Recombination Mechanisms in SARS-CoV-2 Variants

SARS-CoV-2 recombination arises when RNA-dependent RNA polymerase switches templates during genome replication in cells co-infected by distinct viral lineages. This process can shuffle mutations across divergent strains, yielding novel genotypes with altered transmissibility, antigenicity or pathogenicity. Recombination hotspots cluster in the 3′ region of the genome, particularly within the spike glycoprotein, where structural and selective pressures converge. Interlineage events often involve Delta and Omicron parental genomes but have also been observed among Omicron subvariants. While most recombinants circulate at low frequency, some achieve onward transmission, underscoring the need for real-time genomic surveillance. Improved detection pipelines, combining depth of coverage, lineage-defining mutations and phylogenomic frameworks, have clarified the global landscape of SARS-CoV-2 recombination and informed risk assessments of emerging variants.

Research from Nature Portfolio

One large-scale analysis of over two million raw sequencing datasets applied dual detection algorithms to identify intra-host recombination and co-infection events, finding co-infection in approximately 0.35% of samples. This work pinpointed three Delta–Omicron recombination hotspots and provided methodological guidelines to minimise artefactual chimeric calls. A phylogenomic survey of 1.6 million genomes revealed 589 recombination events, indicating that about 2.7% of sequenced viruses carry recombinant ancestry. Breakpoints were disproportionately enriched in the spike-encoding region, highlighting its role in adaptive evolution and the importance of rapid tracking for variants with potential phenotypic impact. Another study documented co-infection by Omicron and Delta in vulnerable haemodialysis patients, demonstrating how integrated genomic surveillance in at-risk populations can detect subpopulations of each variant and pre-empt the emergence of recombinants.

Recombination Mechanisms in SARS-CoV-2 Variants publication trend

The graph below shows the total number of articles in recombination mechanisms in sars-cov-2 variants across all publications each year (not limited to Nature Index journals).

Technical terms

Template switching: Process by which viral RNA polymerase transitions from one RNA genome to another during replication, generating chimeric sequences.

Co-infection: Simultaneous infection of a single host cell or individual by two or more genetically distinct viral lineages, creating conditions for recombination.

Recombination hotspot: Genomic region where recombination breakpoints occur with higher frequency, often within or adjacent to the spike glycoprotein gene.

Phylogenomics: Integration of whole-genome sequencing data and phylogenetic analysis to reconstruct evolutionary relationships and detect recombination events.

RNA-dependent RNA polymerase (RdRP): Viral enzyme responsible for copying the RNA genome and mediating template switching that underlies recombination.

References

1. Systematic detection of co-infection and intra-host recombination in more than 2 million global SARS-CoV-2 samples. Nature Communications (2024).
2. Pandemic-scale phylogenomics reveals the SARS-CoV-2 recombination landscape. Nature (2022).
3. Co-infection with SARS-CoV-2 Omicron and Delta variants revealed by genomic surveillance. Nature Communications (2022).
4. Comprehensive detection and dissection of interlineage recombination events in the SARS-CoV-2 pandemic. Virus Evolution (2024).
5. Detection of High Level of Co-Infection and the Emergence of Novel SARS CoV-2 Delta-Omicron and Omicron-Omicron Recombinants in the Epidemiological Surveillance of Andalusia. International Journal of Molecular Sciences (2023).
6. Tracking SARS-CoV-2 Omicron diverse spike gene mutations identifies multiple inter-variant recombination events. Signal Transduction and Targeted Therapy (2022).
7. Recombinant SARS-CoV-2 genomes circulated at low levels over the first year of the pandemic. Virus Evolution (2021).