Articles written in Journal of Genetics

    • Assessment of risk conferred by coding and regulatory variations of TMPRSS2 and CD26 in susceptibility to SARS-CoV-2 infection in human


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      At present, more than 200 countries and territories are directly affected by the coronavirus disease-19 (COVID-19) pandemic. Incidence and case fatality rate are significantly higher among elderly individuals (age>60 years), type 2 diabetes and hypertension patients. Cellular receptor ACE2, serine protease TMPRSS2 and exopeptidase CD26 (also known as DPP4) are the three membrane bound proteins potentially implicated in SARS-CoV-2 infection. We hypothesised that common variants from TMPRSS2 and CD26 may play critical role in infection susceptibility of predisposed population or group of individuals. Coding (missense) and regulatory variants from TMPRSS2 and CD26 were studied across 26 global populations. Two missense and five regulatory SNPs were identified to have differential allelic frequency. Significant linkage disequilibrium (LD) signature was observed in different populations. Modelled protein–protein interaction (PPI) predicted strong molecular interaction between these two receptors and SARS-CoV-2 spike protein (S1 domain). However, two missense SNPs, rs12329760 (TMPRSS2) and rs1129599 (CD26), were not found to be involved physically in the said interaction. Four regulatory variants (rs112657409, rs11910678, rs77675406 and rs713400) from TMPRSS2 were found to influence the expression of TMPRSS2 and pathologically relevant MX1. rs13015258 a 50 UTR variant from CD26 have significant role in regulation of expression of key regulatory genes that could be involved in SARS-CoV-2 internalization. Overexpression of CD26 through epigenetic modification at rs13015258-C allele was found critical and could explain the higher SARS-CoV-2 infected fatality rate among type 2 diabetes.

    • Contributions of human ACE2 and TMPRSS2 in determining host–pathogen interaction of COVID-19


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      Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is at present an emerging global public health crisis.Angiotensin converting enzyme 2 (ACE2) and trans-membrane protease serine 2 (TMPRSS2) are the two major host factors that contributeto the virulence of SARS-CoV-2 and pathogenesis of coronavirus disease-19 (COVID-19). Transmission of SARS-CoV-2 from animal tohuman is considered a rare event that necessarily requires strong evolutionary adaptations. Till date no other human cellular receptors areidentified beside ACE2 for SARS-CoV-2 entry inside the human cell. Proteolytic cleavage of viral spike (S)-protein and ACE2 byTMPRSS2 began the entire host–pathogen interaction initiated with the physical binding of ACE2 to S-protein. SARS-CoV-2 S-proteinbinds to ACE2 with much higher affinity and stability than that of SARS-CoVs. Molecular interactions between ACE2-S and TMPRSS2-Sare crucial and preciously mediated by specific residues. Structural stability, binding affinity and level of expression of these threeinteracting proteins are key susceptibility factors for COVID-19. Specific protein–protein interactions (PPI) are being identified thatexplains uniqueness of SARS-CoV-2 infection. Amino acid substitutions due to naturally occurring genetic polymorphisms potentially alterthese PPIs and poses further clinical heterogeneity of COVID-19. Repurposing of several phytochemicals and approved drugs againstACE2, TMPRSS2 and S-protein have been proposed that could inhibit PPI between them. We have also identified some novel leadphytochemicals present in Azadirachta indica and Aloe barbadensis which could be utilized for further in vitro and in vivo anti-COVID-19drug discovery. Uncovering details of ACE2-S and TMPRSS2-S interactions would further contribute to future research on COVID-19.

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