ACE2 diversity in placental mammals reveals the evolutionary strategy of SARS-CoV-2

Abstract

The recent emergence of SARS-CoV-2 is responsible for the current pandemic of COVID-19, which uses the human membrane protein ACE2 as a gateway to host-cell infection. We performed a comparative genomic analysis of 70 ACE2 placental mammal orthologues to identify variations and contribute to the understanding of evolutionary dynamics behind this successful adaptation to infect humans. Our results reveal that 4% of the ACE2 sites are under positive selection, all located in the catalytic domain, suggesting possibly taxon-specific adaptations related to the ACE2 function, such as cardiovascular physiology. Considering all variable sites, we selected 30 of them located at the critical ACE2 binding sites to the SARS-CoV-like viruses for analysis in more detail. Our results reveal a relatively high diversity of ACE2 between placental mammal species, while showing no polymorphism within human populations, at least considering the 30 inter-species variable sites. A perfect scenario for natural selection favored this opportunistic new coronavirus in its trajectory of infecting humans. We suggest that SARS-CoV-2 became a specialist coronavirus for human hosts. Differences in the rate of infection and mortality could be related to the innate immune responses, other unknown genetic factors, as well as non-biological factors.

COVID-19 susceptibility: potential of ACE2 polymorphisms

“…These facts highlight the importance of SNP variation within the identified crucial binding sites [27,41] and at amino acid residues responsible for either TMPR SS2-or ADAM17-mediated proteolysis of ACE2 [35]. This idea gets support from other studies also where change in key amino acids responsible for interaction is considered crucial for cross-species infections, multihost infection, and differences in disease susceptibility [17]. Screening of these sites along with promoter regions in different populations can result in identification of novel SNPs that might affect susceptibility to SARS infection (Fig.…”

“…Additionally, same sites were also studied for intraspecific variation in humans. These sites were highly conserved within Homo sapiens and showed great variation among placental mammalian species [17]. Recent reports have hypothesized correlation between ACE2 levels and susceptibility to present infection.…”

“…Recent metagenomic study considered pangolins (Manis javanica) as possible intermediate host that might have acquired the SARS-CoV-2 virus from bats. This consideration was based on putative recombination signals between coronavirus of pangolin, bat, and human [17]. Dependence of this newly discovered virus on the ACE2 receptor to infect humans has again drawn the attention of entire scientific communities towards the binding mechanism of this receptor with viral protein which is considered as a critical step for the entry of the virus.…”

Assessing the SARS-CoV-2 threat to wildlife: Potential risk to a broad range of mammals

“…The RBD interacts specifically on a region termed receptor-binding-motif (RBM) with an ACE2, receptor for SARS-CoV. The ACE2 is formed by a domain and collectrin domain that are involved in the renin-angiotensin pathway, thereby regulating blood pressure (it is one of the most important volume regulator systems in vertebrates); in fact, ACE2 is subjected to selection pressure since deep physiological differences exist between vertebrates ( Fournier et al, 2012 , Li, 2013 , Fam et al, 2020 ). The ACE2 was originally characterized as receptor of SARS-CoV, and now has also been identified as receptor for SARS-CoV-2 ( Hoffmann et al, 2020 , Letko et al, 2020 , Ou et al, 2020 ).…”

“…Since there is a ACE2 great diversity among vertebrates, this positive selection is likely to be due to blood pressure physiology across vertebrate taxa. However, instead of this divergence among taxa, some convergence event is also noted, especially in some particular site of importance for SARS-CoV-2 recognition ( Fam et al, 2020 , Hajibabaei and Singer, 2020 ). At species level (humans), ACE2 is highly conserved, even when some amino acid sequence variations have been reported, nonetheless none of them are related with the sites of interaction between ACE2 and SARS-CoV-2 ( Cao et al, 2020 , Fam et al, 2020 ).…”