HIV virus
Viruses that infected our primate ancestors 30 to 50 million years ago may be putting some modern humans at an increased risk of amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease.
Mounting research suggests about half the human genome is made up of bits of DNA left behind by retroviruses and similar virus-like parasites (VLP), known as transposons, from primate ancestors. Now, new research from Alexandra Whiteley’s laboratory at the University of Colorado at Boulder has added to the evidence.
In a new study published in eLife, Whiteley’s team linked the protein PEG10—an ancient, virus-like protein best known for its essential role in enabling placental development—to the development of ALS. Currently, over 5,000 people a year are diagnosed with the fatal neurodegenerative disease that attacks nerve cells in the brain and spinal cord, resulting in loss of speech, movement, eating and breathing.
Whiteley does not study ALS or even ancient viruses. Rather, she studies how cells rid themselves of extra protein since—in the case of neurodegenerative diseases—too much of a good thing can be bad. Specifically, Whiteley’s lab studies a class of genes called ubiquilins, which serve to keep problem proteins from accumulating in cells.
For this research, and colleagues focused on the ubiquilin-2 gene (UBQLN2), as it had previously been linked to some cases of inherited ALS. Almost all—90%—of ALS cases are classified as sporadic, but about 10% are inherited.
Among thousands of proteins that could accumulate when UBQLN2 misfires, the research team discovered PEG10 at the top of the list in animal models. PEG10, or Paternally Expressed Gene 10, is a “domesticated retrotransposon” protein, meaning it served a purpose in ancestors millions of years ago, became domesticated, lost its ability to replicate, but continued to pass from generation to generation, shaping human evolution and health—and not always in a good way.
Given the initial findings, the scientists turned to humans next. They collected spinal tissue of deceased ALS patients and used proteomics to see if any proteins seemed overexpressed. Again, among more than 7,000 possible proteins, PEG10 was in the top five. Overall, the study found that PEG10 was overexpressed in the tissue of individuals with both sporadic and familial ALS, meaning the virus-like protein may be playing a key role in both.
In another experiment, the team also found that with when ubiquilin misfires, the PEG10 protein piles up and disrupts the development of axons—the cords that carry electrical signals from the brain to the body. This could explain the symptoms of ALS, in which patients gradually lose the ability to speak, move, eat and even breathe.
“The fact that PEG10 is likely contributing to this disease means we may have a new target for treating ALS,” said Whiteley. “For a terrible disease in which there are no effective therapeutics that lengthen lifespan more than a couple of months, that could be huge.”
Evolutionary studies show that PEG10 likely played a key role in enabling mammals to develop placentas, a critical step in human evolution. Modern studies, however, suggest that when PEG10 is overly abundant I the wrong places, it can fuel disease, including certain cancers and a rare neurological disorder called Angelman’s syndrome. This new research is the first to link PEG10 to ALS specifically, showing the protein is present in high levels in the spinal cord tissue of ALS patients.
“It appears that PEG10 accumulation is a hallmark of ALS,” said Whiteley, who has already secured a patent for PEG10 as a biomarker, or way of diagnosing, the disease.
The study’s findings are not only positive for ALS patients, but for the overall understanding of all diseases that result from protein accumulation.
Other viruses
As DNA sequencing and analysis techniques continue to improve, scientists have been able to link ancient genes with modern development over the last decade or so.
In 2020, for example, researchers at Max Planck in Germany showed that a specific gene variant—chromosome 3—inherited from Neanderthals makes it 3x more likely for modern-day humans to develop severe COVID-19 when infected with the virus. Anthropologists linked the variant to a specific sect of Neanderthals from Southern Europe.
A month later, that same research team showed another Neandertals-derived variant—this time on chromosome 12—reduces the risk that an individual will require intensive care after COVID-19 infection by 22%.
Similarly, analyzing DNA as old as the 1300s, an international research team identified key genetic differences that determined who lived and who died during the Black Death—and showed that those genetic variants continue to affect human susceptibility to modern disease. For example, the same genes that once conferred protection against the Black Death are today associated with an increased susceptibility to autoimmune diseases, such as Crohn’s disease and rheumatoid arthritis.
Also last year, scientists in Japan discovered that two mouse genes left behind by a viral infection at least 120 million years ago evolved to help defend the human brain against new infections. The genes, known as retrotransposon Gag-like 5 and 6 (Rtl5/Rtl6), are carried by almost all mammals, and are similar to genes found in retroviruses, such as HIV.