Comparative Genomics of Zoonotic Pathogens: Genetic Determinants of Host Switching and Cross-Species Transmission

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Emerging infectious diseases of animals that spread to humans (zoonoses) continue to represent a major threat to public health throughout the world. Knowledge of genetic elements that enable pathogens to navigate host shifts and species jumps is crucial for predicting and preventing zoonotic cross-species transmission. Comparative genomics, comparing whole-genome sequences across a range of hosts and pathogens, provides a powerful means to dissect the molecular determinants of zoonotic emergence. Here, we summarize and discuss recent advances in the understanding of genetic modifications that enable host switching and cross-species transmission by selected zoonotic pathogens. We review how comparative genomic analyses revealed the critical importance of factors such as receptor-binding domain evolution, immune evasion genes, and virulence determinants in improving pathogen fitness in new hosts.The review also highlights the integration of genomic data into One Health surveillance frameworks, enabling real-time monitoring, early detection, and improved outbreak response. Despite these advances, challenges including sampling bias, incomplete genomic databases, misannotation, and the complexity of predicting phenotype from genotype limit the field’s potential. Furthermore, ethical and biosafety concerns in studying high-risk zoonotic pathogens necessitate careful governance. We outline future directions, emphasizing the need for expanded wildlife sampling, longitudinal studies of host-pathogen co-evolution, and the application of artificial intelligence in zoonotic risk assessment. Building comprehensive, globally accessible genomic databases is essential for coordinated pathogen tracking and risk mitigation. Ultimately, comparative genomics is indispensable for understanding and managing zoonotic threats, and its continued advancement, integrated within interdisciplinary, data-driven One Health strategies, will be critical to preventing future pandemics.