Feature SOURCE: STRUCTURAL DATA FROM K. SHEN & J. LUBAN K. SHEN FROM DATA STRUCTURAL SOURCE: The spike protein of SARS-CoV-2 has a common mutation (circled) that seems to shift the protein from a closed (left) to an open (right) form. MAKING SENSE OF CORONAVIRUS MUTATIONS Different SARS-CoV-2 strains haven’t yet had a major impact on the course of the pandemic — but they might in future. By Ewen Callaway hen COVID-19 spread around started scouring thousands of coronavirus In April, Korber, Montefiori and others the globe this year, David genetic sequences for mutations that might warned in a preprint posted to the bioRxiv Montefiori wondered how the have changed the virus’s properties as it made server that “D614G is increasing in frequency deadly virus behind the pan- its way around the world. at an alarming rate”1. It had rapidly become demic might be changing as it Compared with HIV, SARS-CoV-2 is chang- the dominant SARS-CoV-2 lineage in Europe passed from person to person. ing much more slowly as it spreads. But one and had then taken hold in the United States, Montefiori is a virologist who mutation stood out to Korber. It was in the Canada and Australia. D614G represented a has spent much of his career gene encoding the spike protein, which helps “more transmissible form of SARS-CoV-2”, Wstudying how chance mutations in HIV help it virus particles to penetrate cells. Korber saw the paper declared, one that had emerged as to evade the immune system. The same thing the mutation appearing again and again in a product of natural selection. might happen with SARS-CoV-2, he thought. samples from people with COVID-19. At the These assertions dismayed many scientists. In March, Montefiori, who directs an 614th amino-acid position of the spike pro- It wasn’t clear that the D614G viral lineage was AIDS-vaccine research laboratory at Duke tein, the amino acid aspartate (D, in biochem- more transmissible, or that its rise indicated University in Durham, North Carolina, con- ical shorthand) was regularly being replaced anything unusual, they said. But alarm spread tacted Bette Korber, an expert in HIV evolution by glycine (G) because of a copying fault fast across the media. Although many news and a long-time collaborator. Korber, a compu- that altered a single nucleotide in the virus’s stories included researchers’ caveats, some tational biologist at the Los Alamos National 29,903-letter RNA code. Virologists were call- headlines declared that the virus was mutat- Laboratory (LANL) in New Mexico, had already ing it the D614G mutation. ing to become more dangerous. In retrospect, 174 | Nature | Vol 585 | 10 September 2020 | Corrected 16 September ©2020 Spri nger Nature Li mited. All rights reserved. ©2020 Spri nger Nature Li mited. All rights reserved. 2 mm Montefiori says he and his colleagues regret GLOBAL SPREAD even potentially beneficial mutations might describing the variant’s rise as “alarming”. The By the end of June, the D614G mutation was found not flourish. “As far as the virus is concerned, word was scrubbed from the peer-reviewed in almost all SARS-CoV-2 samples worldwide. every single person that it comes to is a good 2 3 mm version of the paper, published in Cell in July . 1.0 piece of meat,” says William Hanage, an epi- The work sparked a frenzy of interest in demiologist at the Harvard T. H. Chan School 3 mm D614G. Even those who were sceptical that of Public Health in Boston, Massachusetts. 0.8 the mutation had changed the virus’s prop- “There’s no selection to be doing it any better.” erties agreed that it was intriguing, because of its meteoric rise and ubiquity. For months, 0.6 Faster spread? that lineage has been found in almost all When Korber saw the rapid spread of D614G, sequenced samples of SARS-CoV-2 (see ‘Global she thought she might have found an example 0.4 spread’). “This variant now is the pandemic. of meaningful natural selection. The muta- As a result, its properties matter,” wrote of D614G* Frequency tion caught her eye because of its position in Nathan Grubaugh, a viral epidemiologist at 0.2 the spike protein, which is a major target for the Yale School of Public Health in New Haven, ‘neutralizing’ antibodies that bind to the virus Connecticut, and two colleagues in a Cell essay and render it non-infectious. And viruses with 3 0 on Korber and Montefiori’s findings . Jan Feb Mar Apr May Jun the mutation were also rising in frequency in So far, the upshot of this work is less clear 2020 more than one part of the world. *Number of samples = 52,292 SOURCE: REF. 8 REF. SOURCE: than Montefiori and Korber’s preprint sug- D614G was first spotted in viruses collected gested. Some experiments suggest that mistakes. A typical SARS-CoV-2 virus accu- in China and Germany in late January; most viruses carrying the variant infect cells more mulates only two single-letter mutations per scientists suspect the mutation arose in China. easily. Other work has revealed possible good month in its genome — a rate of change about It’s now almost always accompanied by three news: the variant might mean that vaccines half that of influenza and one-quarter that of mutations in other parts of the SARS-CoV-2 can target SARS-CoV-2 more easily. But many HIV, says Emma Hodcroft, a molecular epidemi- genome — possible evidence that most D614G scientists say there remains no solid proof that ologist at the University of Basel, Switzerland. viruses share a common ancestor. D614G has a significant effect on the spread of Other genome data have emphasized D614G’s rapid rise in Europe drew Korber’s the virus, or that a process of natural selection this stability — more than 90,000 isolates attention. Before March — when much of the explains its rise. “The jury’s out,” says Timothy have been sequenced and made public (see continent went into lockdown — both unmu- Sheahan, a coronavirologist at the University www.gisaid.org). Two SARS-CoV-2 viruses tated ‘D’ viruses and mutated ‘G’ viruses were of North Carolina at Chapel Hill. “This muta- collected from anywhere in the world differ by present, with D viruses prevalent in most of tion might mean something, or it might not.” an average of just 10 RNA letters out of 29,903, the western European countries that geneti- Researchers still have more questions says Lucy Van Dorp, a computational geneticist cists sampled at the time. In March, G viruses than answers about coronavirus mutations, at University College London, who is tracking rose in frequency across the continent, and by and no one has yet found any change in the differences for signs that they confer an April they were dominant, reported Korber, SARS-CoV-2 that should raise public-health evolutionary advantage. Montefiori and their team1,2. concerns, Sheahan, Grubaugh and others Despite the virus’s sluggish mutation rate, But natural selection in favour of G viruses say. But studying mutations in detail could researchers have catalogued more than 12,000 isn’t the only, or even the most likely, explana- be important for controlling the pandemic. mutations in SARS-CoV-2 genomes. But scien- tion for this pattern. The European dominance It might also help to pre-empt the most tists can spot mutations faster than they can of G variants could be simply down to chance worrying of mutations: those that could help — if, for instance, the mutation happened to the virus to evade immune systems, vaccines “This variant now is the be slightly more common in the viruses that or antibody therapies. arrived in Europe. A small number of indi- pandemic. As a result, its viduals seem to be responsible for most of Slow change properties matter.” the virus’s spread, and an early, chance tilt in Soon after SARS-CoV-2 was detected in China, favour of G viruses could explain the lineage’s researchers began analysing viral samples and apparent takeover now. Such ‘founder effects’ posting the genetic codes online. Mutations — make sense of them. Many mutations will are common in viruses, especially when they most of them single-letter alterations between have no consequence for the virus’s ability spread unchecked, as SARS-CoV-2 did in much viruses from different people — allowed to spread or cause disease, because they do of Europe until mid- to late March. researchers to track the spread by linking not alter the shape of a protein, whereas those Korber and her colleagues tried to rule out closely related viruses, and to estimate when mutations that do change proteins are more a founder effect, by showing in their April pre- SARS-CoV-2 started infecting humans. likely to harm the virus than improve it (see print1 that D614G rose to dominance quickly Viruses that encode their genome in RNA, ‘A catalogue of coronavirus mutations’). “It’s in Canada, Australia and parts of the United such as SARS-CoV-2, HIV and influenza, tend much easier to break something than it is to States (an exception was Iceland, where to pick up mutations quickly as they are cop- fix it,” says Hodcroft, who is part of Nextstrain G viruses present early in its outbreak were ied inside their hosts, because enzymes that (https://nextstrain.org), an effort to analyse overtaken by D viruses). Analysing hospitali- copy RNA are prone to making errors. After SARS-CoV-2 genomes in real time. zation data from Sheffield, UK, the team found the severe acute respiratory syndrome (SARS) Many researchers suspect that if a mutation no evidence that viruses carrying the mutation virus began circulating in humans, for instance, did help the virus to spread faster, it probably made people any sicker.