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Rabbit Populations Developed Resistance to Myxoma Virus Through Parallel Evolution

NEW YORK (GenomeWeb) – Rabbit populations in Australia and Europe that were exposed to the myxoma virus underwent parallel evolution to become resistant, according to a new genetic study based on exome analysis.

European settlers introduced rabbits to Australia in the late 19th century, and the rabbits' numbers took off, reaching about a billion by 1950. This led to the introduction of the myxoma virus in 1950 to control their numbers. Independently it was also released in France in 1952 and spread to the UK in 1953. After the introduction of the virus, the rabbit populations in the three regions plummeted, but then the fatality rate dropped as the virus evolved to be less lethal and the rabbits evolved resistance. This interplay became a textbook example of host-parasite co-evolution.

A team led by researchers at the University of Cambridge has now examined the DNA of rabbits that lived before and after the introduction of the myxoma virus to tease out how they developed resistance to the virus. As they reported in Science yesterday, the researchers found that rabbit populations in Australia, France, and the UK experienced similar gene alterations.

"Many of these genes play a key role in the rabbit immune system," Cambridge's Joel Alves said in a statement. "Often evolution works through big changes in single genes, but our findings show that resistance to myxomatosis likely evolved through lots of small effects spread across the genome."

He and his colleagues sequenced the exomes, mitochondrial genomes, and major histocompatibility complex regions of DNA samples from 152 rabbits from Australia, France, and the UK. Seventy-five of the rabbit samples dated back to before the introduction of the virus, coming from museum specimens, for example. In all, the scientists generated a mean sequencing coverage of 33X per sample.

Both principal component and structure analysis uncovered three clusters within this rabbit cohort that matched their region of origin. This suggested to the researchers that the historical and modern populations from the same regions had similar patterns of genetic structure and diversity, despite the population collapse they underwent.

The researchers then measured genetic variation between the historical and modern rabbit populations using the Fst statistic and compiled a list of 1,000 SNPs with the highest Fst for each country. More than 90 SNPs were among the highest ranked variants in at least two of the three populations.

At the same time, they found 193 SNPs in 98 genes and seven intergenic regions that experienced a swing in allele frequency between the historical and modern samples. Of these, 94 SNPs had significant signatures of parallel evolution.

In most cases, the SNPs under selection were present in at least one of the historical populations. This, the researchers noted, indicates that selection worked on standing genetic variation present among European rabbits. In addition, the populations harbored genetic alterations specific to them.

Overall, many of these variants affected immune system genes like the interferon-α21A gene (IFN-α21A), which plays a role in the innate immune response.

The researchers synthesized two isoforms of IFN-α21A and tested their effect in a rabbit cell line exposed to either the wild-type myxoma virus or an attenuated strain. Neither isoform of IFN-α21A affected the replication of the wild-type virus but the variant favored by selection more strongly inhibited replication of the attenuated strain. As the allele also affects the vesicular stomatitis virus, the researchers suggested it leads to a general increase in the protein's anti-viral activity.

Likewise, the researchers uncovered a number of SNPs under positive selection in the three rabbit populations in the MHC region that influence the adaptive immune response, as well as in other immune-related genes like FCRL3 and CD96.

All together, the findings suggest myxoma virus resistance is a polygenic trait, the researchers said.

Still, Alves noted that the myxoma virus remains a threat to rabbits. "Viral evolution appears to be finding ways to counter the genetic adaptations which we've observed," he said. "[M]ore virulent recent strains of myxoma virus have been found to be extremely immunosuppressive. So the arms race goes on."