Tuesday, 30 June 2020

How easy is it for viruses to mutate?

It is a pleasure to be back, and believe me it hasn't been easy being away for so long. However, in all honesty, my absence wasn't result of my immediate choice. I have been flooded with work and the current world crisis didn't really help anyone. From having my children under my responsibility 24/7, plus all the extra work that results immediately from living, or better put, adapting to survive in a quarantined existence/lockdown-style, meets new thresholds that none of us had been exposed to before.

I have struggled to write a single line but I have struggled a lot more with reading the enormous idiotic and, sometimes, overtly ignorant information spread out in different platforms, covid-wise! I realised that for some questions the official sources out there are quite good, even though, and I remain with my personal view on it, numbers do no immediately add-up.

Information and counter-information got to such ludicrous levels of ignorant presumptuousness that I decided to educate myself directly form few selected sources and experts. But during my self informing I wasn't able to find an adequate simplified explanation that would respond to different aspects of all this covid-19 pandemics. One of such aspects emerged exactly whilst trying to understand how Italy, UK, Portugal and Spain met such different levels of infectiousness and lethality when presented to basically similar approaches and external/internal pressures/strategies. I just couldn't make sense of certain aspects but the one that caught me empty handed was hearing from a specialist in virology that the virus had just mutated from country to country. I can't easily recall who this person was or what organisation was he speaking from, but to be fair it is not my role to criticise these people, let alone try to play a role of key opinion leader on a matter I am not specialised at all. But because I am a curious person with a thirst for knowledge I researched further in order to try and understand how can that be feasible. How mutable is a viral strain? In even more simplified words....

How easy is it for viruses to mutate?

To be able to address this complex question with a simplified answer it is imperative to accurately estimate virus mutation rates, so then one can infer on the individual and particular evolution of the different object viruses. Only then applicable strategies can be designed to control spread, infectivity and foresee a plausible safe future ahead of any epidemic. That was the work of Sanjuan et al (2010) where different methods of estimation (that in their own nature are quite varied and usually fairly complex) were applied [1]. But how can one define mutation rate? Well, the authors defined it as substitutions per nucleotide per cell infection (s/n/c) (so to account for viability rather than just mutations with no biological meaning at all) and corrected for selection bias where applicable and deemed necessary. 

Their observations were quite impressive as the obtained rates stretched from from 10−8 to10−6 (in DNA viruses) and from 10−6 to 10−4 (in RNA viruses) supporting the classic idea of a negative correlation (meaning one decreases when the other increases, and vice-versa) between mutation rate and genome size among RNA viruses and also DNA viruses. In addition, [1] shows that nucleotide substitutions are on average 4 times more frequent than insertions of nucleotides and deletions of nucletotides in the 'viral genome', the usually called 'indels'. But another very useful public tool they came up with is the regularly updated (so they say) virus mutation rate data that one can find at the url: www.uv.es/rsanjuan/virmut [2] with the main objective of providing an easily available, organised and professional data set on viral mutation rates. Just for the sake of curiosity and example, I can tell you that corona virus, as expected, is not part of the studied viruses, and that HIV-1 has a mutation rate of 4.9E-5 (s/n/c) whereas Influenza A virus sits at 4.5E-5 (s/n/c) - both these values are mutation rates per cell infection.

It is easy to understand that not all mutations are biologically effective and significant and that lethality power can actually undermine the relevance of the virus because a virus with a deadly mutation to humans, basically kills rapidly the host on which the virus itself depends on (for viruses are not living beings, they are merely simple algorithms of genetic code that operate not knowing very well in what overall program do they actually integrate - that is how funny and scary viruses are!!!).  If they kill the host quickly, let's say even faster than Ebola kills, the virus would require an immediate host to progress with spreading infection... and in that sense its associated lethality can undermine it's biological success. To avoid disappearing, a virus should be very infectious and lesser lethal! That is my understanding.

But what about their mutation 'strategy'? Apparently there are several types of consequential mutation 'strategies' if we can exaggerate and affirm these things even have a subliminal plan. Basically pure evolutionary and external pressures and forces shape their 'swarming' but apparently, at least in what relates to HIV and Influenza, their mutation is linked to antigenic drift and antigenic shift. The former occurs with a change in aspect of the outer surface protein where the host won't be able to identify the virus, hence an insufficient defensive response takes place; and the latter is defined by 'fusion' of different types of the same virus merging and becoming a new very different type from its root strains - that will catch the host by surprise and their limited antibodies will not be able to cope with the new profile of viral infection [3] - the 2003 zoonotic H5N1 influenza A virus epidemic that infected humans is a good example, but luckily one with limited infectivity/lethality correlation!

The mutational capability and profiling of viruses is a world of knowledge. And not only time is limited but also your patience. So allow me to save these last two short paragraphs to discur on two straight points:

What other factors participate on the mutational rate of viruses? Population density where the highest density (overcrowding) will find successful jumps of viruses from one host to another, more rapidly and more effectively. Also, a virus with longer incubation times associated to what I had explained in the previous paragraphs, lesser pronounced lethality. This will even allow a zoonotic virus to live freely in migratory animals and spread happily to distant geographical points. Biologically clever, isn't it?! But in a nutshell, the best answer to how easy it is for viruses to mutate, can be found in the work of Sanjuan and Domingo-Calap (2016) [4] where the authors state that impressive capacity of some viral strains to adapt to new hosts and environments is strongly determined by their capacity to produce newer viral proteins in a short period of time. As the authors state, the present knowledge of viral mutation rates shows that "viral genetic diversity is determined by multiple virus- and host-dependent processes, and that viral mutation rates can evolve in response to specific selective pressures", as discussed above. Viral mutation rates are programmed and performed by means of polymerase fidelity inclusion, at sequence context, at template secondary structure, at cellular microenvironment, through replication mechanisms, during proofreading and/or during access to post-replicative repairing,  by means of virus-encoded diversity-generating elements or even by host-encoded cytidine/adenine deaminases [4]. 

What is the mutational rate of SARS-CoV-2? The jury is unfortunately still out there and so will be for a long time, but I suspect that a recent article by Tang et al (2020) [5] offers the best most up-to-date original information we have accomplished so far (though naturally limited, as you may well understand). They propose that SARS-CoV-2 can be classified in two major lineages (L and S) defined by just two tightly linked SNPs (single nucleotide polymorphisms) at positions 8,782 (orf1ab: T8517C, synonymous) and 28,144 (ORF8: C251T, S84L). Their mutational load analysis reports that "the L lineage had accumulated a significantly higher number of derived mutations than S lineage". Moreover, they also found merely 4% variability in genomic nucleotides between SARS-CoV-2 and a used-for-reference "bat SARS-related coronavirus (SARSr-CoV; RaTG13)", and the identified "difference at neutral sites was 17%", pointing towards the idea that, as the result of different selective pressures, "the divergence between the two viruses is way larger than initially thought. 

[1] Sanjuan, R., Nebot. M. R., Chirico, N., Mansky, L. M., Belshaw, R. (2010). "Viral Mutation Rates". Journal of Virology, 84(19), pp. 9733-9748.

[2] Viral Mutation Rates, Institute for Integrative Systems Biology (I2SysBio), [https://www.uv.es/rsanjuan/virmut], last access on 29th of June 2020, last updated on 2010.

[3] Viruses and Evolution, The History of Vaccines - An Educational Resource by the Colleage of Physicians of Philadelphia, [https://www.historyofvaccines.org/content/articles/viruses-and-evolution], last accessed on 29th of June 2020, last updated on the 10th of January 2018.

[4] Sanjuan, R., Domingo-Calap, P. (2016). "Mechanisms of viral mutation". Cell Mol Life Sci, 73(23), , pp. 4433-4448.

[5] Tang, X., Wu, C., Li, X. et al (2020). "On the origin and continuing evolution of SARS-CoV-2". Natural Science Review, 7(6), pp. 1012-1023.

Post photo by CDC on Unsplash.

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