The rapid spread of novel coronavirus, namely, SARS-CoV-2, around the world has become a significant challenge to humankind. Now, the emphasis is on combatting the Covid-19 pandemic, on social distancing, and lockdown of cities to avoid medical care bottlenecks and to spread-out critical care over time. However, the shooting death toll in some of the countries is alarming, rather frightening. There are certain factors, including age and comorbid health conditions, which have been significantly linked to higher fatalities, particularly in Italy. Such vast differences in fatality rates could be linked to genetic variations in SARS-CoV-2, but it is not proved yet.
Presently, complete SARS-CoV-2 sequences, using NGS technology are being deposited at Global Initiative on Sharing All Influenza Data (GISAID), which are being extensively scrutinised to understand their transmission, evolutionary, and genetic relationships through phylogeny. It is not however, clear if the genetic mutations of the virus affect its transmissibility and/or its virulence, which caused higher fatalities in some countries.
For this purpose, the phylogenetic tree of 4,246 SARS-CoV-2 genomes obtained from GISAID is utilised. Its analysis may predict a possible link between higher fatalities and SARS-CoV-2 codon 614 in Spike protein (S), which replaces Aspartic acid (D) with Glycine (G) at this site. The SARS-CoV-2 genomes with the S-D614G variant have been classified under a larger phylogenetic clade G, which constitutes most strains from Europe. Significantly, mutations in the S protein may induce conformational modifications that alter antigenicity, plausibly by mimicking the open status, and eases the exposure of the cleavage domain to proteases, FURIN, or TMPRSS2, and could speed up the cleavage.
The researchers have observed the variant S-D614G, which distinguishes the SARS-CoV-2 strains that may have caused fatal infections in European populations, such as a substantial number of strains with the S-D614G variant are from Belgium, Spain, Italy, France, Netherlands, and Switzerland that top the death toll, while Germany and Kuwait, with a lower death toll, constitute most strains with the wild-type 614D at S. Notably, this scenario in Germany and other European countries remains uncertain as the number of cases is increasing on daily basis.
Speculations are that the S-D614G strains may be more virulent, may increase the severity in infected individuals, especially in European countries, where the mutation is prevalent. Examining the amino acid 614 at S protein site (or other mutations) in mildly ill patients versus critically ill patients may be an asset in the arsenal against Covid-19 as the above evidence is circumstantial. Expectedly, however, the above interpretation with limited data will be of much help for researchers.
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D614G mutation is a missense mutation wherein an alteration in single DNA base pair causes the substitution of aspartic acid (single-letter code: D) with glycine (single-letter code: G) in the protein encoded by the mutated gene. A genetic mutation is characterised by a permanent change in the DNA sequence that may occur due to environmental factors (UV radiation), or due to an error during DNA replication process. Genetic mutations can be of many types, including missense, nonsense, insertion, deletion, duplication, frameshift, and repeat expansion mutations.
The GISAID Initiative (Global Initiative on Sharing All Influenza Data) involves public-private-partnerships between the Initiative’s administrative arm, Freunde of GISAID, a registered non-profit association, and governments of the Federal Republic of Germany, Singapore, the official host of the GISAID platform, and the USA with support from private and corporate philanthropy.
FURIN is a protein coding gene, which causes diseases like Avian influenza and Cerebral Amyloid Angiopathy, Itm2b-Related,1. Lipoprotein metabolism and Signaling by GPCR are among its related pathways. Serine-type endopeptidase activity and serine-type endopeptidase inhibitor activity are part of gene ontology (GO) annotations related to it. PCSK4 is an important paralog of this gene.
TMPRSS2 (Transmembrane Serine Protease 2) is a protein coding gene, which leads to diseases, such as Covid-19 and influenza. Trancriptional misregulation in cancer and coregulation of androgen receptor activity are among its related pathways. Serine-type endopeptidase activity and scavenger receptor activity are part of gene ontology (GO) annotations related to it. TMPRSS3 is an important paralog of this gene.
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Courtesy: sciencedirect.com, oneindia.com, gsaid.org, genecards.org