Comparative Utility of Targeted Amplicon Sequencing vs. Whole Genome Approaches in SARS-CoV-2 Molecular Surveillance: A ComprehensiveReview

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious and pathogenic coronavirus that first emerged in Wuhan, China, in December 2019, leading to a global pandemic. Sequencing was crucial for early detection of SARS-CoV-2 during the initial stages of the pandemic. The virus acquires spontaneous mutations throughout its replication cycle, which help it escape immune responses and better adapt to its host. The rapid emergence and spread of new variants underscore the urgent need for intensified sequencing activities to identify mutations and control the dissemination of novel strains quickly. Whole genome sequencing (WGS) offers a powerful approach for discovering new coronavirus variants without prior organism-specific knowledge. Despite its effectiveness, WGS is still relatively costly. Since the onset of the COVID-19 pandemic, considerable focus has been placed on exploring the changes in the viral nucleotide and amino acid sequences. A comprehensive literature search was performed across databases such as PubMed, Google Scholar, and Scopus to collect studies related to SARS-CoV-2 sequencing and genome variation. This review is the first effort to compare mutations in the S gene with those in other viral genes, evaluating their roles in viral transmission, replication, pathogenicity, immune evasion, and evolutionary trends. Furthermore, we compared whole-genome sequencing data with S gene-specific sequencing results. In addition, we provide a structured comparison of whole genome and S-gene sequencing in terms of cost, turnaround time, analytical resolution, and suitability for different surveillance objectives. As most mutations aiding transmission are found in the S gene, its sequencing can effectively monitor transmissibility. Conversely, mutations influencing pathogenicity are scattered throughout both the S gene and other genomic regions, thus requiring whole-genome analyses to fully understand viral disease mechanisms.