A survey of genetic variants in SARS-CoV-2 interacting domains of ACE2, TMPRSS2 and TLR3/7/8 across populations

Abstract

The COVID-19 pandemic highlighted healthcare disparities in multiple countries. As such morbidity and mortality vary significantly around the globe between populations and ethnic groups. Underlying medical conditions and environmental factors contribute higher incidence in some populations and a genetic predisposition may play a role for severe cases with respiratory failure. Here we investigated whether genetic variation in the key genes for viral entry to host cells-ACE2 and TMPRSS2-and sensing of viral genomic RNAs (i.e., TLR3/7/8) could explain the variation in incidence across diverse ethnic groups. Overall, these genes are under strong selection pressure and have very few nonsynonymous variants in all populations. Genetic determinant for the binding affinity between SARS-CoV-2 and ACE2 does not show significant difference between populations. Non-genetic factors are likely to contribute differential population characteristics affected by COVID-19. Nonetheless, a systematic mutagenesis study on the receptor binding domain of ACE2 is required to understand the difference in host-viral interaction across populations.

Keywords: ACE2; COVID-19; Genetic variant; SARS-CoV-2; TLRs; TMPRSS2.

Fig. 1

Location of genetic variants relative to known functional domains of (A) ACE2, (B) CTLB/L and (C) TLR3/7/8. For each gene, x-axis represents positions in protein sequence. The block diagram directly above the x-axis depicts major protein domains in different colored boxes. The vertical red lines above domains correspond to the critical residues investigated in this study. Each of the circles with grey lines represents variant found on the critical loci. The circles are colored differently based on their calculated effect on protein: loss-of-function (LoF) variants (red), missense variants (orange), and synonymous variants (green). The height of each circle denotes variant allele frequency (in -log10 scale). The higher the circle, the lower the allele frequency. Of note, TMPRSS2 does not have any reported genetic variant in enzymatically active functional domain. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)