Genetic variation analyses indicate conserved SARS-CoV-2-host interaction and varied genetic adaptation in immune response factors in modern human evolution

Abstract

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a pandemic as of early 2020. Upon infection, SARS-CoV-2 attaches to its receptor, that is, angiotensin-converting enzyme 2 (ACE2), on the surface of host cells and is then internalized into host cells via enzymatic machineries. This subsequently stimulates immune response factors. Since the host immune response and severity of COVID-19 vary among individuals, genetic risk factors for severe COVID-19 cases have been investigated. Our research group recently conducted a survey of genetic variants among SARS-CoV-2-interacting molecules across populations, noting near absence of difference in allele frequency spectrum between populations in these genes. Recent genome-wide association studies have identified genetic risk factors for severe COVID-19 cases in a segment of chromosome 3 that involves six genes encoding three immune-regulatory chemokine receptors and another three molecules. The risk haplotype seemed to be inherited from Neanderthals, suggesting genetic adaptation against pathogens in modern human evolution. Therefore, SARS-CoV-2 uses highly conserved molecules as its virion interaction, whereas its immune response appears to be genetically biased in individuals to some extent. We herein review the molecular process of SARS-CoV-2 infection as well as our further survey of genetic variants of its related immune effectors. We also discuss aspects of modern human evolution.

Keywords: COVID-19; genetic variant; human evolution.

FIGURE 1

Proposed host immune responses to SARS‐CoV‐2. The spike (S) protein of virus binds to the ACE2 receptor in a host cell. Viral RNA is recognized by innate immune receptors, such as TLRs and the inflammasome sensor NLRP3. This process is involved in the activation of transcription factor NF‐κB and subsequent signals for proinflammatory cytokines (for example, IL‐6, CXCL10, etc.). Cytokines and chemokines released from infected cells regulate the adaptive immune response by recruiting immune cells, such as macrophages, T cells, and B cells, to eliminate the virus. A dysregulated immune response can lead to hyperinflammation, causing severe clinical symptoms of COVID‐19