Jinan University Zhang Qiwei / Wu Jianguo and others found that Omicron had undergone multiple genetic recombinations

The current COVID-19 pandemic around the world is primarily caused by the more contagious Omicron variant
.

Scientists have been continuously paying attention to the possible emergence of new recombination variants, because genetic recombination is an important evolutionary mechanism for the production of new and re-emerging human viral pathogens, and an important way of evolutionary adaptation of coronaviruses
.

Coronaviruses can rapidly accumulate multiple mutations after a single evolutionary event through genetic recombination, leading to increased viral infectivity or enhanced immune escape
.

Due to the high similarity between the sequences of the new coronavirus epidemic strains and relatively conservative evolution, the classical recombination detection method is difficult to detect the recombination signals and corresponding evolutionary trajectories between different strains.
The recombination found by a single sequence needs to be distinguished from co-infection
.

Recently, Professor Zhang Qiwei and Professor Wu Jianguo from the pathogenic microorganism research team of Jinan University published a research paper titled: Tracking SARS-CoV-2 Omicron diverse spike gene mutations identifies multiple inter-variant recombination events in the preprint bioRxiv
.

The study carried out a fine analysis of the whole genome sequence of the new coronavirus Omicron variant and its spike gene sequence, and found for the first time that the spike protein gene of the Omicron variant is related to Alpha (Alpha).
Reliable evidence of multiple cross-variant recombination between mutant strains such as , Beta, Delta, etc.
, and it is speculated that the recombination of the Omicron strain and the Delta strain produces "Delta Coron" "Deltacron"-like Variants have appeared in South Africa and Botswana as early as November 2021
.

The spike protein (Spike) of the new coronavirus is mainly responsible for receptor recognition and mediating the invasion of the coronavirus into host cells
.

The mutation of the amino acid sequence of the viral S protein can change the binding efficiency of the S protein to the host cell receptor, thereby affecting the viral infection and infectivity
.

The S protein is immunogenic and has many T lymphocyte and B lymphocyte epitopes.
The mutation of the antigen recognition site will lead to changes in the binding efficiency of neutralizing antibodies and antigens, affecting the neutralizing titers of antibodies, and even antigen drift and Immune escape phenomenon
.

The research team first conducted a comprehensive and detailed comparison of the 52,563 gene sequences of the S protein of the new coronavirus Omikron variant that was prevalent before January 15, 2022, and found that the early Omikron variant itself had carried many more genes.
The characteristic amino acid mutation of a previous VOC epidemic strain suggests that the S protein gene of the Omicron variant has undergone multiple gene recombination events (Fig.
1)
.

Further identification revealed 18 core mutations (>99% frequency) of BA.
1 subvariants (8 in NTD, 5 near the S1/S2 cleavage site, and 5 in S2)
.

The BA.
2 subvariant shares three additional amino acid deletions with the Alpha variant
.

The BA.
1 subvariant and the VOC variant had a total of 9 common amino acid mutations in the S protein (three more than BA.
2), suggesting that the Omicron variant may have come from recombination with these VOCs
.

BA.
1 contains three more alpha-related mutations (del69-70, del144) than BA.
2, so BA.
1 may be phylogenetically closer to the alpha variant
.

Figure 1.
The BA.
1 subvariant of the omicron strain shares 6 mutations with the alpha variant (del69-70, delY144, N501Y, D614G and P681H) and 3 mutations with the beta strain (K417N, N501Y and D614G) ), shared 3 mutations (N501Y, D614G and H655Y) with the gamma strain and 2 mutations (T478K and D614G) with the delta strain
.

By analyzing the genome sequence of the Omicron variant released globally from November 2020 to January 2021, and screening the S protein gene sequence of the Omicron variant, the research team found that the Omicron variant during the epidemic, Continuously adding and integrating multiple non-native amino acid mutations typical of other legacy VOC/VOI strains
.

Most notably, L452R and R346K mutations appeared in the S protein RBD region of some Omicron mutants, which may have been obtained by recombination with Delta (Delta) and Miao (B.
1.
621) mutants
.

The L452R and R346K mutations are located in the receptor binding region of the S protein.
Previous studies have shown that L452R and R346K can reduce the binding efficiency of neutralizing antibodies in the corresponding regions, resulting in enhanced virus immune evasion (Figure 2)
.

Figure 2.
Amino acid mutations from other mutants were newly added to each region of the spike protein of some Omicron mutants
.

A phylogenetic network was established for the S protein sequences published globally from November 2021 to January 2022, and it was found that during the first 2 months of the epidemic of the Omicron variant, there were polymorphisms in the haplotype of the S protein, and the sequence type It is mainly BA.
1 sub-variety, and has also evolved a sub-group integrating mutations such as S protein A701V, R346K, L452R, etc.
on the basis of BA.
1, as well as BA.
2 sub-variant, Reversion and other sub-groups swarm (Figure 3)
.

During the initial co-circulation of the Omicron variant with other variants, multiple recombination events may have occurred, resulting in gene transfer that acquired characteristic mutations derived from other variants
.

The sequence exchange between the Omicron variant strain and other earlier circulating strains may lead to the loss of part of the original mutation of the S protein gene of the Omicron variant strain, and the reversion occurs, and the amino acid sequence is closer to the original strain
.

Figure 3.
(A) The S gene of the Omicron variant strain exhibits certain genetic polymorphisms and forms multiple subgroups
.

(B) Some regions of the S gene of some subsets show atavism
.

(C) Co-circulation and recombination of the Omicron variant with other strains resulted in the formation of various subpopulations of the S gene
.

The L452R mutation is a characteristic mutation carried by the delta variant
.

The research team conducted source traceability and whole-genome analysis of the Omicron recombinant strains suspected of carrying the L452R mutation of the delta variant strain L452R, and found that "Deltacron"-like Variants Variants have been detected in many countries around the world
.

The L452R "Deltacron"-like recombinant strain of Omicron appeared in the new crown specimens collected in South Africa and Botswana as early as November 2021.
At present, the recombinant strain is mainly distributed in North America, Europe, and West Asia (Figure 4).
), with a frequency of nearly a thousand plants
.

The recombinant Omicron variant also showed polymorphism at the level of whole genome sequence, showing complex and diverse sources, suggesting that the Omicron variant was co-infected with other strains (Fig.
4)
.

Figure 4.
(A) Global distribution of the BA.
1 subvariety of Omicron carrying the L452R mutation
.

(B) The genome-wide phylogenetic tree of the Omicron BA.
1 subvariety carrying the L452R mutation exhibits sequence polymorphisms
.

In addition to the Omicron BA.
1 subvariant, the research team also found a small number of delta mutations suspected of recombination in the S gene of some Omicron BA.
2 subvariants
.

Through the analysis of the S gene sequence of a large number of Omicron strains, the study found that there are multiple cross-variant recombination events in the S gene of Omicron and other strains, indicating that co-infection and subsequent genome recombination promote the continuous evolution of the new coronavirus
.

Some recombination events may lead to changes in viral infectivity and immune evasion capabilities
.

Therefore, continuous monitoring of mutations in the 2019-nCoV genome is crucial for understanding the evolution and origin of the virus.
At the same time, the design of anti-2019-nCoV drugs and new vaccines also needs to consider the impact of recombination on the formation of virus targeting sites
.

Professor Zhang Qiwei and Professor Wu Jianguo from the Institute of Pathogenic Microbiology of Jinan University/Guangdong Provincial Key Laboratory of Virology are the corresponding authors of the paper, and doctoral student Ou Junxian is the first author of the paper.
Research provides guidance and assistance
.

Paper link: https://doi.
org/10.
1101/2022.
03.
13.
484129 Open for reprinting, welcome to forward to Moments and WeChat groups