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Rabies Virus Genetic Diversity, Evolutionary History Spelled Out With Genome Sequence Set

NEW YORK (GenomeWeb) – Contemporary rabies viruses (RABVs) appear to fall into two main groups that have been undergoing distinct evolutionary trajectories, according to a new study of the virus' diversity and history.

Investigators from the Pasteur Institute and elsewhere considered hundreds of RABV genome sequences for a phylogenetic analysis appearing in the journal PLOS Pathogens. Based on patterns detected in RABV isolates collected from domestic and wild animals in dozens of countries over more than six decades, they identified a dog-related RABV that seems to be undergoing slow-but-steady evolution, and a distinct group of bat-related RABVs.

"RABV is capable of infecting many mammals but paradoxically is maintained in distinct epidemiological cycles associated with animals almost exclusively from the orders Carnivora and Chiroptera," senior author Hervé Bourhy, a lyssavirus dynamics and host adaptation researcher at the Pasteur Institute, and his co-authors wrote. "This strict association between RABV and host-species most likely arose from a combination of historical human-mediated spread of RABV and jumps into new primary host species."

The RABV genome is made up of single-stranded, negative-sense RNA, the team explained, placing it in the lyssavirus genus within the broader group of RNA-based viruses that have been implicated in emerging and re-emerging infections.

With that in mind, Bourhy told GenomeWeb in an email message, he and his colleagues set out to not only "provide a large scale and detailed reconstruction of the evolutionary history of rabies virus," but also to "analyze the evolutionary patterns and processes that underpin cross-species transmission."

In particular, the researchers considered 321 RABV isolates collected in 66 countries over 65 years, from 1950 to 2015. While many of those had been sequenced previously, the team did whole-genome sequencing on 170 of the RABV isolates using Illumina NextSeq 500, HiSeq 2000, HiSeq 2500, or MiSeq instruments.

Based on the new and available genome sequences, Bourhy and his colleagues found that these isolates clustered into two large groups, each containing multiple clades. Two main clades made up the bat-related RABV cluster: one clade was comprised of isolates from bats in the Americas, while a second clade containing American skunk and raccoon isolates could be further splintered into skunk sub-clades from Mexico and from South and Central America, and a raccoon sub-clade from North America.

Half a dozen major clades turned up in the dog-related RABV group, the researchers reported: two clades in Africa, an Arctic-related clade, clades in Asia and the Indian sub-continent, and a more widespread, "cosmopolitan" clade.

The team could not find evidence for increased genetic divergence over time when the bat- and rabies-related RABVs were analyzed as a single set. On the other hand, the dog-related RABV group did show signs of these so-called 'molecular clock effects.

Based on the substitution rates in five RABV genes, Bourhy and his colleagues estimated that the latter group has been evolving independently since around 1308 to 1510, roughly corresponding with inter-continental trade during the 15th century.

The Asian clade appeared to be one of the oldest dog-related clades, stretching back to 1535 to 1677. The cosmopolitan clade appeared to have a most recent common ancestor in around 1730, while the African and Arctic clades seem to have emerged at different points between the early 1700s and mid-1800s.

Even within the dog-related RABV group, the team saw some substitution rate differences. In particular, it saw a surge in changes to the RABV's N gene in viruses found in ferrets and badgers in Asia. Isolates in African mongooses showed a similar spurt in N gene changes, perhaps reflecting some of the adaptations that took place as the virus became adept at infecting new hosts.

"Overall, our data indicate that the establishment of dog-related RABV in new carnivore hosts may only require subtle adaptive evolution and therefore results from a combination of genetic and ecologic factors," Bourhy told GenomeWeb.

He and his team are now in the process of analyzing additional full-length RABV genomes to build on their current findings. They also plan to take a closer look at the process of host switching, using a combination of evolutionary information, reverse genetics experiments on mutant RABVs, phenotypic testing, and other approaches.