(Variant names follow the Greek alphabet,
but WHO skipped the letters Nu and Xi, it
said, “because Nu is too easily confounded
with ‘new’ and Xi was not used because it is
a common surname.”)
One reason for concern about Omicron
is that sequenced samples indicate it has
rapidly replaced other variants in South
Africa. But that picture might be skewed.
For one, sequencing might have been fo-
cused on possible cases of the new variant
in recent days, which could make it appear
more frequent than it is. PCR data provide
broader coverage and a less biased view,
but there, too, samples with the S gene fail-
ure indicate a rapid rise of Omicron.
The rising frequency could still be due
in part to chance. In San Diego, a series
of superspreading events at a university
resulted in an explosion of one particu-
lar strain of SARS-CoV-2 earlier this year,
Andersen says: “It was thousands of cases
and they were all the same virus.” But the
virus wasn’t notably more infectious. South
Africa has seen relatively few cases re-
cently, so a series of superspreading events
could have led to the rapid increase of
Omicron. “I suspect that a lot of that signal
is explained by that and I desperately hope
so,” Andersen says. Based on a comparison
of different Omicron genomes, Andersen
estimates the virus emerged sometime
around late September or early October,
which suggests it might be spreading more
slowly than it appears to have.
The other reason to be concerned is
Omicron’s confusing genome. Its spike
protein, which latches on to receptors on
human cells, has 30 amino acid differ-
ences from that of the original virus from
Wuhan, China. In addition, amino acids
have disappeared in three places and new
ones appeared in one place. Many of the
changes are around the receptor-binding
domain, the part of the protein that makes
contact with the human cell. “That is very
troubling,” Farrar says. Structural biology
mapping in 2020 showed some of these
changes made the virus bind to the recep-
tor much better.
It’s hard to tell how infectious a virus
is based on mutations alone, says Aris
Katzourakis, an evolutionary biologist at the
University of Oxford. “But if we were looking
out for mutations that do affect transmissibil-
ity, it’s got all of them,” he says.
The sequence also suggests the virus
could excel at evading human antibodies,
says Jesse Bloom, an evolutionary biologist
at the Fred Hutchinson Cancer Research
Center. The human immune system pro-
duces a host of different antibodies that
can neutralize SARS-CoV-2, but many of
the most important ones fall into three
categories that each target a slightly differ-
ent site on the spike protein of the virus,
simply called 1, 2, and 3. A mutation called
E484K has long been worrying because it
changes the shape of the site that class 2
antibodies recognize, making them less
potent. Omicron carries a mutation called
E484A in this site and similar changes in thesites for the other two classes of antibodies.
“It seems clear to me that our antibodies
and the spike protein are sort of in a genetic
arms race,” says virologist Paul Bieniasz of
the Rockefeller University. “A week ago, I
was more confident that antibodies were go-
ing to come out on top, and I’m a little less
confident now.” Bloom thinks people whoSCIENCE science.org 3 DECEMBER 2021 • VOL 374 ISSUE 6572 1179Where did ‘weird’ Omicron come from?
T
he unsettling new SARS-CoV-2 vari-
ant did not develop out of one of the
earlier variants of concern, such as
Alpha or Delta, but instead appears
to have evolved in parallel—and in
the dark. Omicron is so different from
the millions of SARS-CoV-2 genomes
that have been shared publicly that
pinpointing its closest relative is difficult,
says Emma Hodcroft, a virologist at the
University of Bern. It likely diverged early
from other strains, she suggests. “I would
say it goes back to mid-2020.”
That raises the question of where Omi-
cron’s predecessors lurked for more than
a year. Scientists see essentially three
possible explanations: The virus could
have circulated and evolved in a popula-
tion with little surveillance and sequenc-
ing. It could have gestated in a chronically
infected COVID-19 patient. Or it might
have evolved in a nonhuman species, from
which it spilled back into humans recently.
Christian Drosten, a virologist at
Charité University Hospital in Berlin,
favors the first possibility. “I assume this
evolved not in South Africa, where a lot of
sequencing is going on, but somewhere
else in southern Africa during the winter
wave,” he says. “There were a lot of infec-
tions going on for a long time and for this
kind of virus to evolve you really need a
huge evolutionary pressure.”
But Andrew Rambaut of the University
of Edinburgh can’t see how the virus could
have stayed hidden in a group of people
for so long. “I’m not sure there’s really
anywhere in the world that is isolated
enough for this sort of virus to transmit
for that length of time without it emerging
in various places,” he says.
Instead, Rambaut and others prefer
option two. When Alpha was discovered
in late 2020, that variant also appeared
to have acquired numerous mutations
all at once, leading researchers to postu-
late it came from a chronically infected
COVID-19 patient. Sequencing of SARS-
CoV-2 samples from some chronically
infected patients bolstered the idea byshowing their viruses developed some
of the same mutations seen in Alpha
and other variants.
Drosten says experience with chronic
infections of influenza and other viruses
in immunosuppressed patients argues
against this hypothesis. Variants able to
elude the immune system do develop in
such people, but they come with a host
of other changes that make them less
able to transmit from person to person.
“These viruses have very low fitness out
in the real world,” he says. That’s because
the mutations allowing a virus to survive
in one individual over time may be very
different from those needed to best
spread from one person to the next.
Jessica Metcalfe, an evolutionary
biologist at the Institute for Advanced
Study in Berlin, isn’t so sure. “I think one
reason that this virus has done so well is
that better binding to ACE2 [its receptor
on human cells] helps for both within-
host spread and between-host spread,”
she says. Still, Metcalfe agrees with
Drosten that Omicron likely circulated
and evolved in a hidden population.
Some scientists suspect the virus
was hidden in animals rather than
people.“The genome is just so weird,”
says Kristian Andersen of Scripps Re-
search, pointing to its medley of muta-
tions, many of which have not been seen
before in other variants.
Aris Katzourakis, an evolutionary
biologist at the University of Oxford, is
skeptical of a nonhuman origin. “I’d start
worrying about animal reservoirs more if
we were succeeding in suppressing the
virus, and then I could see it as some-
where it might hide,” he says.
It is also unclear whether the poor vac-
cination rates in Africa played a role in
Omicron’s emergence, as public health
officials concerned about vaccine equity
have suggested. “The idea that if we had
vaccinated more in Africa, we wouldn’t
have this: I’d like that to be true, but
we have literally no way of knowing.”
Katzourakis says. —K.K.