Impact of Genetic Variability in ACE2 Expression on the Evolutionary Dynamics of SARS-CoV-2 Spike D614G Mutation

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) glycoprotein D614G mutation became the predominant globally circulating variant after its emergence in the early coronavirus disease 2019 (COVID-19) pandemic. Studies showed that this mutation results in an open conformation of the S glycoprotein receptor-binding domain (RBD), and increased angiotensin 1-converting enzyme 2 (ACE2) binding and fusion, which result in an increase in SARS-CoV-2 transmissibility and infectivity. Dynamic tracking of SARS-CoV-2 showed that the D614G variant became predominant after emergence in Europe and North America, but not in China. The current absence of selective pressures from antiviral treatment suggests that the driving force for viral evolution could be variations in human population genetics. Results show that ACE2 expression is higher in Asian populations than that in European, North American, and African populations. This supports the idea that lower ACE2 expression is a driving force in the positive selection for the D614G mutation. This study suggests that the dynamics of the SARS-CoV-2 D614G mutation during the early-to-mid pandemic is associated with enhanced transmission efficiency in populations with lower ACE2 expression. Understanding the role that human genetic diversity plays in the adaptive evolution of SARS-CoV-2 may have an important impact on public health and measures to control the pandemic.

Keywords: ACE2; D 614G; SARS-CoV-2; evolution; genetic variation; spike.

Figure 1

Transition of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) glycoprotein D614 to G614 variant in different geographic regions. (A) Weekly ratio of D614 and G614 variants globally, and in China, Europe, North America, South Asia, and Africa. Data analyzed from COVID-19 Viral Genome Analysis Pipeline (https://cov.lanl.gov/). (B) Angiotensin 1-converting enzyme 2 (ACE2) expression level in different geographical regions. ACE2 expression score analyzed by 21 ACE2 genetic polymorphisms that significantly affect its expression level according to the current study [18]. (C) Pearson’s correlation coefficient (r) and p value between ACE2 expression score and prevalence of D614 variants in different geographical regions.

Figure 2

Genetic variability in ACE2 expression as potential driving force for presence of D614G mutation in SARS-CoV-2 S glycoprotein.