Alarming Discovery In America Of New SARS-CoV-2 Variants Bearing Mutations Q677H And Q677P Leading To Greater Transmissibility.
: A team of researchers from University of Bern-Switzerland, University of New Mexico-USA, Microbial Genome Sequencing Center-Pittsburg, Louisiana State University, Icahn Mt Sinai School of Medicine, Louisiana Department of Health, New Mexico Department of Health, Wyoming Public Health Laboratory and the University of Pittsburgh have discovered new variants emerging in the United States through Independent genomic surveillance programs based in New Mexico and Louisiana showing selectively neutral mutations taking place at the amino acid position 677 of the spike protein.
These mutations have given rise to the numerous variants from the clade 20G (lineage B.1.2) carrying the Q677P
or Q677H mutations.
According to the research team, these mutations being at the proximity to the polybasic cleavage site at the S1/S2 boundary are consistent with its potential functional relevance during cell entry, suggesting parallel evolution of a trait that may confer an advantage in spread or transmission.
The research findings were published on a preprint server but are currently being peer reviewed.
One of the study leading authors, Emma B Hodcrofy from the Institute of Social and Preventive Medicine, University of Bern, Switzerland also runs a website that is monitoring the emergence of various SARS-CoV-2 variants that is still in its infant stages but is an initiative that is worthy of mention for other worldwide researchers to contribute for more concerted and collaborative global effort to identify emerging variants of interests. https://covariants.org/
The new variants from the 20G clade (lineage B.1.2) carrying a Q677P substitution in the Spike protein was first discovered in the United States in October 23rd 2020. However from the period 01 Dec 2020 to 19 Jan 2021 it rose to represent 27.8% and 11.3% of all SARS-CoV-2 genomes sequenced from Louisiana and New Mexico, respectively.
COVID-19 infections bearing the Q677P mutations have been detected predominantly in the south central and southwest United States.
Alarmingly on the 3rd
of Feb 2021, GISAID data show 499 viral sequences of this variant from the USA. Taking into consideration that very little genomic sequencings are done in the United States, such a number infers the scale of the prevalence of this mutation.
Detailed phylogenetic analyses revealed the independent evolution and spread of at least six distinct Q677H sub-lineages, with first collection dates ranging from mid August to late November, 2020. Four 677H clades from clade 20G (B.1.2) , 20A (B.1.234), and 20B (B.1.1.220, and B.1.1.222) each contain roughly 100 or fewer sequenced cases, while a distinct pair of clade 20G clusters are represented by 754 and 298 cases, respectively.
The largest of the 677 variant sub-lineages (“Robin 1”) is a B.1.2 / 20G clade virus carrying Q677H that first appears in GISAID data from a sample with a August 17, 2020 collection date. As of Feb 4, 2021, this su
b-lineage contained 754 sequences. Robin 1 is found in over 30 US states, but predominates in the Midwest.
A second Q677H clade, distinguished from Robin 1 by an N2361K substitution in orf1a, first appeared from a Oct 6, 2020 sample from Alabama and is named “Robin 2” owing to its similarity to the parental Robin 1 sub-lineage. This cluster contains 303 sequences, and is found mostly in the Southeast.
The next largest cluster is the (“Pelican”), which was first detected in Oregon from a sample with collection date of Oct 23, 2020 and as of Feb 3, 2021 contains 504 sequences. The Q677P variant has been detected in LA, NM, NC, WY, MA, ID, MI AZ, CA, TX, WI, and MD.
This Q677P variant of 20G (B.1.2) has also been found in five international sequences (Australia (2), Denmark, Switzerland, India).
The remaining Q677H sub-lineages each contain around 100 or fewer sequences, and are named: Yellowhammer, detected mostly in the southeast US; Bluebird, mostly in the northeast United States; Quail, mainly in the Southwest and Northeast; and Mockingbird, mainly in the South-central and East coast states.
The S1/S2 cleavage site contains the multibasic cleavage site and is found in a disordered region within Spike.
The study team used SWISS MODEL to model this inherently flexible region and spotlight the Q677P residue.
Although the Q677P position is outside the furin binding pocket, the team speculates that the presence of a proline at this site may introduce a favorable kink that promotes the dynamic, conformational changes necessary for cleavage at the S1/S2 junction, which is governed not only by furin-like activities, but also by trypsin-like proteases and cathepsins.
Moreover, the introduction of a proline in this model appears to be 3.7 angstroms away from the carbon backbone of S689 (relative to 4.9 angstroms for the native glutamine), which may promote atomic interactions that encourage conformations favorable for proteolytic cleavage. In the case of the S: Q677H substitution, histidine protonation could similarly act as a conformational switch affecting accessibility to proteases.
Importantly cleavage at the S1/S2 boundary promotes a more ‘open’ S conformation that is more competent to bind ACE2, these putative mechanisms for enhanced cleavage at the S1/S2 junction may promote more efficient viral entry.
These mutations reflect strong evidence of adaptation via selectively neutral mutations to enhance its transmission capability.
According to the study team this coincidental rise and spread on independent genetic backgrounds is remarkable and suggests some fitness advantage.
The United States with fewer deposited sequences may simply have missed detection of these variants. To date, all 677H/P mutants collected from the US stem from the S:614G lineage that now predominates worldwide, but alongside varied polymorphisms in S, N, ORF1a, ORF1b, and other genes, suggesting any fitness advantage of S:677 mutations is largely independent of these other mutations.
Still the relatively slow rise of lineages with S:677 substitutions may suggest that any fitness benefits are modest relative to other circulating variants, which may have also independently gained adaptive mutations. Given their relatively recent emergence, however, Q677P/H lineages may continue to rise as a percentage of total cases. Additional laboratory and genetic surveillance data will be needed to define their biological relevance.
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