IDDF2023-ABS-0053 PacBio sequencing reveals human enteric virus DNA methylation and its roles for viruses

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Background Enteric viruses have an important impact on human health. Methylation plays a key role in DNA recognition and replication for viruses. However, the DNA methylation of enteric viruses is largely unknown. We aim to uncover human enteric virus DNA methylation based on the PacBio sequencing. Methods The human faecal samples were collected and subjected to virus-like particle enrichment. Extracted virus DNA (10 μg) was used for ultra-deep sequencing on the PacBio Sequel II System. The enteric virus genomes were assembled using Canu. The virus DNA methylation status was detected using SMRTlinks. The virus restriction-modification (RM) system was annotated through homology comparison with the REBASE database. Results After assembling and filtering, a total of 34,332 virus genomes were obtained, 44.60% of which were novel viruses. The average assembled genome length was 23,704 bp with an average genome sequencing depth of more than 2,000×. The methylation signals and diverse methyltransferases recognition motifs were detected on 94.07% of the virus genomes. The GCAACT (e value < 1e-10) and GATC (e value < 1e-10) were the most identified 4mC and 6mA motifs, respectively. We found that the relative abundance of the virus was significantly positively correlated with the total methylation rate (R = 0.64, P < 2.2e-16). The methylation rate of phage was significantly higher than that of eukaryotic virus (P < 0.05), and the 6mA methylation rate of temperate phage (0.54% on average) was significantly higher than that of virulent phage (0.45% on average) (P < 2.2e-16), suggesting the important roles of methylation in phage-host interaction. In particular, we found that 4,827 virus genomes contained RM system, which could methylate the recognized motifs (for example, GATC, the recognition motif of methyltransferase and restriction endonuclease) to protect the virus from being eliminated by the host. Conclusions This study revealed human enteric virus DNA methylation and found methylation was associated with virus abundance, lifestyle, and evading the host’s RM system clearance. These identifications will expand our understanding of the survival mechanisms of enteric viruses and thus boost their clinical application.

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