Graham Jones

• PhD
• Researcher at University of Gothenburg

I have experience in phylogenetic analysis, but not virology. I would like to develop a substitution model for the mutations that occur in SARS-CoV-2, and would like feedback from virologists. A substitution model provides values for the 12 mutation rates A->C, A->G, ..., T->G at a particular site. There are lots of substitution models used in phylogenetic analysis, from the simplest Jukes-Cantor model, which says all 12 rates are equal, to one with 12 individual rates, and more complicated ones still, which take into account neighbouring nucleotides.

Here are some observed values:

A C G T

A - 52 308 68

C 58 - 18 1098

G 255 46 - 437

T 56 327 52 -

(Fig 6 of http://virological.org/t/issues-with-sars-cov-2-sequencing-data/473)

These may be mutations produced by the virus, or by host editing, and there are sequencing errors which can confuse matters. Note the large number of C->Ts and G->Ts, and high C->T/G->A and G->T/C->A ratios.

Please correct me if I am wrong, but this is how I understand the mechanisms within a cell:

Virus-mediated mutations. If the polymerase mismatches a pair like G:T instead of G:C, at a certain rate, it will do this when copying positive sense to negative sense, and negative to positive, at the same rate. (If not, why not?) Every virus genome that exits a cell must be the result of an equal number of positive-to-negative and negative-to-positive copies. This implies a symmetry among the rates like this:

A->C ~= T->G

A->G ~= T->C

A->T ~= T->A

C->A ~= G->T

C->G ~= G->C

C->T ~= G->A

For example,

C mispaired with A, A correctly paired with T produces a C->T.

G correctly paired with C, C mispaired with A produces a G->A.

Host-mediated mutations. (See refs below.) These do not have to obey the above symmetry, if they act preferentially on positive or negative sense RNA. The APOBEC proteins can cause a C->T mutations, but that would produce as many G->A mutations as C->T mutations if it acted on positive or negative sense RNA equally. So it seems it must mainly act on positive sense RNA. What would be the most likely reason for this? (I can think of various ideas, but don't know how plausible they are.)

Are there any known mechanisms (virus or host) which can produce more G->T mutations than C->A mutations?

RG project:

References:

The divergence between SARS-CoV-2 and RaTG13 might be overestimated due to the extensive RNA modification,

Yue Li, Xinai Yang, Na Wang, Haiyan Wang, Bin Yin, Xiaoping Yang& Wenqing Jiang.

Evidence for host-dependent RNA editing in the transcriptome of SARS-CoV-2,

Salvatore Di Giorgio, Filippo Martignano, Maria Gabriella Torcia, Giorgio Mattiuz, Silvestro G. Conticello.

Evidence for strong mutation bias towards, and selection against, T/U content in SARS-CoV2: implications for attenuated vaccine design,

Alan M Rice, Atahualpa Castillo Morales, Alexander T Ho, Christine Mordstein, Stefanie Mühlhausen, Samir Watson, Laura Cano, Bethan Young, Grzegorz Kudla, Laurence D. Hurst.

Rampant C to U hypermutation in the genomes of SARS-CoV-2 and other coronaviruses – causes and consequences for their short and long evolutionary trajectories,

Peter Simmonds.