Abstract:
The SARS-CoV-2 pandemic provided an unprecedented opportunity to study viral evolution and host-virus interactions. In this thesis, I explored the mutational dynamics of the SARS-CoV-2 genome, focusing on host-driven genome editing mechanisms, including those mediated by apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) proteins, adenosine deaminase acting on RNA (ADAR), and reactive oxygen species (ROS). Through analysis of over 14.9 million full-length SARS-CoV-2 genome sequences collected over 4.5 years, I identified key mutation patterns driven by these host factors.
The findings revealed that APOBEC-induced cytosine-to-uracil (C>U) mutations were the most prevalent, accounting for nearly half of the observed mutations. These mutations, particularly in CpG motifs, suggested that APOBEC activity reduces CpG content, potentially helping the virus evade immune defenses like the zinc-finger antiviral protein (ZAP). G-to-U transversions, likely driven by ROS, were the second most common mutation type, contributing to viral diversification. Possible ADAR-mediated A-to-G transitions, although less frequent, also played a role in viral evolution, especially in double-stranded RNA contexts.
To further investigate these host-directed editing mechanisms, I developed an integrated multi-omics pipeline combining bulk RNA sequencing and Reduced Representation Bisulfite Sequencing (RRBS) to analyze nasopharyngeal samples from COVID-19 patients. This methodological approach enabled simultaneous profiling of transcriptional and epigenetic landscapes at the primary site of infection. Application to a pilot cohort of ICU versus non-ICU patients (n=11) revealed distinct molecular signatures of disease severity. APOBEC3A and APOBEC3B showed elevated expression in severe cases, suggesting increased APOBEC activity contributes to both viral genome editing and disease progression. Cellular deconvolution analysis demonstrated that ICU patients had higher proportions of inflammatory macrophages and VEGFA-high squamous cells, while non-ICU patients showed greater proportions of interferon-responsive ciliated cells. Integration with DNA methylation data identified coordinated epigenetic regulation of immune response genes. These findings were validated using publicly available datasets from over 100 COVID-19 patients.
By combining large-scale viral genome analysis with initial insights from patient-specific molecular profiling, this work contributes to our understanding of how host antiviral mechanisms influence SARS-CoV-2 evolution and the potential role of tissue-specific responses in COVID-19 severity. These findings may help inform future studies of viral evolution and host responses in ongoing and future pandemics.

Bio:
Mukhtar Sadykov is set to defend his PhD in Bioscience. His doctoral research was conducted under the mentorship of Prof. Arnab Pain and Prof. David Gomez-Cabrero. His work analyzed over 14.9 million SARS-CoV-2 viral genomes to understand host-driven mutational dynamics, such as APOBEC-mediated editing; and also studied nasopharyngeal responses in COVID-19 patients. Prior to his doctoral studies, Mukhtar completed a Bachelor of Sciences (BSc) in Biological Sciences and a Doctor of Medicine (MD), both at Nazarbayev University, Kazakhstan. He is now engaged in postdoctoral training at the University of California, Berkeley, with Prof. Filipa Rijo-Ferreira, focusing on in-silico approaches to uncover the circadian clocks in malaria parasites.