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Published on: July 16, 2012
Selective Depletion of ZAP-Binding CpG Motifs in HCV Evolution
Sanket Mukherjee1, Akhil Kumar1, Jasmine Samal2
1Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, New Delhi 110016, India.
Insights
Hepatitis C virus (HCV) genomes show decreased CpG content over time in humans. This CpG depletion is linked to the host
Area of Science:
- Virology
- Evolutionary Biology
- Genomics
Background:
- Hepatitis C virus (HCV) causes chronic liver disease and cancer.
- CpG depletion in viral genomes aids escape from host antiviral defenses, like the zinc-finger antiviral protein (ZAP).
- The evolutionary impact of CpG depletion in HCV within human hosts remains under-explored.
Purpose of the Study:
- To investigate the evolutionary dynamics of CpG depletion in Hepatitis C virus genomes over four decades.
- To determine the relationship between CpG loss, ZAP-binding motifs, and HCV evolution in humans.
- To identify specific viral genes influenced by ZAP-mediated selection pressures.
Main Methods:
- Analysis of 2616 full-length Hepatitis C virus genomes collected between 1977 and 2021.
- Quantification of CpG dinucleotides and CpG Observed/Expected (O/E) ratios across viral genomes.
- Identification and analysis of ZAP-binding motifs within HCV genomes.
Main Results:
- Significant genome-wide depletion of CpG numbers and CpG O/E ratios observed in HCV over time.
- A strong correlation between CpG loss and the reduction in ZAP-binding motifs, suggesting ZAP-mediated selection.
- The HCV core gene shows enrichment in CpGs and ZAP-binding motifs, with CpG loss not driven by ZAP selection.
Conclusions:
- Hepatitis C virus genomes have undergone significant CpG depletion during human evolution.
- ZAP-mediated selection is a key driver of CpG depletion in most of the HCV genome.
- The HCV core gene exhibits distinct evolutionary pressures regarding CpG content and ZAP interactions.
Abstract:
Hepatitis C virus (HCV) is a bloodborne pathogen that can cause chronic liver disease and hepatocellular carcinoma. The loss of CpGs from virus genomes allows escape from restriction by the host zinc-finger antiviral protein (ZAP). The evolution of HCV in the human host has not been explored in the context of CpG depletion. We analysed 2616 full-length HCV genomes from 1977 to 2021. During the four decades of evolution in humans, we found that HCV genomes have become significantly depleted in (a) CpG numbers, (b) CpG O/E ratios (i.e., relative abundance of CpGs), and (c) the number of ZAP-binding motifs. Interestingly, our data suggests that the loss of CpGs in HCV genomes over time is primarily driven by the loss of ZAP-binding motifs; thus suggesting a yet unknown role for ZAP-mediated selection pressures in HCV evolution. The HCV core gene is significantly enriched for the number of CpGs and ZAP-binding motifs. In contrast to the rest of the HCV genome, the loss of CpGs from the core gene does not appear to be driven by ZAP-mediated selection. This work highlights CpG depletion in HCV genomes during their evolution in humans and the role of ZAP-mediated selection in HCV evolution.
