critical function for maintaining neural networks and synaptic stability. While these findings offer initial evidence for the involvement of HERVs in disease mechanisms, the precise molecular and cellular pathways remain unclear, requiring further research.
“By exploring how genetic risk factors interact with this often-overlooked portion of our genome, we’re gaining a deeper understanding of the factors underlying these conditions,” Duarte said. “This knowledge could eventually inform new approaches for diagnosis and treatment.”
However, “it’s important to understand that our results relate to broader processes underlying these diseases rather than having specific implications for individual patients,” Duarte added. “These findings highlight one piece of a much larger puzzle, as conditions like motor neuron disease and multiple sclerosis are highly polygenic, meaning many genes contribute to susceptibility.”
“The HERVs we identified represent only a small fraction of the overall genetic component. This underscores the complexity of these diseases and the need for further research to fully understand how these elements interact with other genetic and environmental factors.”
Long-term, the findings may open new doors for therapeutic strategies. If HERVs contribute to disease processes, targeting their activity with drugs or gene editing tools could become a novel approach to treatment.
“Our long-term goal is to deepen our understanding of the non-coding genome, particularly the role of HERVs in health and disease,” Duarte explained. “In the future, clinical studies could investigate whether changes in HERV expression are linked to disease progression or clinical outcomes, and whether these elements could serve as biomarkers for early diagnosis or treatment response. Ultimately, we hope to translate these insights into new tools for understanding and potentially treating complex diseases.”
The study, “Ancient viral DNA in the human genome linked to neurodegenerative diseases,” was authored by Rodrigo R.R. Duarte, Douglas F. Nixon, and Timothy R. Powell.
