Empowering Efficient Phylogenetic Network Analysis through High-Performance Computing

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The SARS-Cov-2 Phyogeny is sensitive to alignment parameters and outgroup selection

The talk entitled “The SARS-Cov-2 [hyogeny is sensitive to alignment parameters and outgroup selection,” by Omkar Marne and Denis Jacob Machado, was delivered by Omkar at the UNC Charlotte’s Graduate Research Symposium (GRS) of 2026.

Orthocoronavirinae are enveloped, positive-sense, single-stranded RNA viruses with large (27–32 Kbp) genomes that infect birds and mammals and include pathogens of major veterinary and public health importance, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Their health, economic, and societal impacts demand rigorous evolutionary analyses to inform epidemiology, clinical response, and public policy. Yet rapid responses to emerging outbreaks have sometimes relied on phylogenetic practices that overlook critical methodological considerations, including inadequate outgroup sampling, improper rooting, and alignment strategies that ignore gene annotation. Such shortcomings have been argued to produce questionable inferences about viral origins and transmission, but the sensitivity of SARS-CoV-2 phylogeny to these analytical decisions has not been systematically evaluated. We assembled a dataset of 69 complete coronavirus genomes from NCBI’s GenBank and RefSeq, including 47 SARS-CoV-2 genomes (>29 Kbp) representing 47 variants and 21 animal-hosted coronaviruses used as outgroup. Genes were annotated using FLAVi-CoV, and sequences were aligned either as whole genomes or by annotated partitions using MAFFT, Clustal, or MUSCLE. Twelve matrices were generated by varying three factors: outgroup inclusion, annotation-guided versus whole-genome alignment, and alignment strategy. Phylogenies were inferred under maximum likelihood in IQ-TREE, and topological sensitivity was quantified using YBYRÁ. Results demonstrate that SARS-CoV-2 topology is sensitive to alignment strategy, gene annotations, and outgroup presence, underscoring that deviations from best phylogenetic practices can yield conflicting evolutionary interpretations and therefore require explicit methodological justification.

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