A genetic clue on RNA virus tissue tropism (selection by ZAP)

Contributed by Cory Schlesener
It is useful to apply known biological concepts to empower bioinformatics to make the most out of analyzing genetic sequences (in proper context). Here is an example of a simple genetic analysis that can carry a lot of meaning when applied in a specific context.
Zinc finger antiviral protein (ZAP) is part of the innate immune response mediated by interferon, and is expressed at different levels by tissue type in mammals. The protein’s RNA binding domain specifically targets CpG sites in the viral RNA genome. This leads to selection against having CpG dinucleotide sequences in viral genomes. Indexing the relative deficiency of CpG sites, from what would be expected by GC content, indicates a selective pressure (likely by ZAP).  The difference in CpG deficiencies between strains has been observed to correlate with host tissue tropism (e.g. between respiratory and gastrointestinal tracts) where ZAP levels differ. In a recent analysis, SARS-CoV-2 was observed to have a much greater deficiency in CpG sites than other beta-coronaviruses. This indicates much of the genome’s sequence is showing a history of
replication in higher ZAP level cellular environments, likely in the gastrointestinal tract of bats.

Reference:
Xuhua Xia (April 2020) Molecular Biology and Evolution
https://doi.org/10.1093/molbev/msaa094

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