Positive selection within the genomes of SARS-CoV-2 and other Coronaviruses independent of impact on protein function

Alejandro Berrio,Valerie Gartner,Gregory A Wray

doi:10.7717/peerj.10234

Abstract

BackgroundThe emergence of a novel coronavirus (SARS-CoV-2) associated with severe acute respiratory disease (COVID-19) has prompted efforts to understand the genetic basis for its unique characteristics and its jump from non-primate hosts to humans. Tests for positive selection can identify apparently nonrandom patterns of mutation accumulation within genomes, highlighting regions where molecular function may have changed during the origin of a species. Several recent studies of the SARS-CoV-2 genome have identified signals of conservation and positive selection within the gene encoding Spike protein based on the ratio of synonymous to nonsynonymous substitution. Such tests cannot, however, detect changes in the function of RNA molecules.MethodsHere we apply a test for branch-specific oversubstitution of mutations within narrow windows of the genome without reference to the genetic code.ResultsWe recapitulate the finding that the gene encoding Spike protein has been a target of both purifying and positive selection. In addition, we find other likely targets of positive selection within the genome of SARS-CoV-2, specifically within the genes encoding Nsp4 and Nsp16. Homology-directed modeling indicates no change in either Nsp4 or Nsp16 protein structure relative to the most recent common ancestor. These SARS-CoV-2-specific mutations may affect molecular processes mediated by the positive or negative RNA molecules, including transcription, translation, RNA stability, and evasion of the host innate immune system. Our results highlight the importance of considering mutations in viral genomes not only from the perspective of their impact on protein structure, but also how they may impact other molecular processes critical to the viral life cycle.

Highlights

An important challenge in understanding zoonotic events is identifying the genetic changes that allow a pathogen to infect a new host
Formal tests for natural selection are a powerful tool in this endeavor because they can be applied in an unbiased manner throughout the viral genome: evidence of negative selection can reveal regions of the genome that are broadly constrained functionally and unlikely to contribute to species-specific traits, while evidence of branchspecific positive selection can identify candidate regions of the genome where molecular processes may have diverged from that of other species
The results reveal several signals of positive selection that are unique to a single species and others that are recapitulated in multiple species

Summary

Introduction

An important challenge in understanding zoonotic events is identifying the genetic changes that allow a pathogen to infect a new host. The most prominent signal to emerge from these studies is a mix of positive and purifying selection within the gene encoding the Spike glycoprotein, which mediates invasion of host cells by binding to the angiotensin-converting enzyme 2 (ACE2) receptor in host cells (Gallagher & Buchmeier, 2001; Tortorici & Veesler, 2019) This finding makes good biological sense, because structural changes in the spike protein are common and are known to influence the ability of the virus to infect new hosts and jump between species (Hulswit, de Haan & Bosch, 2016). Several recent studies of the SARS-CoV-2 genome have identified signals of conservation and positive selection within the gene encoding Spike protein based on the ratio of synonymous to nonsynonymous substitution Such tests cannot, detect changes in the function of RNA molecules

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