First comprehensive computational analysis of functional consequences of TMPRSS2 SNPs in susceptibility to SARS-CoV-2 among different populations

Abstract

To cite this article: Alireza Paniri, Mohammad Mahdi Hosseini & Haleh Akhavan-Niaki (2020): First comprehensive computational analysis of functional consequences of TMPRSS2 SNPs in susceptibility to SARS-CoV-2 among different populations, Journal of Biomolecular Structure and Dynamics, ABSTRACT Current SARS-CoV-2 pandemy mortality created the hypothesis that some populations may be more susceptible to SARS-CoV-2. TMPRSS2 encodes a transmembrane serine protease which plays a crucial role in SARS-CoV-2 cell entry. Single nucleotide polymorphisms (SNPs) in TMPRSS2 might influence SARS-CoV2 entry into the cell. This study aimed to investigate the impact of SNPs on TMPRSS2 function and structure. In silico tools such as Ensembl, Gtex, ExPASY 2, GEPIA, CCLE, KEGG and GO were engaged to characterize TMPRSS2 and its expression profile. The functional effects of SNPs were analyzed by PolyPhen-2, PROVEN, SNAP2, SIFT and HSF. Also, Phyre2, GOR IV and PSIPRED were used to predict the secondary structure of TMPRSS2. Moreover, post-translational modification (PTM) and secretory properties were analyzed through Modpredand Phobius, respectively. Finally, miRNA profiles were investigated by PolymiRTS and miRSNPs. Out of 11,184 retrieved SNPs from dbSNP, 92 showed a different frequency between Asians and other populations. Only 21 SNPs affected the function and structure of TMPRSS2 by influencing the protein folding, PTM, splicing and miRNA function. Particularly, rs12329760 may create a de novo pocket protein. rs875393 can create a donor site, silencer and broken enhancer motifs. rs12627374 affects a wide spectrum of miRNAs profile. This study highlighted the role of TMPRSS2 SNPs and epigenetic mechanisms especially non-coding RNAs in appearance of different susceptibility to SARS-CoV-2 among different populations. Also, this study could pave the way to potential therapeutic implication of TMPRSS2 in designing antiviral drugs. ARTICLE HISTORY

Ethnicity-dependent allele frequencies are correlated with COVID-19 case fatality rate

“…In line with previous reports, we suggest that V197M acts to indirectly compromise the binding a nity of TMPRSS2 to SARS-CoV-2 spike protein and ACE2 [35][36][37] . This implies a protective role of the V197M variant against SARS-CoV-2 infections, but neither we nor previous researchers [36][37][38] have uncovered any clear evidence or explanation for causation. Interestingly, the change from valine to methionine has a Grantham distance matrix value of only 22, the shortest distance from valine to any amino acid.…”

Correlation of the two most frequent HLA haplotypes in the Italian population to the differential regional incidence of Covid-19

“…Genetic polymorphisms of key genes of the virus entry machinery (Ace2, Tmprss2, CtsB, and CtsL) or of the inflammatory/immune response (e.g. cytokines and their receptors) or epigenetic mechanisms may influence virus susceptibility and the severity/ outcome of the infection among different individuals and populations, too [42,43]. A novel susceptibility locus containing a cluster of six genes (SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6, and XCR1) on chromosome 3p21.31, most of whose involved in the regulation of inflammatory and immune response, has been indeed found [41].…”

Correlation of the two most frequent HLA haplotypes in the Italian population to the differential regional incidence of Covid-19

“…Genetic polymorphisms of key genes of the virus entry machinery (Ace2, Tmprss2, CtsB, and CtsL) or of the in ammatory/immune response (e.g. cytokines and their receptors) or epigenetic mechanisms may in uence virus susceptibility and the severity/outcome of the infection among different individuals and populations, too [38,39].…”