Genetic Variants of SARS-CoV-2—What Do They Mean?

Over the course of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, the clinical, scientific, and public health communities have had to respond to new viral genetic variants. Each one has triggered a flurry of media attention, a range of reactions from the scientific community, and calls from governments to either «stay calm» or pursue immediate countermeasures. While many scientists were initially skeptical about the significance of the D614G alteration, the emergence of the new «UK variant"—lineage B.1.1.7—has raised widespread concern. Understanding which variants are concerning, and why, requires an appreciation of virus evolution and the genomic epidemiology of SARS-CoV-2.

Mutations, Variants, and Spread

Mutations arise as a natural by-product of viral replication.¹ RNA viruses typically have higher mutation rates than DNA viruses. Coronaviruses, however, make fewer mutations than most RNA viruses because they encode an enzyme that corrects some of the errors made during replication. In most cases, the fate of a newly arising mutation is determined by natural selection. Those that confer a competitive advantage with respect to viral replication, transmission, or escape from immunity will increase in frequency, and those that reduce viral fitness tend to be culled from the population of circulating viruses. However, mutations can also increase and decrease in frequency due to chance events. For example, a «founder effect» occurs when a limited number of individual viruses establish a new population during transmission. The mutations present in the genomes of these viral ancestors will dominate the population regardless of their effects on viral fitness. This same interplay of natural selection and chance events shapes virus evolution within hosts, in communities, and across countries.

Although the terms mutation, variant, and strain are often used interchangeably in describing the epidemiology of SARS-CoV-2, the distinctions are important. Mutation refers to the actual change in sequence: D614G is an aspartic acid-to-glycine substitution at position 614 of the spike glycoprotein. Genomes that differ in sequence are often called variants. This term is somewhat less precise because 2 variants can differ by 1 mutation or many. Strictly speaking, a variant is a strain when it has a demonstrably different phenotype (eg, a difference in antigenicity, transmissibility, or virulence).

Evaluation of a new SARS-CoV-2 variant should include assessment of the following questions: Did the variant achieve prominence through natural selection or chance events? If the evidence suggests natural selection, which mutation (s) are being selected? What is the adaptive benefit of these mutations? What effect do these mutations have on transmissibility and spread, antigenicity, or virulence?

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