Bioinformatics Tools and Approaches for Virus Discovery in Genomic Data: A Systematic Review

The exponential growth of viral metagenomic data has created an urgent need for accurate and scalable tools for virus discovery, yet the extreme diversity, rapid evolution, and limited reference databases for viruses pose unique computational challenges that traditional sequence comparison methods struggle to address. This systematic review, conducted in accordance with PRISMA 2020, examines current trends and methodological advances in virus discovery tools from 1990 to 2025. As virus discovery is a broad and multi-dimensional topic, this review focuses on the first-line tools used to analyze the results of high-throughput sequencing. The review was conducted using the PubMed database with a snowballing approach, with over 54 key studies selected for the analysis. These studies encompass the following approaches: alignment-based methods, rapid similarity estimation techniques, profile hidden Markov model methods, combination pipelines, k-mer-based approaches, and machine learning-based methods. The transition from alignment-based to machine learning methods has dramatically improved the detection of divergent viruses, yet challenges remain in interpreting model decisions and handling incomplete viral genomes. This review summarizes current knowledge and potential future directions for the development of virus detection capabilities.