Explaining Mutations and Variants
Blogger and Commenter Professor Joel Essenberg addresses Covid variants being called mutations.
As a geneticist, I am troubled by the promiscuous use of the word “mutation” to describe amino acid or nucleotide differences from a reference sequence. In nearly all cases, there is no known functional significance attached to these differences. Accordingly, the differences are best referred to as “variants,” not mutations.
I’ve had my genome sequenced and I have a variant call file based on that sequence. I know all the amino acid variants in my genome compared to the reference human genome And I’ve checked for variants associated with risk for disease (mutations); so far, none have been detected. But our ability to detect variants runs far ahead of our ability to assign significance to them (or alternatively, to confidently say they are neutral).
run75441: At this point I went back to Professor Joel Eissenberg asking him to explain the above paragraph.
Prof. Joel: I’m making an analogy between my genome and a COVID genome. Sequencing my own genome revealed many differences between my genes and the ‘human genome.’ Of course, I’m pretty normal, so most of these differences are probably not contributing to my health. So, I wouldn’t classify these differences as ‘mutations’ but just inconsequential variants.
Similarly, some, many or most of the differences in the spike protein that have been detected by sequencing Omicron virus could be inconsequential ‘variants’ and not ‘mutations’ in the sense that they change the virus behavior (infectiousness, ability to replicate, ability to evade vaccine antibodies). As it is, it is really fast and cheap to obtain COVID virus sequence information and to classify new variants, but it slower to determine which of the variants constitute ‘mutations’ or are inconsequential in terms of virus behavior in an epidemiological sense.”
There’s a lot of concern and chin scratching over the Omicron variant of COVID that was recently discovered in Africa:
“Dr. Dan Barouch, head of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center, said: ‘he was concerned because the new variant has 30 mutations, a large number, in the spike protein that the virus uses to infect human cells. His researchers first saw Omicron’s genetic sequence on Thanksgiving after South African scientists posted it online. The mutations are concentrated at a location on the virus that antibodies target, he said, which “raises the question as to whether the virus will still be covered by the vaccines.'”
At this point, most of these amino acid changes should be called variants, not mutations. We don’t yet know which, or how many, of these difference from the reference COVID spike protein sequence have functional significance. They might make the virus more infectious. They might make infection more severe. They might allow the virus to elude antibodies made to current vaccines. Time will tell. This is the best advice right now:
Dr. Ashish Jha, Dean of the Brown University School of Public Health, wrote on Twitter. “We’ll know more in coming days to weeks. There will be those who will spread fear ― and those who downplay it. Please ignore both groups.'”
Worrisome new COVID variant prompts travel restrictions from Africa – The Boston Globe (Account Required)
New ‘omicron’ variant prompts global travel restrictions | PBS NewsHour
Hmm. . . Well, seems to me the question relates to how we explain the origin of changes in the nucleotide sequence. It’s been many years since I took a genetics class but my recollection is that any change in the sequence of nucleotides, i.e. a novel sequence, is technically a mutation. Seems highly arbitrary to assign the word “mutant” to only nucleotide sequence changes that happen to render the virus more pathogenic.
I agree with the comment above, and was going to write the same thing. I’m a biologist, and the use of mutation to mean any change in the DNA sequence is very common. It seems to me that “variant” is used for the different forms of the virus (e.g., Delta variant, Omicron variant), while mutation is used to refer to positions in the DNA sequence at which differences occur. That’s how they are used in one of the quotes above: “the new variant has 30 mutations.” What has people concerned is that this is many more than other variants, so there is a higher probability that one or more will be significant.
@Mike,
“I’m a biologist, and the use of mutation to mean any change in the DNA sequence is very common. “
I’m a PhD geneticist and a medical school professor. You are right that this error is very common. It is a casual and informal usage, but imprecise and potentially misleading.
Variant virus is used to describe different forms of the virus. Variant alleles are used to describe different nucleotide changes in genes that may or may not result in variant amino acids. Variants that also result in a change in function qualify as mutants. Neutral variants are sometimes misleadingly called mutations, but to do so implies knowledge about a changed property of the gene in some environment.
What has people concerned is that some of these variants may be mutations that make the virus more infectious, more virulent or more resistant to vaccines.
I am a (partially trained, never employed as such) physicist, and admirer of Albert Einstein.
I am often troubled by the hoi polloi mixing up General & Special Relativity.
It troubles me less, somehow, that my poorly educated father was
quite sure that ‘hoi polloi’ meant ‘the upper class’. So be it.
(Also, same people misconstruing ‘Schrödinger’s cat’,
sure that it represents horrific animal-cruelty
in the physics community’)
The 1917 influenza petered out. Will this one, or will it be like polio, measles, … ?
The most plausible explanation for the dispersal of the new
variant (& its predecessors) is that infected people travel
worldwide before they are symptomatic, infecting those
around them as they go. If your area is not affected yet,
it (probably) will be soon. Get vaccinated or get a booster!
Omicron cases are discovered on flights into Amsterdam as scientists race to evaluate the new threat
Fred, there’s a bit more to that story:
Omicron is mild so far, South African health experts say
Joel, i am interpreting this post to mean that we should be calling these changes to the virus variants rather than mutations, much as in the way we would call Caucasians and Orientals variants of homo sapiens, not mutations of other races…
given that, how does a variant like Omicron suddenly develop with, and i’m paraphrasing, with “over 50 variations, with 32 on the virus’ spike protein”….ie, it’s difficult for me to conceive that i might one day wake up with 50 physical changes, without a lot of intermediate changes in between..
@rjs,
“we should be calling these changes to the virus variants rather than mutations, much as in the way we would call Caucasians and Orientals variants of homo sapiens, not mutations of other races…”
Yes, fair analogy.
“it’s difficult for me to conceive that i might one day wake up with 50 physical changes, without a lot of intermediate changes in between..”
If you were able to compare the genomic DNA sequence from one of your skin or white blood cells to the genomic DNA of you when you were a blastula, you might easily find more than 50 sequence differences. Of course, many rounds of DNA replication occurred between the time you were a blastula and the time those skin/blood cells appeared during your adulthood, and many errors in DNA replication occurred in each of those cell lineages during that time. The intermediates could have been found among cells in between those time periods.
A single virus doesn’t cause COVID, and many rounds of DNA replication occur in each subject between infection and transmission, with each round capable of creating a specific sequence variant. In the case of S. Africa, ca. 20% of citizens have HIV/AIDS, and if they are immunocompromised, many more rounds of viral replication can occur before the virus is cleared.
Hope this helps.
a little, Joel…what i am having trouble seeing is an original strain that is viable becoming a new strain that is also viable with over 50 differences from its parent….if we see many rounds of DNA changes in the subject between infection and transmission to get to the new strain with all those differences, what happened to the intermediate covid viruses that formed between the original and omicron? did they all die off because they were somehow unfit while their omicron offspring somehow ended up as the one variant that was more viable than the original?
i just have a hard time envisioning the process….& i’m not sure i’m even asking the right questions..
The most repeated hypothesis is that this variant likely came one infected person, possible HIV positive. Such an individual may keep many generations of virus going as their weak immune systems just cannot respond well enough to get rid of the infection, but also can survive without it killing them for a long time, much longer than in typical COVID cases. So there were likely many intermediate stages within the individual, but only omicron proved successful enough to propagate in wider population. Proof positive of this will be hard to find, however.
Eric:
Citation on the HIV-COVID carrying person please . . . This comment can incite people.
Sorry. I mess up every link I ever try. I need training. But you guys reference the blog Naked Capitalism, and pretty sure I’ve seen a couple regulars here over there. Anyway they had a review on Friday and another today. Like here, the comments provide a wealth of extra information. Southern Africa is kind of world’s top concentration of people living with HIV. It is not that HIV is associated with it, just that with HIV viruses can continue on in the body replicating longer. Proving it would be hard and not sure of the real utility of doing so.
Eric:
I did not reference anything. A commenter might have referenced something. You can quote them if you like. I suggest you read Joel’s comment.
@run,
“Scientists say that the unusual constellation of mutations suggests it may have emerged during a chronic infection of an immunocompromised person, such as an untreated HIV/Aids patient.”
https://www.theguardian.com/world/2021/nov/26/vaccine-resistant-what-scientists-know-new-covid-variant
Eric, in re ” I mess up every link I ever try. I need training.”
let me give that a shot…assuming to start with that you know how to copy and paste, you take the part of what you’ve written here that you want to link and drag over it as if you were going to copy it; then you hit the link shaped icon on the AB toolbar (second from the end) and a blank for inserting a link will appear…you paste your link into that blank and then hit the little arrow gadget, as i’ve just done with part of my text above, and your link should take, just as mine has above…
alternatively, you can hit the link icon first, past your link, and then hit the gear shaped icon that appears, which will give you a blank to paste or type text that you want linked into…then you hit the update button at yourand your link should take…
so give one of those methods a try and see how it works…if you’re still having trouble, or don’t know how to copy & paste, let me know & i’ll try to come up with a more complete explanation…
note that in the course of typing this, i’ve chosen to just link back to this post..
NB: the last sentence in the second last paragraph of my comment should read:
and one other thing you can do, Eric, if you want to link to a site such as Naked Capitalism, or any other site that hot links its own posts, is copy the text link right from that site and just paste it here…in the case of the post i believe you were referring to, you could copy that link directly from Naked Capitalism and paste it here without using the AB comment toolbar at all, ie:
Probable Vaccine-Escaping Covid Variant Sequenced in Gauteng, South Africa and Spreading Rapidly; Press Underplaying Downside Risk
@rjs,
You only see what you can measure. The 50 differences certainly didn’t occur simultaneously. It isn’t necessary that the intermediates all died out, just that they are less infectious/replicated less rapidly than the Omicron variant. Or they may have been so lethal that they killed everyone they infected, and only a milder form survived to proliferate.
Ultimately, we don’t know enough yet, and we may not ever know the entire pathway.