One of the deadliest human diseases is far older than we ever imagined: ScienceAlert

Smallpox has left an unmistakable mark on human history, killing at least 300 million people in the 20th century alone. Despite its notoriety, the origins of the virus still remain elusive.

Now, a team of scientists in Italy have pushed back our best estimates of the emergence of smallpox by another 2,000 years, verifying historical sources suggesting the disease has plagued human societies since ancient times, when the pharaohs ruled.

Advances in genetic sequencing technologies have allowed researchers to undertake increasingly detailed analyzes of fragments of ancient viral DNA in recent years.gradually bringing them closer to knowing where and when smallpox appeared.

Thanks to a find in Lithuania in 2016, scientists have traced smallpox back to the 1500s using viral DNA taken from the remains of a young boy. In 2020, viral DNA from Viking Age skeletons has pushed back genetic evidence for the last emergence of smallpox by a few more years, to some time before 1050 CE.

However, historical records have suggested that something like smallpox afflicted ancient societies even earlier than that. Descriptions of symptoms resembling those of the disease have been found in 4th-century Chinese texts, and Egyptian mummies with pockmark scars also suggest that smallpox was circulating around 3,000 to 4,000 years ago.

But definitive genetic evidence – akin to the molecular fingerprint of a virus – to support this theory has been hard to come by.

Scientists can still infer a lot about a virus’ past and its evolutionary history when they have enough samples to compare. They can see how a virus has changed over time and determine how quickly or quickly a virus picks up on genetic mutations. From there, scientists can wind the “molecular clock” back to estimate when an ancestral version of the virus likely existed.

In the case of smallpox, the disease is caused by the smallpox virus or VARV. In this new study, bioinformatician Diego Forni of the Scientific Institute for Research, Hospitalization and Healthcare (IRCCS) in Italy led a team to review the genetic sequences of 54 VARV samples, taken from previously published or from a research database.

This included four ancient VARV genomes from the Viking Age and two historical VARV genomes from the 17th and 18th centuries, as well as 48 modern VARV sequences dating from before the eradication of smallpox in 1980.

Using this set of viral sequences, the researchers pieced together the evolutionary history of the smallpox virus, showing how it branched from a single common ancestor into different strains that either spread through the world or have died out.

In their models, they adjusted for how the rate of viral evolution appears to slow when looking at longer time periods and accelerate over shorter time periods. The most recent common ancestor of all VARV genomes, they found, dates back to around 3,800 years or earlier.

By comparing the sequences of VARV to those of two related orthopoxviruses – taterapox (which infects gerbils) and camelpox – the analysis also showed that the ancestor of the smallpox virus split from its parents some time ago. about 7700 years old.

That still leaves a pretty big window into when smallpox might have spread to humans, around 8,000 to 4,000 years ago, the researchers say. But even so, it adds to the evidence suggesting that smallpox has been with us for millennia longer than previous analyzes of viral DNA samples had suggested.

“The smallpox virus may be much, much older than we thought,” Forni says. “It’s important because it confirms the historical assumption that smallpox existed in ancient societies.”

Although these new dating estimates place smallpox in the correct time frame to match historical accounts of Egyptian pharaohs bearing smallpox scars, some skepticism remains as to whether the disease was widespread at the time, as records contemporary writings contain few mentions of smallpox-like symptoms.

“A number of other infectious diseases cause a smallpox-like rash and only sequencing of archaeological specimens will provide information about ancient societies that were affected by the disease,” Forni and colleagues conclude in their paper.

The study was published in Microbial genomics.

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