The evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen responsible for the coronavirus disease 2019 (COVID-19) pandemic, remains a focus of researchers throughout the world. Certain mutations increase viral fitness and survival, whereas others are associated with increasing the transmissibility and infectiousness of the virus. Comparatively, other escape mutations facilitate viral spread, despite the presence of antibodies to other variants of the virus.

A new study published on the bioRxiv* preprint server describes mutations found in the SARS-CoV-2 BA.1 variant in Hong Kong and New Zealand (NZ), which may have been instrumental in the sudden spike in COVID-19 cases in these areas.

Study: Omicron Variant of SARS-COV-2 Gains New Mutations in New Zealand and Hong Kong. Image Credit: FOTOGRIN / Shutterstock.com

Introduction

With the availability of next-generation whole-genome sequencing tools, genomic surveillance was carried out on SARS-CoV-2 almost from the beginning of the pandemic. These efforts revealed that the main force facilitating the circulation of SARS-CoV-2 at high levels in the global population is its ongoing evolution.

Among the several SARS-CoV-2 variants that have been identified, five have been designated variants of concern (VOCs), including the Alpha, Beta, Gamma, Delta, and Omicron variants. First reported in South Africa, Botswana, and Hong Kong in November 2021, the Omicron variant rapidly rose to dominance worldwide and quickly displaced the Delta variant.

Three subvariants of the SARS-CoV-2 Omicron variant have been reported, of which include BA.1, BA.2, and BA.3. BA.1 is characterized by the spike R346K mutation and has a sublineage BA.1.1. which, along with the parent BA.1, has accounted for most Omicron cases in the current phase of the pandemic.

Study findings

The examination of new SARS-CoV-2 genomes from these areas of the world led to the discovery of the BA.1.1 and BA.2 variants. Interestingly, these areas have witnessed the resurgence of COVID-19, despite previously good control. This indicates that the new mutations may have contributed to the rise in new cases in both countries.

Unlike the rest of the world, NZ reported its first Omicron case due to BA.1 on December 2021, and the first BA.1.1 only on the first day of 2022. Meanwhile, the rise in COVID-19 cases in NZ occurred from February 22, 2022, which leads to the postulate that during this period, viral evolution continued to occur.

This was facilitated by the occurrence of up to 70 mutations per viral genome, with BA.1.1 and BA.2 variants accounting for most cases, while BA.1 appeared to be fading out.

The new mutations were found in the non-structural protein (NSP)3, NSP10, and NSP14, all three of which are present in BA.1.1 genomes. The NSP10 mutation was found in more than 700 SARS-CoV-2 genomes; however, the NSP3 and NSP14 mutations do not occur together and affect different parts of the BA.1.1 genome.

Mechanistic impact of NSP10 and NSP14 substitutions. (A) Location of L133 of NSP10 and R289 of NSP14 in a trimeric RNA-protein complex. L133 of NSP10 is located within an unstructured C-terminal tail close to D131, whereas R289 of NSP14 is away from the binding sites for NSP10 and RNA. Based on PyMol presentation of 7N0B from the PDB database. (B) Structural details on spike R289H of NSP14. R289 is a part of a key motif forming the binding pocket for S-adenosyl methionine, a cofactor required for the guanine-N⁷ methyltransferase activity. Shown in the structure is S-adenosyl homocysteine (SAH), an S-adenosyl methionine analog, bound to the pocket [12]. Based on PyMol presentation of 7R2V from the PDB database. (C) Same as (B) with the area for the SAM-binding pocket enlarged.

The impact of these mutations is not known; however, the NSP14 mutation forms part of the binding pocket of the important cofactor S-adenosyl methionine (SAM) of the protein’s guanine-N7 methyltransferase activity. Since the last three residues of the motif where this mutation occurs are hardly ever changed, this mutation reduces the activity of NSP14 as a guanine-N7 methyltransferase.

A new Delta subvariant was also found in New Zealand in almost 120 genomes. First found on December 28, 2021, this subvariant has ten new substitutions in the spike, nucleocapsid, and non-structural proteins. There are numerous precursor genomes as well, thus suggesting that this subvariant arose gradually.

Furthermore, this Delta subvariant carries 50 or 51 mutations, on average, per genome, making it among the Delta variants with the highest mutational load. However, this is far less than Omicron, which contains around 70 mutations per genome.

This new Delta strain has not spread very fast or extensively, as it has been outcompeted by Omicron BA.1.1 and BA.2. Among these, the two BA.1.1 subvariants outnumber the BA.2 variant, which may indicate that they are responsible for more of the current spike in cases than the latter.

In Hong Kong, Omicron began to cause a surge in cases only in February 2022, even though this variant was originally identified in Hong Kong in mid-November 2021. This might indicate that new mutations occurred during this lag period. In fact, the current study reports that BA.2 accounted for the vast majority of genomes after February 1, 2022, rather than BA.1 or BA.1.1.

Three new mutations were found among the BA.2 genomes from Hong Kong. One is on the spike protein and may affect its function in cell attachment and entry, whereas the other mutations appear to affect NSP3 and NSP8. Almost all BA.2 genomes carry all these mutations.

These were found to have arisen separately, with two being reported in several cases from Singapore, Indonesia, and other countries including the United Kingdom from December 31, 2021, onward, until all three were found in a genome from January 12, 2022. This subvariant appears to be the major force driving the current wave of cases in Hong Kong.

No genomic data has emerged from mainland China in 2022. Therefore, it is not known whether this strain has contributed to the outbreak there, though the proximity to Hong Kong and mainland China raises this possibility.

Conclusions

Omicron does not appear to be more prone to mutations than other variants, with no obvious new variants having arisen since its identification. The emergence of dominant subvariants in NZ and Hong Kong appears to be a random process. Even the dominant subvariants in these regions showed only two or three new mutations, which supports the postulate that this variant has the same baseline mutational rate as other variants.

Further research is required to understand what led to the emergence of Omicron, while the current findings suggest that the new mutations in the dominant BA.1.1 and BA.2 subvariants in Hong Kong and NZ led to their enhanced spread in these regions.

Continued genomic surveillance is, therefore, necessary to trace the evolution of SARS-CoV-2, as this may drive the prolongation of the pandemic.

*Important notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.