Because the onset of the COVID-19 pandemic, a number of extreme acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) variants of concern (VOC) have emerged, resulting in repeated surges in instances, deaths, and hospitalizations all through the world. Classification of those variants by the Phylogenetic Project of Named International Outbreak Lineages (PANGO) nomenclature exhibits that though they’ve descended from a standard ancestor, they don’t seem to be direct descendants of each other.
The PANGO lineages which were corresponded to the VOCs embody Alpha variant (B.1.1.7 and Q lineages), Beta variant (B.1.351 and descendant lineages), Gamma variant (P.1, which is a descendant of B.1.1.28, and descendant lineages), Delta variant (B.1.617.2 and AY lineages), and Omicron variant (B.1.1.529 and BA lineages).
All of the variants had been reported to have developed from the B.1 lineage, whereas Alpha, Gamma, and Omicron even have B.1.1 as an extra mother or father lineage. Nonetheless, these classifications don’t describe the diploma of distinctiveness between the variants or present insights into the genetic properties of the variants.
The evolution of SARS-CoV-2, like all different viruses, happens by way of the mutation of its genome; these mutations alter the amino acid sequences of the viral proteins. The mutations will be both positively or negatively chosen based mostly on their impression on viral health. Mutations in a number of areas, such because the N-terminal area (NTD) of the Spike glycoprotein and receptor-binding area (RBD), improved viral health. Though a lot consideration has been given to particular person mutations on the amino acid degree, restricted consideration has been given to the nucleotide sequence degree.
A brand new examine revealed within the pre-print server medRxiv* hypothesized that the emergence of extra immune invasive or transmissible variants of SARS-CoV-2 was related to elevated genetic distinctiveness from the unique or earlier strains.
Research: Genomic diversification of lengthy polynucleotide fragments is a signature of rising SARS-CoV-2 variants of concern. Picture Credit score: NIAID
To check the speculation, the examine launched a brand new methodology that quantifies the variety of distinct nucleotide n-mers (of assorted sizes) in VOCs to estimate the diploma of viral evolution.
Concerning the examine
The examine concerned calculating and quantifying the variety of distinctive n-mers for SARS-CoV-2 sequences from the unique reference pressure (PANGO lineage A) and 5 VOCs, Alpha, Beta, Gamma, Delta, and Omicron, that had been obtained from the GISAID database. As well as, the variety of amino acid mutations for the sequences obtained from GISAID had been decided and in comparison with the unique Wuhan-Hu-1 pressure of SARS-CoV-2.
A number of sequence alignment (MSA) was carried out for the sub-sampled SARS-CoV-2 genomes to calculate the phylogenetic distance. Lastly, the distinctiveness of n-mers for a selected SARSCoV-2 lineage was calculated utilizing another metric, A*(1-B).
Distribution of polynucleotide distinctiveness for SARS-CoV-2 variants of concern (VOCs). (A) Schematic illustration of polynucleotide sequence evaluation. SARS-CoV-2 sequences are analyzed to generate a set of distinct n-mer polynucleotide sequences (max n-mer dimension = 240). (B) Venn Diagram displaying the imply of the distributions for shared and distinctive nucleotide 9-mers between all combos of variants throughout 100,000 replicate comparisons. The Beta variant was excluded from this visualization to scale back litter. (C) Density plots displaying 9-mer sequence distinctiveness for VOCs, as measured by the variety of distinct 9-mer polynucleotide sequences. (D-E) Heatmaps displaying Cohen’s D and Jensen-Shannon divergence values from pairwise comparisons of the distributions proven in (C). (F) Cohen’s D of the distinctive n-mer distributions of Alpha, Beta, Gamma, Delta, and Omicron variants towards the unique pressure for varied n-mer lengths (n = 3, 6, 9, 12, 15, 18, 21, 24, 30, 45, 60, 75, 120, and 240). (G) Density plots displaying an extra instance for genomic distinctiveness of VOCs, as measured by the variety of distinct 15-mer polynucleotide sequences. Knowledge proven in panels B-G had been generated utilizing 287,739 distinctive SARS-CoV-2 sequences in complete, break up throughout the variants as proven within the legend of C. Abbreviations: μ – imply; IQR – interquartile vary; VOC – variant of concern.
Research findings
The outcomes reported that from every genome, a particular nucleotide 9-mers (DN9s) had been derived that was current in a given lineage however absent from all others. The variety of DN9s corresponded to the time of emergence and was discovered to be highest for Omicron, adopted by Delta, Alpha, Gamma, and at last Beta variant. The Omicron sequence was additionally discovered to have extra DN9s than all different VOCs.
Map of SARS-CoV-2 VOC prevalence by geographic area. Geographical distribution of Alpha (B.1.1.7), Beta (B.1.351) and Gamma (P.1) variants based mostly on sequences deposited in GISAID by December 14, 2021. Every pie chart exhibits the proportion of Alpha, Beta or Gamma sequences deposited within the nation. Word that the denominator is the variety of sequences labeled as any of those three variants, quite than the whole variety of sequences deposited in that nation. Thus, every pie chart solutions the next query: “Of all genomes deposited in a given nation which had been assigned as Alpha, Beta, or Gamma, what quantity of genomes was assigned to every of those three lineages?” The prevalence of Delta and Omicron should not proven to raised spotlight the geographical distribution of Alpha, Beta, and Gamma; nonetheless, Delta and Omicron are presently or have beforehand been extremely prevalent within the areas proven. Solely nations the place at the very least 1000 sequences are deposited are proven. The variants depicted, which circulated at roughly the identical time, typically turned distinguished in geographically distinct areas.
Omicron was indicated to be essentially the most extremely mutated VOC, whereas the phylogenetic distance between Gamma from Alpha and Beta was essentially the most notable. The outcomes additionally counsel that the newly rising SARS-CoV-2 variants had been genetically distinct from the unique pressure and that they comprised distinctive nucleotide sequences that resulted within the distinctiveness. The distinctiveness was additionally discovered to extend inside a lineage with evolutionary time.
The present examine thus supplies a brand new methodology that can assist the researchers determine and assess the distinctiveness of any new SARS-CoV-2 variants in comparison with the earlier ones. Nonetheless, additional analysis is required to find out whether or not this methodology will be capable of classify lineages as VOCs sooner than the time taken presently, how vaccination would impression the SARS-CoV-2 genomic variety, and in addition decide whether or not SAR-CoV-2 an infection would progress in the direction of seasonality or endemicity.
Limitations
The examine had sure limitations. First, for the reason that variety of Omicron sequences out there within the GISAID database is presently low, it might result in oversampling. Second, other than nucleotide 9-mers, protein-coding nucleotide n-mers or amino acid n-mers must also be thought-about within the willpower of genomic variety. Third, the examine will be delicate to the lineage composition within the complement group. Lastly, additional analysis is required concerning the connection between genomic distinctiveness metrics with phylogenetic depth and evolutionary time.
*Essential discover
medRxiv publishes preliminary scientific studies that aren’t peer-reviewed and, subsequently, shouldn’t be thought to be conclusive, information medical apply/health-related conduct, or handled as established data.
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