Omicron variant of SARS-COV-2 gains new mutations in New Zealand and Hong Kong (preprint)

SARS-COV-2 evolution is a key factor that drives the pandemic. As the previous four variants of concern, omicron variant arose from complete obscurity and have rapidly become the prominent pandemic driver around the world. After initial identification in November 2021, this variant has yielded three different subvariants, BA.1, BA.2 and BA.3. Among them, BA.1 is dominant around the world although BA.2 is gradually taking over this role. BA.1 has acquired spike R346K and yielded a sub-lineage known as BA.1.1. An important question is how these variants continue their evolution. To address this question, I analyzed new SARS-COV-2 genomes identified in Oceania and Asia, where there are many ongoing pandemic hotspots. This analysis revealed that together with BA.2, two different BA.1.1 strains are dominant in New Zealand. Each of them carries two new substitutions, with L133F of NSP10 as the common one. This residue is located at an unstructured C-terminal tail, so the impact of L133F is not obvious. The other new substitutions are T1368I of NSP3 and R289H of NSP14. While T1368I of NSP3 is located close to its first transmembrane domain, R289H of NSP14 is right at a key motif of the binding pocket for S-adenosyl methionine, a cofactor required for the guanine-N7 methyltransferase activity. Analysis of SARS-COV-2 genomes from New Zealand also identified a delta subvariant with over ten new mutations (including spike N481K and R765H), but the subvariant is still negligible in driving the pandemic. Analysis of SARS-COV-2 genomes from Hong Kong uncovered a predominant BA.2 subvariant with three new substitutions: I1221T of spike protein (located at the transmembrane domain), T725I of NSP3 (within the C-terminal third of a SARS-unique domain) and T145I of NSP8 (at a surface area away from the site for interaction with NSP7 and NSP12). By contrast, no dominant mutations are obvious in omicron genomes from Australia, Indonesia, Singapore, Malaysia, Thailand, Japan and South Korea, suggesting that emergence of the dominant omicron subvariants in New Zealand and Hong Kong is of random nature. These findings partly explain the current situation in these two pandemic hotspots and reiterate the importance to continue tracking SARS-COV-2 evolution.

Delta subvariants of SARS-COV-2 in Israel, Qatar and Bahrain: Optimal vaccination as an effective strategy to block viral evolution and control the pandemic (preprint)

Delta variant has rapidly become the predominant pandemic driver and yielded four subvariants (delta1, delta2, delta3 and delta4). Among them, delta1 has been mainly responsible for the latest COVID-19 waves in India, Southeast Asia, Europe and the USA. A relevant question is how delta subvariants may have driven the pandemic in the rest of the world. In both Israel and Qatar, mRNA-based vaccination has been rolled out competitively, but the outcomes are quite different in terms of controlling the recent waves resulting from delta variant. This raises the question whether delta subvariants have acted differently in Israel and Qatar. In both countries, delta variant was first identified in April 2021 and delta1 subvariant constituted ~50% delta genomes from April to May 2021. But the situation started to diverge in June 2021: In Israel, delta1 variant was encoded by 92.0% delta genomes, whereas this fraction was only 43.9% in Qatar. Moreover, a delta1 sublineage encoding spike T791I was identified in Israel but not Qatar. This sublineage accounted for 31.8% delta genomes sequenced in June 2021 and declined to 13.3% in October 2021. In August 2021, delta1 also became dominant in Qatar and a major sublineage encoding spike D1259H emerged. This sublineage has evolved further and acquired additional spike substitutions, including K97E, S255F, I693S, I712S, I1104L, E1258D and/or V1177I, in Qatar and other countries, such as Czech Republic, France and Mexico. Monthly distribution of the above sublineages suggests that the one from Qatar is much more of concern than that from Israel. Different from what was in Israel and Qatar, delta2 subvariant has also been important in Bahrain, whereas a delta2 sublineage encoding spike V1264L and A1736V of NSP3 was dominant in June 2021, but was gradually taken over by delta1 subvariant. These results suggest that delta1 and delta2 subvariants continue their evolution in different countries. The recent successful pandemic control in Israel, Qatar and Bahrain supports that delta1 and delta2 subvariants are still sensitive to timed vaccination, thereby urging the use of optimal immunity as a strategy to block SARS-COV-2 evolution and control the pandemic.

Delta-1 variant of SARS-COV-2 acquires spike V1264L and drives the pandemic in Indonesia, Singapore and Malaysia (preprint)

Since April 2021, delta variant of SARS-COV-2 has gradually overtaken all other variants and become a dominant pandemic driver around the world. It has evolved and yielded four subvariants: delta1, delta2, delta3 and delta4. While trying to understand how these subvariants drive the pandemic in Southeast Asia, I noticed that many d1 genomes from Indonesia encode an extra spike substitution, V1264L. Coincidentally, this confers an acidic dileucine motif because residues 1157-1262 are acidic and residue 1265 is leucine. Such a motif may affect subcellular trafficking of the resulting spike protein. Alarmingly, this V1264L-encoding delta1 subvariant (referred to as delta1L) has become the dominant pandemic driver in Indonesia, Singapore, Malaysia and East Timor. Moreover, it has acquired additional spike substitutions: L1234L in Singapore and D215Y/N in Malaysia. On the average, the resulting sublineages carry 46-48 mutations per genome, making them some of the most mutated variants identified so far. Moreover, a d1 sublineage from the United Kingdom has acquired V1264L along with spike Y145H and A222V, a signature substitution of a SARS-COV-2 clade that was a major pandemic driver in Europe during the summer of 2020. A222V improves an extensive hydrophobic interaction network at the N-terminal domain of spike protein and may make this sublineage more virulent than delta1 and delta1L. Some delta2 subvariant genomes identified in the United States of America and other countries also encode V1264L. Thus, V1264L is a recurrent spike substitution frequently acquired by d subvariants during convergent evolution. This recurrence also suggests that V1264L is one key mechanism by which d variant adopts to expand its ‘evolutionary cage.’

SARS-COV-2 δ variant drives the pandemic in India and Europe via two subvariants (preprint)

ABSTRACT SARS-COV-2 evolution generates different variants and drives the pandemic. As the current main driver, δ variant bears little resemblance to the other three variants of concern, raising the question what features future variants of concern may possess. To address this important question, I compared different variant genomes and specifically analyzed δ genomes in the GISAID database for potential clues. The analysis revealed that δ genomes identified in India by April 2021 form four different groups (referred to as δ1, δ2, δ3 and δ4) with signature spike, nucleocapsid and NSP3 substitutions defining each group. Since May 2021, δ1 has gradually overtaken all other subvariants and become the dominant pandemic driver, whereas δ2 has played a less prominent role and the remaining two (δ3 and δ4) are insignificant. This group composition and variant transition are also apparent across Europe. In the United Kingdom, δ1 has quickly become predominant and is the sole pandemic driver underlying the current wave of COVID-19 cases. Alarmingly, δ1 subvariant has evolved further in the country and yielded a sublineage encoding spike V36F, A222V and V1264L. These substitutions may make the sublineage more virulent than δ1 itself. In the rest of Europe, δ1 is also the main pandemic driver, but δ2 still plays a role. In many European countries, there is a δ1 sublineage encoding spike T29A, T250I and Q613H. This sublineage originated from Morocco and has been a key pandemic driver there. Therefore, δ variant drives the pandemic in India and across Europe mainly through δ1 and δ2, with the former acquiring additional substitutions and yielding sublineages with the potential to drive the pandemic further. These results suggest a continuously branching model by which δ variant evolves and generates more virulent subvariants.

SARS-COV-2 δ variant drives the pandemic in the USA through two subvariants (preprint)

Delta variant of SARS-COV-2 has overtaken all other variants and become a dominant pandemic driver aggressively. In India, it has evolved and yielded delta1, delta2, delta3 and delta4 subvariants. Delta1 has also gradually become the dominant pandemic driver there and across Europe, raising the question whether this is true in other regions around the world. Here I demonstrate that delta1 has also become the dominant pandemic driver in the USA. In April and May 2021, alpha variant was the major pandemic driver, with Ida and gamma variants playing minor roles. Delta variant only started to emerge in April and May, but it rose exponentially and became a major driver one month later. By September, it was detected in ~99% COVID-19 cases and emerged as almost the sole pandemic driver. In the country, ~50% of its population was fully vaccinated in the summer of 2021; vaccination may have selected against all other variants and thereby helped delta variant achieve such an alarming status. One puzzling question is what genomic features make delta variant so highly competitive. Related to this, delta1, but not delta2, delta3 and delta4, has risen exponentially after May 2021, suggesting that unique NSP3 and nucleocapsid mutations that delta1 carries make it so competitive as a predominant pandemic driver. These results indicate that it is not delta variant per se , but its offspring, delta1, that makes delta variant a predominant pandemic driver. Alarmingly, delta1 subvariant has evolved further and gained additional mutations to finetune functions of spike, nucleocapsid and NSP3 proteins. Compared to delta1, delta2 subvariant is less important in driving the ongoing pandemic in the USA, but this subvariant has also evolved further and gained extra mutations. These results suggest a continuously branching model on delta variant evolution and reiterate urgent need to track and block the evolution.

SARS-COV-2 C.1.2 variant is highly mutated but may possess reduced affinity for ACE2 receptor (preprint)

SUMMARY SARS-COV-2 evolution generates different variants and drives the pandemic. As the current main driver, delta variant bears little resemblance to the other three variants of concern (alpha, beta and gamma), raising the question what features the future variants of concern may possess. To address this important question, I searched through the GISAID database for potential clues. While investigating how beta variant has been evolving in South Africa, I noticed a small group of genomes mainly classified as C.1.2 variant, with one-year old boy identified in March 2021 being the index case. Over 80% patients are younger than 60. At the average, there are 46-47 mutations per genome, making this variant one of the most mutated lineages identified. A signature substitution is spike Y449H. Like beta and gamma variants, C.1.2 possesses E484K and N501Y. The genomes are heterogenous and encode different subvariants. Like alpha variant, one such subvariant encodes the spike substitution P681H at the furin cleavage site. In a related genome, this substitution is replaced by P681R, which is present in delta variant. In addition, similar to this variant of concern, three C.1.2 subvariants also encode T478K. Mechanistically, spike Y449 recognizes two key residues of the cell-entry receptor ACE2 and Y449H is known to impair the binding to ACE2 receptor, so C.1.2 variant may show reduced affinity for this receptor. If so, this variant needs other mutations to compensate for such deficiency. These results raise the question whether C.1.2 variant is as virulent as suggested by its unexpected high number of mutations.

SARS-COV-2 γ variant acquires spike P681H or P681R for improved viral fitness (preprint)

Severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) evolves and generates different variants through a continuously branching model. Four variants of concern have been the major pandemic drivers around the world. One important question is how they may evolve and generate subvariants, some of which may be even more virulent and drive the pandemic further. While investigating how {gamma} (or P.1) variant has been evolving, I noticed the spike substitution P681H in a group of genomes encoding a new subvariant, which has been designated P.1.7. This subvariant has become the dominant P.1 sublineage in Brazil, Italy, Spain and Peru, supporting that P681H confers evolutionary advantage to P.1.7. In Brazil and Peru, P.1.7 was still responsible for ~30% and ~40% cases, respectively, in August 2021. However, it has been competed out by {delta}1 (a {delta} subvariant) in both countries, Italy and Spain, suggesting that P.1.7 is not as virulent as {delta}1. In addition, 160 P.1 genomes possess a related substitution, P681R, and 120 of them encode a new subvariant, designated P.1.8. This P.1 subvariant carries two additional spike substitutions, T470N and C1235F, located at the receptor-binding pocket and cytoplasmic tail of spike protein, respectively. More P.1.8 genomes have been identified than P.1 genomes that encode P681R but not T470N and C1235F, suggesting that these two substitutions improve virulence of P.1.8 subvariant. Some P.1 genomes carry other substitutions (such as N679K, V687L and C1250F) that affect the furin cleavage site or cytoplasmic tail of spike protein. Thus, to improve viral fitness and expand its evolutionary cage, {gamma} variant acquires mutations to finetune the furin cleavage site and cytoplasmic tail of spike protein.

δ1 variant of SARS-COV-2 acquires spike V1176F and yields a highly mutated subvariant in Europe (preprint)

Genomic surveillance of SARS-COV-2 has revealed that in addition to many variants of interests, this virus has yielded four variants of concern, , {beta}, {gamma} and {delta}, as designated by the World Health Organization. Delta variant has recently become the predominant pandemic driver around the world and yielded four different subvariants ({delta}1, {delta}2, {delta}3 and {delta}4). Among them, {delta}1 has emerged as the key subvariant that drives the pandemic in India, Europe and the USA. A relevant question is whether {delta}1 subvariant continues to evolve and acquires additional mutations. Related to this, this subvariant has acquired spike V1176F, a signature substitution of {gamma} variant, and yielded a new sublineage, {delta}1F. The substitution alters heptad repeat 2 of spike protein and is expected to improve interaction with heptad repeat 1 and enhance virus entry. Moreover, there are {delta}1F sublineages encoding spike N501Y, A783, Q836E and V1264L. While N501Y is a signature substitution shared by , {beta}, {gamma} variants, V1264L is a key substitution in a {delta}1 sublineage that is a major pandemic driver in Southeast Asia. The Q836E-encoding lineage carries an average of 50 mutations per genome, making it the most mutated variant identified so far. Similar to {delta}1 subvariant, {delta}2 subvariant has also acquired spike V1176F and yielded new sublineages. Together, these results suggest that V1176F is a recurrent spike substitution that is frequently acquired by SARS-COV-2 variants to improve viral fitness. It is thus important to track the evolutionary trajectory of related variants for considering and instituting the most effective public health measures.