Genetic variation in SARS-CoV-2 may explain variable severity of COVID-19.

To the Editor

The coronavirus disease 2019 (COVID-19) is highly contagious and is rapidly spreading all over the world. Although the majority of the COVID-19 patients are either asymptomatic or mildly symptomatic, many symptomatic patients who require hospitalization and intensive care are dying. Disease severity and fatality have been found to be associated with many host factors, including age, gender, race, ethnicity and presence of co-morbidities. Disease severity and fatality have also been noted to differ between countries and between geographical locations within the same country. Many hypotheses have so far been proposed to explain the underlying basis of the variation in the severity of COVID-19 in the population but none of the proposed hypotheses has been proved or appeared to be convincing.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was discovered as the viral pathogen that causes COVID-19. The reference sequence of the full-genome of the SARS-CoV-2 was explored soon after the manifestation of the disease in Wuhan, China in December 2019. When COVID-19 quickly spread outside China, sequencing of the viral genome was conducted from infected patients in other countries to compare the sequence with the reference sequence. Intriguingly, genomic sequence of SARS-CoV-2 of the first two COVID-19 patients diagnosed in Italy during January and February 2020 already showed mutations compared to the reference sequence established in China [1]. Variations in the genomic sequences were also observed when sequencing data from viral isolates of patients from other European and North American countries were compared with each other and with reference sequence [1].

Several studies have so far been conducted utilizing sequencing data of SARS-CoV-2 obtained from publicly available repositories. One such study, analyzed 95 SARS-CoV-2 complete genome sequences obtained from GenBank, found 156 variants in total and 116 unique variants [2]. However, this recent study [2] did not explore the association between genetic variation in SARS-CoV-2 and the severity of COVID-19. Another analysis of 86 genomic sequences obtained from GISAID database (https://www.gisaid.org/) identified 3 deletions in the genomes of SARS-CoV-2 from Japan, USA and Australia, and 93 mutations over the entire SARS-CoV-2 genomes [3]. Several of these mutations were located in the receptor binding domain (RBD) of the spike surface glycoprotein [3]. Since the RBD of the spike surface glycoprotein plays essential role in binding with receptors on the host cell, mutation in spike protein may alter the virulence of the virus. Pachetti et al. [4] analyzed 220 SARS-CoV-2 genomic sequences from the GISAID database and found 8 novel mutation hot spots: 5 of them were predominantly observed in Europe and 3 were exclusively present in North America but none of them was detected in Asia. They also identified a novel mutation in the viral gene for RNA dependent RNA polymerase (RdRp), an enzyme that is related to proofreading functionality [4]. Mutation in the RdRp gene in European viral genome was associated with higher numbers of point mutations compared to viral genomes from Asia [4]. These findings suggest that the SARS-CoV-2 is evolving, and European, North American and Asian variants with different mutation pattern may coexist. Therefore, it is an urgent need to explore the association of the mutation pattern of SARS-CoV-2 genome with the severity and fatality of COVID-19.

Based on the above discussion, we hypothesize that the genetic variation in SARS-CoV-2 may explain variable severity of COVID-19 in the population. Analysis of sequencing data of SARS-CoV-2 genome showed evidence of mutation at the beginning of the worldwide spread of COVID-19 [1]. Existence of multiple genetic variants of the virus was also identified in the same population, same country or same geographical location. On the other hand, some unique variants have been found in a particular region or country [4]. Furthermore, mutations have been identified in the RdRp gene that determines frequency of mutation that will be acquired in the future generation of the virus [4]. Mutations have also been detected in the RBD of the spike surface glycoprotein that determines viral virulence [3]. Thus, among the various variants of SARS-CoV-2 circulating in the population, some may be highly virulent and lethal whereas others may be less virulent.

In conclusion, it is plausible that genetic variation in SARS-CoV-2 may at least partly explain variable severity of COVID-19. It is now very important to test this hypothesis. This hypothesis can be tested by obtaining genetic sequences of SARS-CoV-2 from two groups of COVID-19 patients. One group will include patients who have died due to severe COVID-19 and another group will include patients who had only mild symptoms of COVID-19. Genetic sequences of SARS-CoV-2 will be compared between the groups to identify unique variation in the genomic sequence, and will be compared within group to identify similarities in the genomic sequence. This hypothesis, if accepted, will help identify virulent variant of SARS-CoV-2 and will thus help in drug design and vaccine development.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.