Understanding omicron’s many mutations

The virus’s spikes have far more changes than we’ve seen in any previous variant, and researchers are racing to figure out how they affect it — and us

Number of mutations identified in each variant’s

spike, date of earliest documented sample

BETA

ALPHA

DELTA

GAMMA

May 2020

Sept. 2020

Oct. 2020

NOV. 2020

11

10

9

12

OMICRON

Nov. 2021

36

BETA

ALPHA

DELTA

GAMMA

May 2020

Sept. 2020

Oct. 2020

NOV. 2020

11

10

9

12

OMICRON

Nov. 2021

36

Number of mutations identified in each variant’s

spike, date of earliest documented sample

BETA

ALPHA

DELTA

GAMMA

OMICRON

May 2020

Sept. 2020

Oct. 2020

NOV. 2020

Nov. 2021

11

10

9

12

36

Number of mutations identified in each variant’s

spike, date of earliest documented sample

BETA

ALPHA

DELTA

GAMMA

OMICRON

May 2020

Sept. 2020

Oct. 2020

Nov. 2020

Nov. 2021

11

10

9

12

36

Number of mutations identified in each variant’s spike, date of earliest documented sample

BETA

ALPHA

DELTA

GAMMA

OMICRON

May 2020

Sept. 2020

Oct. 2020

Nov. 2020

Nov. 2021

11

10

9

12

36

Number of mutations identified in each variant’s spike, date of earliest documented sample

BETA

ALPHA

DELTA

GAMMA

OMICRON

May 2020

Sept. 2020

Oct. 2020

Nov. 2020

Nov. 2021

11

10

9

12

36

Number of mutations identified in each variant’s spike, date of earliest documented sample

The omicron variant of the coronavirus has about 50 genetic mutations, and a whopping 36 of them are in the all-important spike. That is the part that lets the virus attach to human cells and worm its way inside.

Those spikes play a critical role in the biggest unknowns about this new variant: How easily will omicron pass from person to person? How sick will it make us? And how well will our vaccines and immune systems protect us from it?

Scientists are just beginning to untangle omicron’s mysteries, but the locations of mutations in key parts of the spike provide some clues.

A look at the spike

Every spike on a coronavirus’s surface is made of three identical proteins twisted together, making it look a little like a head of broccoli with three stalks.

Each stalk has three vital regions — the receptor binding domain (RBD), the N-terminal domain (NTD) and the furin cleavage site (FCS) — and most of omicron’s mutations are in these three areas.

ORIGINAL

SPIKE

GENOME

(N-Terminal

domain)

NTD

RBD

RBD

RBD

(Receptor

binding

domain)

RBD

NTD

NTD

NTD

FCS

(Furin cleavage site)

Spike

sequence

of genome

Spike

structure

SARS-CoV-2

SARS-CoV-2

genome

The genetic code of the spike takes up a small portion of the virus’s full genome — about 1,270 of its roughly 10,000 coded amino acids. Each part of the spike’s structure is created using a specific section of code.

Mutations are changes to amino acids within the genome. If mutations change the virus enough, it becomes a new variant. D614G, an early mutation to the original strain, is now present in all the most concerning variants.

Magnified view

mutation D614G

A mutation is identified by its position in the genetic code and the amino acids that were switched there. In this case, aspartic acid (D) was swapped for glycine (G) at position 614.

D614G

ALPHA

BETA

GAMMA

DELTA

OMICRON

ALPHA

SPIKE

GENOME

NTD

RBD

NTD

RBD

FCS

Omicron mutations shard with other variants

ORIGINAL

SPIKE

GENOME

(N-Terminal

domain)

NTD

RBD

RBD

RBD

RBD

(Receptor

binding

domain)

NTD

NTD

NTD

FCS

(Furin

cleavage

site)

Spike

sequence

of genome

Spike

structure

SARS-CoV-2

SARS-CoV-2

genome

The genetic code of the spike takes up a small portion of the virus’s full genome — about 1,270 of its roughly 10,000 coded amino acids. Each part of the spike’s structure is created using a specific section of code.

Mutations are changes to amino acids within the genome. If mutations change the virus enough, it becomes a new variant. D614G, an early mutation to the original strain, is now present in all the most concerning variants.

Magnified view mutation D614G

A mutation is identified by its position in the genetic code and the amino acids that were switched there. In this case, aspartic acid (D) was swapped for glycine (G) at position 614.

D614G

ALPHA

SPIKE

GENOME

ALPHA

BETA

GAMMA

DELTA

OMICRON

NTD

RBD

NTD

RBD

FCS

Omicron mutations shard with other variants

SARS-CoV-2

DETAIL

RBD

NTD

Spike structure

RBD

NTD

RBD

NTD

FCS

(Furin cleavage site)

The genetic code of the spike takes up a small portion of the virus’s full genome — about 1,270 of its roughly 10,000 coded amino acids. Each part of the spike’s structure is created using a specific section of code.

SARS-CoV-2 genome

Spike sequence of genome

ORIGINAL SPIKE GENOME

NTD

RBD

(N-Terminal

domain)

(Receptor binding

domain)

Magnified view

mutation D614G

A mutation is identified by its position in the genetic code and the amino acids that were switched there. In this case, aspartic acid (D) was swapped for glycine (G) at position 614.

Mutations are changes to amino acids within the genome. If mutations change the virus enough, it becomes a new variant. D614G, an early mutation to the original strain, is now present in all the most concerning variants.

D614G

ALPHA SPIKE GENOME

NTD

RBD

FCS

Vraiants

NTD

RBD

ALPHA

BETA

GAMMA

DELTA

OMICRON

Omicron mutations present in other variants

SARS-CoV-2

DETAIL

RBD

NTD

Spike structure

RBD

NTD

RBD

NTD

FCS

(Furin cleavage site)

The genetic code of the spike takes up a small portion of the virus’s full genome — about 1,270 of its roughly 10,000 coded amino acids. Each part of the spike’s structure is created using a specific section of code.

SARS-CoV-2 full genome

Spike sequence of genome

ORIGINAL SPIKE GENOME

NTD

RBD

(N-Terminal

domain)

(Receptor binding

domain)

Magnified view

mutation D614G

A mutation is identified by its position in the genetic code and the amino acids that were switched there. In this case, aspartic acid (D) was swapped for glycine (G) at position 614.

Mutations are changes to amino acids within the genome. If mutations change the virus enough, it becomes a new variant. D614G, an early mutation to the original strain, is now present in all the most concerning variants.

D614G

ALPHA SPIKE GENOME

NTD

RBD

FCS

Variants

NTD

RBD

ALPHA

BETA

GAMMA

DELTA

OMICRON

Omicron mutations present in other variants

SARS-CoV-2

DETAIL

RBD

NTD

Spike structure

RBD

NTD

RBD

NTD

FCS

(Furin cleavage site)

The genetic code of the spike takes up a small portion of the virus’s full genome — about 1,270 of its roughly 10,000 coded amino acids. Each part of the spike’s structure is created using a specific section of code.

SARS-CoV-2 genome

Spike sequence of genome

ORIGINAL SPIKE GENOME

NTD

RBD

(N-Terminal

domain)

(Receptor binding

domain)

Mutations are changes to amino acids within the genome. If mutations change the virus enough, it becomes a new variant. D614G, an early mutation to the original strain, is now present in all the most concerning variants.

Magnified view mutation D614G

A mutation is identified by its position in the genetic code and the amino acids that were switched there. In this case, aspartic acid (D) was swapped for glycine (G) at position 614.

D614G

ALPHA SPIKE GENOME

NTD

RBD

FCS

Variants

NTD

RBD

ALPHA

BETA

GAMMA

DELTA

OMICRON

Omicron mutations present in other variants

SARS-CoV-2

DETAIL

RBD

NTD

Spike structure

RBD

NTD

RBD

NTD

FCS

(Furin cleavage site)

The spike’s genomic sequence takes up a small portion of the virus’s full genome — about 1,270 of its 10,000 coded amino acids. Each part of the spike’s structure is created using a specific section of code.

SARS-CoV-2 genome

Spike sequence of genome

ORIGINAL SPIKE GENOME

NTD

RBD

(N-Terminal

domain)

(Receptor binding

domain)

Mutations are changes to amino acids within the genome. If mutations change the virus enough, it becomes a new variant. D614G, an early mutation to the original strain, is now present in all the most concerning variants.

Magnified view mutation D614G

A mutation is identified by its position in the genetic code and the amino acids that were switched there. In this case, aspartic acid (D) was swapped for glycine (G) at position 614.

D614G

ALPHA SPIKE GENOME

NTD

RBD

FCS

Variants

NTD

RBD

ALPHA

BETA

GAMMA

DELTA

OMICRON

Omicron mutations present in other variants

A key to transmissibility: the receptor binding domain

Receptor binding domain

Omicron

mutations

Receptor binding domain

Omicron

mutations

Receptor binding domain

Omicron mutations

Amino acids in this area attach to a cell’s receptor like a key in a lock, opening the cell so the virus can enter.

When scientists first peered at omicron’s genetic code, they knew that some of the 15 mutations in this area of the spike would make the virus’s connection to the cell stronger, and they feared that others might strengthen it even more. A tightened connection would allow omicron to spread more easily than its predecessors.

Early data bears that out: Omicron is rapidly spreading in many places, and various models indicate that it may be two to three times more transmissible than the delta variant, which continues to surge through the United States and much of the world.

“There’s no question that this will be more transmissible than delta,” said Mark Zeller, a staff scientist at Scripps Research whose team sequences viruses.

Part of the problem is that in addition to being the location where the virus binds to cells, the domain is ground zero in our immune system’s attack on the virus.

Specialized fighting forces called neutralizing antibodies try to latch on here to block the spike from attaching to cell receptors. (Monoclonal antibody treatments are an example of neutralizing antibodies.)

Those antibodies developed to attack the spikes of a previous version of the virus, which were largely similar to each other. Antibodies may find it more difficult to attach to the vastly different omicron spike.

Early studies suggest omicron is formidable — but not unstoppable

Notable mutations in this area

ALPHA

BETA

GAMMA

DELTA

OMICRON

NTD

RBD

E484K

E484A

N501Y

FCS

ALPHA

BETA

GAMMA

DELTA

OMICRON

NTD

RBD

E484K

E484A

N501Y

FCS

NTD

FCS

E484K

RBD

ALPHA

BETA

GAMMA

DELTA

OMICRON

E484A

N501Y

FCS

NTD

RBD

E484K

ALPHA

BETA

GAMMA

DELTA

OMICRON

E484A

N501Y

If the receptor binding domain were a catcher’s mitt, 10 mutations are right in the pocket. Amino acids in this sweet spot interact most directly with the cell’s receptors.

One of these mutations is N501Y, which omicron shares with the alpha, beta and gamma variants. It helps the virus cling more tightly to cell receptors and muscle out antibodies. How it will work in concert with omicron’s many new mutations around it is not yet known.

Beta and gamma share the E484K mutation, which appears to thwart certain neutralizing antibodies by changing the shape of their target. Omicron has a different amino acid in that spot, and it has changed other immune system targets as well. So the question is whether, and how well, antibodies will still recognize the enemy. Fortunately, at least one type of monoclonal antibody called sotrovimab does not seem fooled by the new variant.

Omicron spreading rapidly in U.S., could bring punishing wave of infections, CDC warns

A key to immunity: the N-terminal domain

N-Terminal domain

Omicron

mutations

N-Terminal domain

Omicron

mutations

N-Terminal domain

Omicron mutations

Scientists are not sure exactly what this area’s function is, said Tulane microbiologist Robert F. Garry, an expert on the virus’s anatomy. It may help viruses attach to cells in some way.

But it is clear that antibodies — both the kind triggered by vaccines and the kind triggered by previous infection — target this area.

Notable mutations in this area

ALPHA

BETA

GAMMA

DELTA

OMICRON

H69, V70

deletion

NTD

RBD

FCS

ALPHA

BETA

GAMMA

DELTA

OMICRON

H69, V70

deletion

NTD

RBD

FCS

NTD

RBD

FCS

ALPHA

BETA

GAMMA

DELTA

OMICRON

H69, V70 deletion

FCS

NTD

RBD

ALPHA

BETA

GAMMA

DELTA

OMICRON

H69, V70 deletion

In omicron, the N-terminal domain has been extensively overhauled, said Zeller. Four amino acids were swapped out, six total were deleted from three locations and three new ones were added together in one spot.

Scientists suspect this extensive remodeling means antibodies will bind less efficiently, so they will be less effective at stopping the virus from infecting new cells.

The first lab study of omicron indicated that it may indeed evade quite a bit of antibody protection. Early data also shows that people who received boosters on top of full vaccination still remain largely protected from the most severe effects of covid, although it will vary greatly from person to person.

First lab results show omicron has ‘much more extensive escape’ from antibodies than previous variants

A key to severe illness: the furin cleavage site

Furin cleavage site

Omicron

mutations

Furin cleavage site

Omicron

mutations

Furin cleavage site

Omicron mutations

Once inside a cell, the coronavirus causes an infection by turning the cell’s machinery into a tiny factory that churns out new copies of the virus.

As new viruses leave the factory, the human enzyme furin acts like a trigger, activating them by snipping their spikes as they head out the door. The place on the spike’s stalk where that snip occurs is called the furin cleavage site.

What happens after that snip is complicated and involves the loose ends helping to fuse cell membranes together. But the upshot is that the virus is able to slip more easily from one cell to the next without exposing itself to antibodies.

Not all viruses have furin cleavage sites, but ones that do can often spread more easily into a wider range of tissues, Garry said. It is probably one of the major reasons SARS-CoV-2, the virus that causes covid, is able to penetrate so deeply into the lungs and make some people extremely sick.

Notable mutations in this area

ALPHA

BETA

GAMMA

DELTA

OMICRON

NTD

RBD

H655Y, N679K, and P681H

FCS

ALPHA

BETA

GAMMA

DELTA

OMICRON

NTD

RBD

H655Y, N679K, and P681H

FCS

NTD

RBD

FCS

ALPHA

BETA

GAMMA

DELTA

OMICRON

H655Y, N679K, and P681H

FCS

NTD

RBD

ALPHA

BETA

GAMMA

DELTA

OMICRON

H655Y, N679K, and P681H

A cluster of mutations near the furin cleavage site may let omicron more easily slide into cells.

Garry said alpha beefed up its site over the original virus’s, and delta’s site is better than alpha’s. Many studies have pegged the mutation at position 681 as a reason delta spreads so efficiently.

Omicron’s mutation at that position is identical to alpha’s, not delta’s, which would appear to be a step backward. However, omicron has two unique mutations nearby. No one knows whether the combination of the three will make omicron’s site better, worse, or about the same as delta’s.

Early data suggests omicron may cause milder illness than delta in most people — an enormous silver lining in the dark cloud of a more highly transmissible variant.

Not every mutation improves a virus. In fact, most either harm the virus or have little effect. But a new variant does not begin to elbow out others unless some mutation or combination of them makes it superior to its predecessors, Garry said. “It’s either making the virus replicate better, transmit better or resist the immune system better.”

So far, he said, omicron appears to be at least two for three.

About this story: Most of the information on the spike protein, its anatomy and mutations came from Robert F. Garry at Tulane and Mark Zeller of the Andersen Lab at Scripps Research. Additional sources were CoVariants, GISAID, Nextstrain, and ViralZone, which is part of the SIB Swiss Institute of Bioinformatics.

Coronavirus: What you need to know

Vaccines: The CDC recommends that everyone age 5 and older get an updated covid booster shot designed to target both the original virus and the omicron variant. Here’s some guidance on when you should get the omicron booster and how vaccine efficacy could be affected by your prior infections.

Variants: Instead of a single new Greek letter variant, a group of immune-evading omicron spinoffs are popping up all over the world. Any dominant variant will likely knock out monoclonal antibodies, targeted drugs that can be used as a treatment or to protect immunocompromised people.

Tripledemic: Hospitals are overwhelmed by a combination of respiratory illnesses, staffing shortages and nursing home closures. And experts believe the problem will deteriorate further in coming months. Here’s how to tell the difference between RSV, the flu and covid-19.

Guidance: CDC guidelines have been confusing — if you get covid, here’s how to tell when you’re no longer contagious. We’ve also created a guide to help you decide when to keep wearing face coverings.

Where do things stand? See the latest coronavirus numbers in the U.S. and across the world. In the U.S., pandemic trends have shifted and now White people are more likely to die from covid than Black people. Nearly nine out of 10 covid deaths are people over the age 65.

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