Summary: Study reveals mutations of SARS-CoV-2, the virus that causes COVID-19, may not be a random process, but instead, humans are mutating it as part of a defense mechanism to degrade the virus. The findings may help in the creation of a vaccine for coronavirus.
Source: University of Bath
Scientists investigating the evolution of the virus that causes Covid19 say that its mutation seems to be directed by human proteins that degrade it, but natural selection of the virus enables it to bounce back. The findings could help in the design of vaccines against the virus.
All organisms mutate. You were for example born with between 10 and 100 new mutations in your DNA. Mutation is usually a random process often owing to mistakes made when DNA is copied. Recent work from researchers at the Universities of Bath and Edinburgh, suggests that in the case of SARS-CoV-2, mutation may well not be a random process and that instead humans are mutating it, as part of a defence mechanism to degrade the virus.
The team looked at over 15,000 virus genomes from all of the sequencing efforts around the world and identified over 6000 mutations. They looked at how much each of the four letters that make up the virus’ genetic code (A, C, U and G) were mutating and discovered that the virus had a very high rate of mutations generating U residues.
Senior author Professor Laurence Hurst, Director of the Milner Centre for Evolution at the University of Bath, said: “I have looked at mutational profiles for many organisms and they all show some sort of bias, but I’ve never seen one as strong and strange as this.”
In particular they found that mutation very commonly generated UU neighbouring pairs, mutating from the original sequence of CU and UC. They noted this is a fingerprint of the mutational profile of a human protein, called APOBEC, that can mutate viruses. Professor Hurst commented: “It looks like mutation isn’t random, but instead we are attacking the virus by mutating it.”
But what are these mutations doing to the virus? Are they helping or hindering it? Looking at the actual composition of the virus and by comparing between different sorts of sites within the virus they found evidence that natural selection – survival of the fittest – is allowing the virus to fight back against the mutational process.
From the mutational profile the team predicts, for example, that 65% of the residues should be a U and 40% should be UU pairs, but in practice U content is much lower and UU content is just about a quarter of that predicted.
Professor Hurst said: “This could be because the viruses that have too much U in them simply don’t survive well enough to reproduce. We estimate that for every 10 mutations that we see, there are another six we never get to see because those mutant viruses are too poor at propagating.”
And there are several reasons why this might be. U rich versions of the viruses’ genes the team found to be less stable and are seen at lower levels. Humans also have other proteins that attack sequences that are rich in U residues that might also force destruction of some versions of the virus.
These results suggest that we are attacking the virus to mutate it in a manner that degrades the virus. This also has implications for some vaccine designs. Several research groups are currently trying to make synthetic versions of the virus in a manner that enables the virus to be viable, but only just, so called attenuated viruses.
Professor Hurst said: “Knowing what selection favours and disfavours in the virus is really helpful in understanding what an attenuated version should look like.
“We suggest for example that increasing U content, as APOBEC does within our cells, would be a sensible strategy.”
About this coronavirus research article
University of Bath
Vicky Just – University of Bath
The image is in the public domain.
Original Research: Open access
“Evidence for strong mutation bias towards, and selection against, U content in SARS-CoV-2: implications for vaccine design”. by Rice et al. Molecular Biology and Evolution.
Evidence for strong mutation bias towards, and selection against, U content in SARS-CoV-2: implications for vaccine design
Large-scale re-engineering of synonymous sites is a promising strategy to generate vaccines either through synthesis of attenuated viruses or via codon optimized genes in DNA vaccines. Attenuation typically relies on de-optimisation of codon pairs and maximization of CpG dinucleotide frequencies. So as to formulate evolutionarily-informed attenuation strategies that aim to force nucleotide usage against the direction favoured by selection, here we examine available whole-genome sequences of SARS-CoV-2 to infer patterns of mutation and selection on synonymous sites. Analysis of mutational profiles indicates a strong mutation bias towards U. In turn, analysis of observed synonymous site composition implicates selection against U. Accounting for dinucleotide effects reinforces this conclusion, observed UU content being a quarter of that expected under neutrality. Possible mechanisms of selection against U mutations includes selection for higher expression, for high mRNA stability or lower immunogenicity of viral genes. Consistent with gene-specific selection against CpG dinucleotides, we observe systematic differences of CpG content between SARS-CoV-2 genes. We propose an evolutionarily-informed approach to attenuation that, unusually, seeks to increase usage of the already most common synonymous codons. Comparable analysis of H1N1 and Ebola finds that GC3 deviated from neutral equilibrium is not a universal feature, cautioning against generalization of results.