Strong SARS-CoV-2 drift affects epistasis network density

Abstract

Understanding the evolutionary dynamics of SARS-CoV-2 has been essential for unraveling how demographic, ecological, and genetic factors interact to influence viral adaptation. This dissertation examines the epidemiological, genomic, and adaptation patterns of SARS-CoV-2 across both continental and island regions of the Americas, combining genomic surveillance, phylogenetic inference, positive selection, and epistatic networks. Collectively, these chapters offer a comprehensive view of how geography and demography shape viral diversity, adaptation, and evolutionary potential.<br /> <br /> The first chapter provides an overview of the global and regional context of SARS-CoV-2 emergence, transmission, and genomic structure, emphasizing its zoonotic origins, viral fitness, and the interplay between mutation and natural selection. It frames the conceptual foundation for understanding the demographic and evolutionary pressures acting on RNA viruses.<br /> <br /> The second chapter examines the epidemiological and genomic dynamics of SARS-CoV-2 within a continent-island comparative framework, focusing on Puerto Rico, Hawaii, New Zealand, and twenty-one Caribbean islands, and comparing them with continental regions, including the United States, the United Kingdom, France, the Netherlands, and Australia. Genomic and epidemiological data (2020-2023) were analyzed to describe the dynamics of clade frequency and epidemic seasonality. The findings reveal that viral surges originated primarily in continental regions before spreading to islands, with variant diversity strongly influenced by political and epidemiological connections rather than geographical proximity. The results underscore the significance of travel-related introductions, the accessibility of genomic surveillance resources, and the impact of seasonality on shaping transmission dynamics.<br /> <br /> The third chapter examines the genetic architecture of viral evolution, focusing on how demographic context influences epistatic interactions (EIs). Using whole-genome SARS-CoV-2 sequences from the GISAID database, the study compares epistatic network structures between insular and continental viral populations. Results demonstrate that island populations-characterized by smaller effective population sizes (N_e) and recurrent transmission bottlenecks-exhibit denser and more fragmented epistatic networks, indicative of intensified local selective pressures and genetic drift. In contrast, continental populations maintain larger, more stable networks dominated by linear selective trajectories. These findings provide empirical evidence that geographic isolation can accentuate the complexity of viral adaptive landscapes, thereby enhancing our understanding of how demographic constraints shape the evolution of RNA viruses.<br /> <br /> The fourth chapter summarizes the general conclusions of the thesis by discussing the functional implications of viral adaptation, focusing on key SARS-CoV-2 proteins under positive selection and epistatic interactions, including NSP3, Spike (S), and ORF3a. These proteins are integral to replication, immune evasion, and host interaction, underscoring how coordinated mutational combinations sustain viral fitness under selective pressure. The analysis suggests that demographic structure not only shapes evolutionary pathways but also modulates the functional consequences of mutation, with direct implications for therapeutic and vaccine design.<br /> <br /> Overall, this dissertation demonstrates that molecular mechanisms do not solely drive SARS-CoV-2 evolution but are deeply intertwined with the demographic and ecological environments through which the virus spreads. By integrating epidemiological patterns, genomic surveillance, and evolutionary modeling, this work highlights the importance of considering population context when interpreting viral adaptation. These insights extend beyond SARS-CoV-2, offering a framework for understanding how demographic heterogeneity and spatial structure influence the evolutionary trajectories of emerging and endemic RNA viruses that are intrinsic to vertebrate ecology.