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Measles Virus Diverged From Related Cow Pathogen Around Sixth Century BC, Sequencing Study Finds

NEW YORK – The measles virus likely diverged from its closest known relative, the now-extinct cow pathogen Rinderpest morbillivirus, more than 2,000 years ago, according to a new study.

An international team of researchers sequenced the genome of a measles virus, Measles morbillivirus, dating back to 1912 and analyzed it in relation to other measles virus and related virus genomes. Measles is a highly contagious disease marked by rash, fever, and sore throat and a runny nose, and it used to affect most children before a vaccine was developed in the 1960s.

When measles first became endemic in the human population is not clear, and researchers led by the Robert Koch Institute's Sébastien Calvignac-Spencer used the measles virus genomes they sequenced and other samples to determine when the Measles morbillivirus and Rinderpest morbillivirus lineages diverged. 

"Our analyses show that the measles virus potentially arose as early as the sixth century BCE, possibly coinciding with the rise of large cities," Calvignac-Spencer and his colleagues wrote in their paper, which appeared on Thursday in Science.

To find measles samples older than the 1954 strain used to develop the first vaccine, the researchers sifted through a pathology collection of lung specimens. Within that set, they uncovered a sample from a patient from 1912 with fatal measles-related bronchopneumonia that harbored measles genetic material. They sequenced that sample to generate 10,960 unique measles virus reads, which enabled the researchers to piece together a near-complete measles virus genome from 1912.

The researchers additionally uncovered two pre-vaccine-era measles virus samples isolated in 1960 by the National Reference Laboratory in Prague, and sequenced them to a mean 109X and 70X coverage, finding they differed at only four sites.

A phylogenetic analysis placed the 1912 measles virus genome as a sister lineage to all the modern genomes, and the 1960s measles virus genomes clustered with the 1954 strain used to develop the first vaccine. 

Using these genomes as well as Rinderpest morbillivirus and Peste des petits ruminants virus genomes, the researchers were able to discern that Rinderpest morbillivirus and the measles virus lineages likely split around 528 BC.

This timing coincides with population growth and the rise of cities in Europe and Asia, which the researchers noted may have enabled the virus to get a toehold within the human population to become endemic.

Based on this, they hypothesized that a common ancestor of Measles morbillivirus and Rinderpest morbillivirus may have circulated in cattle and likely made a number of entrees into the human population, but was limited by its small size. But once populations passed a critical mark, this ancestor of the modern measles virus began to circulate as a human pathogen.

In an accompanying commentary, Simon Ho from the University of Sydney and Sebastián Duchêne from the University of Melbourne wrote that this idea is consistent with findings from other studies that suggest the increasing size of human settlements enable the spread of infectious pathogens, such as the plague bacterium.

Calvignac-Spencer and his colleagues noted, though, that formally proving this scenario would require archaeological genomic evidence. 

More broadly, Ho and Duchêne wrote that similar studies could help refine estimates of when other human pathogens, including SARS-CoV-2, emerged and evolved. Ho noted in a statement that SARS-CoV-2split from its closest known relative decades ago, but likely only made the move to humans recently. 

Increased contact between human populations and animal habitats may further affect when pathogens make that jump into people, he added. "The chance of a virus jumping between species will generally increase with the amount of contact," Ho said.