Viral genomics by next-generation sequencing – investigating intra-host genomic events in human papillomavirus and improving intra-hospital outbreak investigations of SARS-CoV-2

Human Papillomaviruses (HPVs) are one of the oldest human pathogens and the most common sexually transmitted pathogenic infection worldwide. Most HPV infections are cleared by the immune system, but some infections persist and can progress to HPV-induced cancer. Almost all cervical cancer cases are caused by persistent infections with high-risk HPVs, affecting more than 500.000 women worldwide and causing more than 250.000 deaths per year. Compared to HPVs, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is one of the most novel human pathogens, making the jump to human populations late in 2019. Since then, SARS-CoV-2 have spread globally and caused the deaths of more than six million people. While the histories of these viruses differ substantially, they have in common their immense impact on global health. One of the most important tools at our disposal to defend ourselves against viral pathogens is next-generation sequencing (NGS). NGS allows us to investigate genomic events affecting intra-host viral populations found within infected persons and how they contribute to disease severity. It also allows for the rapid retrieval of viral genomic information that can be used to understand and track transmissions of pathogens. In this thesis, NGS is applied to cervical cell samples positive for high-risk HPVs to study how viral intra-host genomic events can contribute to infection persistence and progression to cervical cancer. In total, five high-risk HPV types responsible for ~90% of all cervical cancer cases are investigated with a focus on intra-host minor nucleotide variation (MNV) and integration into human chromosomes. The results show differences between the HPV types, and that these differences extend to the closely related HPV types. Overall, the studies shed light on molecular differences between the HPV types that can reflect type-specific mechanistic routes of HPV-induced cancers, while also presenting much needed knowledge of the lesser studied high-risk HPV types. Additionally, NGS was applied to SARS-CoV-2 positive samples from healthcare workers and patients from Akershus University Hospital to increase the resolution of outbreak investigations. When genomic information was used in combination with contact tracing data, one suspected intra-hospital outbreak was refuted, and another potential outbreak was discovered. The study shows the benefit of including viral whole genome sequencing data when doing outbreak investigations. The