ALS is associated with altered activity of ancient viral DNA in the human genome

Changes in the activity of ancient viral DNA incorporated into the human genome could contribute to the development of amyotrophic lateral sclerosis (ALS), according to a study conducted by researchers at King's College London.

While previous studies had begun to identify links between these ancient viruses and human diseases, the researchers note that this new work is one of the first to find specific viruses that could contribute to the risk of neurodegenerative diseases.

“Our results provide robust evidence that certain viral sequences in our genome contribute to the risk of neurodegenerative diseases,” Rodrigo Duarte, PhD, co-lead author of the study and a research fellow at King's College, said in a university news release.

Duarte and his colleagues, including a researcher from Northwell Health in the US, used data from hundreds of brain samples to analyze the links between gene expression or activity and genetic risk factors for neurodegenerative diseases – such as ALS. The team's focus was on several specific virus sequences.

“These sequences are not just static fossils derived from ancient viral infections – they must actively influence brain function in ways that we are only beginning to understand,” Duarte said.

The study,”Ancient viral DNA in the human genome is linked to neurodegenerative diseases“, was published in the magazine Brain, behavior and immunity.

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Studying ancient DNA

Human endogenous retroviruses, or HERVs, are viruses that were incorporated into human DNA thousands of years ago when ancestors of modern humans were infected with them. Although this viral DNA makes up significant portions of the modern human genetic code – about 8% – they lack the tools they need to replicate and cause an active infection.

In fact, HERVs are often viewed as leftover genetic material with no specific function. However, increasing research is linking some of them to current human diseases, including ALS.

In the new study, the trio of scientists used a technique called retrotranscriptome-wide association analysis to identify possible links between HERVs and neurological diseases. These diseases included ALS and multiple sclerosis (MS), as well as Alzheimer's disease and Parkinson's disease.

The team's approach compared information from two types of databases: databases containing information about genetic variants associated with diseases and others containing data on HERV activity. Essentially, the scientists looked for changes in HERV activity in the presence of disease-associated genetic variants. This could suggest that such changes in HERV activity are involved in the disease.

“Using large genetic data sets and a new analysis pipeline, this study is well-equipped to determine exactly which specific HERVs are important in increasing susceptibility to neurodegenerative diseases,” said Timothy Powell, PhD, co-lead author and senior lecturer at King's College .

Through a series of analyses, the scientists identified a statistically significant association between a HERV signature – called MER61_12q14.2 and found on chromosome 12 – and ALS. Another on chromosome 1 called ERVLE_1p36.32a has been linked to MS. No strong association was found between HERV signatures and Parkinson's or Alzheimer's disease.

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Further research into a more diverse population is needed

Further experiments suggested that the identified virus sequences appeared to be involved in homophilic cell adhesion, a process in which cells in the brain stick together to communicate.

According to the researchers, disruptions in the adhesion of homophilic cells have previously been linked to neurodegeneration. They found that such disruptions can affect the health of neuronal networks and ultimately lead to cell death.

Overall, the team says, “our study represents an important advance in our understanding of how ancient viral DNA in the human genome contributes to neurodegenerative diseases.”

“But some limitations should be acknowledged,” the team added.

Our study represents an important advance in our understanding of how ancient viral DNA in the human genome contributes to neurodegenerative diseases. … Future studies examining genetic and expression differences in more diverse cohorts will likely highlight shared and lineage-specific mechanisms.

A notable limitation of the study, according to the scientists, was that it largely included data from people of European descent. Therefore, it is not yet clear whether the results would be generalizable to a more diverse population.

“Future studies examining genetic and expression differences in more diverse cohorts will likely highlight shared and lineage-specific mechanisms,” the team wrote.

Ultimately, these discoveries could open the door to the development of new therapeutic approaches for ALS, although further research is needed to better understand the mechanisms by which this ancient viral DNA could lead to neurological diseases.

“We now need to better understand how these HERVs affect brain function and whether targeting HERVs could offer new therapeutic opportunities,” Powell said.