Genomic Diversification of Long Polynucleotide Fragments Is a Signature of Emerging SARS-CoV-2 Variants of Concern

Highly transmissible or immuno-evasive SARS-CoV-2 variants have intermittently emerged and outcompeted previously circulating strains, resulting in repeated COVID-19 surges, reinfections, and breakthrough infections in vaccinated individuals. With over 5 million SARS-CoV-2 genomes sequenced globally over the last 2 years, there is unprecedented data to decipher how competitive viral evolution results in the emergence of fitter SARS-CoV-2 variants. Much attention has been directed to studying how specific mutations in the Spike protein impact its binding to the ACE2 receptor or viral neutralization by antibodies, but there is limited knowledge of genomic signatures shared primarily by dominant variants. Here we introduce a methodology to quantify the genome-wide distinctiveness of polynucleotide fragments of various lengths (3- to 240-mers) that constitute SARS-CoV-2 lineage genomes. Compared to standard phylogenetic distance metrics and overall mutational load, the quantification of distinctive 9-mer polynucleotides provides a higher resolution of separation between variants of concern (Reference = 89, IQR: 65-108; Alpha = 166, IQR: 150-182; Beta 130, IQR: 113-147; Gamma = 165, IQR: 152-180; Delta = 234, IQR: 216-253; and Omicron = 294, IQR: 287-315). The similar scoring of the Alpha and Gamma variants by our methodology is consistent with these strains emerging at approximately the same time and circulating in distinct geographical regions as dominant strains. Furthermore, evaluation of genomic distinctiveness for 1,363 lineages annotated in GISAID highlights that polynucleotide diversity has increased over time (R2 = 0.37) and that VOCs show high distinctiveness compared to non-VOC contemporary lineages. To facilitate similar real-time assessments on the competitive fitness potential of future variants, we are launching a freely accessible resource for infusing pandemic preparedness with genomic inference ("GENI" -- https://academia.nferx.com/GENI). This study demonstrates the value of characterizing new SARS-CoV-2 variants by their genome-wide polynucleotide distinctiveness and emphasizes the need to go beyond a narrow set of mutations at known functionally salient sites.