>> Welcome to module 1.4,
"Emerging Variants of SARS-CoV-2."
This presentation is a part
of the COVID-19 genomic epidemiology toolkit
from CDC's Office of Advanced Molecular Detection.
My name is Dr. Michael Weigand
and I am a bioinformatician with the CDC.
This module is a part of our introduction
to genomic epidemiology and the genome of SARS-CoV-2.
Be sure to check out the toolkit's other modules,
which include a combination of training materials
and case studies to help you get started supplementing
epidemiology with genome sequence data.
In module 1.2 we introduce some basic features
of the SARS-CoV-2 genome, shown here with the simple schematic
in which varied colors indicate different genes encoded
within the roughly 30,000 RNA nucleotides.
A single copy of this linear RNA genome is packaged inside
of every SARS-CoV-2 viral particle.
Mutations occur within the genome
as viruses spread among susceptible hosts,
producing a genetic fingerprint that can be used
for phylogenetics and thus genomic epidemiology.
Importantly, this process
of mutation accumulation is never ending,
leading to distinct divisions
within the global SARS-CoV-2 population.
Genomic researchers refer to these subgroups as clades
or lineages, each of which is defined by a specific collection
of mutations in the viral genome.
Nomenclature describing these divisions is an active
and fluid area of development.
The figure here lists three current systems
and the overlaps among them.
In all three systems, names are applied to divisions
within the phylogeny
to facilitate scientific communication,
rather than indicate any significant differences
in viral properties or disease characteristics.
It's within this context that we begin
to recognize specific variants of SARS-CoV-2.
The term "variant" broadly means genetically distinct,
and so any mutation or phylogenetic cluster
of mutations can be called a variant,
simply because it deviates from the reference
or background viral genome sequence.
The term has been applied to SARS-CoV-2
to describe specific clades or lineages
of closely related viruses defined by their collection
of mutations, usually a set of so-called defining mutations,
while still permitting some small amount of variation.
For example, B.1.1.7 is defined by a collection
of mutations occurring throughout the genome
and highlighted in the diagram here.
But the label "variant" can also refer to specific mutations,
usually that cause amino acid substitutions,
which may be recurrent and independent of the rest
of the genome sequence.
Most early attention has been paid to mutations
within the spike protein, which is responsible
for host receptor binding and is also targeted by vaccines.
Some examples are listed here,
named for the amino acid substitution and position
in the spike protein sequence.
Note that we'll avoid using the term "strain"
in our discussion here, although you'll likely hear it used
in popular media.
There are no hard and fast rules for defining strains
of pathogenic microbes,
but typically strain classification is reserved
for variant clades or lineages
when they become sufficiently divergent
to exhibit distinct behavior or epidemiology.
Throughout this module we'll stick to simply calling these
"variants," but be aware
that SARS-CoV-2 nomenclature remains an active area
of development.
Because variant definition can be based on either lineage
or specific mutations,
their assigned names can look very different
and often reflect the motivation behind their recognition.
Mixing of name conventions gets confusing and it helps
if you can recognize the origin of the name
when discussing a particular variant.
For example, a widely publicized variant was first reported
in the UK in late 2020 and can be described by any
of these three names here.
Most common among them is probably its PANGO lineage name,
B.1.1.7, which is derived
from a hierarchical scheme using successive characters
to indicate where the lineage resides
in the global SARS-CoV-2 phylogeny.
Think of it like an address to its location in the tree,
as illustrated here on the right.
But be aware that other analogous names might also be
used to describe this same variant.
All three of those listed here refer to the same lineage
and its full collection of defining mutations.
Alternatively, some variants are named
for one specific defining mutation, such as L452R,
which references an amino acid substitution
at position 452 in the spike protein.
Although researchers assign such names based on mutations
of interest, these variants often still represent clades
within the phylogenetic tree defined
by genetic fingerprint of many mutations.
All variants start out rare because they are the product
of random mutation, and many stay that way.
Others, however, attract attention
by reaching high frequency or expanding rapidly
in a particular region.
The transmission dynamics underlying a variant's increase
in frequency can be fueled by epidemiology or virus phenotype.
Those variants expanding due to altered viral properties,
such as increased transmissibility,
are the ones we're most concerned with identifying.
Of course, shifts in relative frequency are expected
in any evolving pathogen population
and are only detectable with sufficient genomic surveillance.
The speed and drivers of high frequency variants factor
into decisions to recognize them with labels such as
"variant of interest."
Keep in mind that lineages of SARS-CoV-2 can increase
in frequency through human behavior alone.
The virus spreads through human contact
and more quickly among socially mixing populations.
The introduction and subsequent spread of the virus
in a new population can result
in a rapid increase in frequency.
The population genetic term for this is the "founder effect,"
in which a new local virus population is seeded
by a small number of individuals.
The resulting population has little genetic diversity,
giving the appearance of rapid spread of a specific variant.
An example of such epidemiologically driven growth
was observed during the 2020 summer season
as European vacation travel facilitated spread
of a particular variant.
Named 20A.EU1 and later renamed 20E, the variant spread
across many countries, often through multiple introductions,
as vacationers returned home
and subsequently became the most predominant variant
in Europe by the fall.
The spread of 20A.EU1 and investigation
of potential phenotypes associated
with its mutations were described
in the preprint listed here and on the toolkit webpage.
The first recognized variant of SARS-CoV-2 actually emerged
in early 2020 named for its defining mutation, D614G,
which refers to the amino acid substitution from aspartic acid,
abbreviated D, to glycine at position 614
on the spike protein sequence.
This variant appeared as the virus spread through Europe
and then North America, becoming globally dominant.
It was initially unclear if the spread of D614G was due
to a founder effect,
but subsequent laboratory research has suggested
that this mutation increases viral load
and subsequent transmission to secondary cases.
Some variants get our attention
because they feature defining mutations
that are observed multiple times
across the global SARS-CoV-2 phylogeny.
The general phylogenetic term
to describe this phenomenon is homoplasy, which refers
to the observation of a mutation in multiple parts of the tree
that don't share a common ancestor.
Often, this can be interpreted as convergent evolution,
suggesting that the mutation has appeared multiple times
because it confers a beneficial property to the virus.
One example is the frequent mutation
of the spike protein at position 501.
This tree on the right highlights three separate
mutations at position 501 to tyrosine,
abbreviated Y. Although each
of these three variants has a clade- or lineage-derived name,
also listed here, it can be useful to instead describe them
by this shared spike mutation.
These three variants are not phylogenetically closely related
but exhibit similar properties because mutation
at this site is believed
to increase host receptor binding during infection.
Some variants may warrant elevated labels
to indicate particular importance to public health,
such as "variant of interest" or "variant under investigation"
or even "variant of concern."
At this time, formal criteria
for classifying SARS-CoV-2 variants
into such categories are still being debated among researchers
and public health institutions.
In general, these variants are flagged
because they exhibit concerning epidemiological, immunological,
or pathogenic characteristics.
These include observations introduced earlier
in this module, such as rapid expansion
or particular mutations linked to altered viral properties,
some of which may appear multiple times
in the population.
Please refer to the resources provided with this module
on the toolkit webpage for updated information
on such variant classifications.
This toolkit focuses on genomic epidemiology,
and so it's worth asking what impact the emergence
of new variants has on using sequence data
to support public health investigation.
Fortunately, when applying genetic fingerprinting
to investigate transmission, the basic principles described
in the introductory modules of this toolkit still apply.
Phylogeny still approximates epidemiology
and viral sequence data can still be used
to infer linkages among cases infected by new variants.
However, some mutations or perhaps combinations
of mutations, may alter viral properties
and so variant identification
by genome sequencing becomes another powerful tool
to inform epidemiologic investigation.
For example, these data could be used
to prioritize control measures like contact tracing
or patient isolation, if the identified variant is known
to cause more secondary cases
through increased transmissibility.
To summarize, continued transmission and replication
of SARS-CoV-2 naturally results in the emergence
of new variants through mutation.
These variants may not impact genomic epidemiology,
but do highlight the broader importance
of genomic surveillance for detecting any variants that may,
for example, spread more rapidly,
increase disease severity,
or even evade vaccine-induced immunity.
In practice, genomic surveillance often allows
detection of new mutations and variants before any such impact
on the virus or disease can be determined.
This is intended as an introductory module
to provide useful background information regarding the
emergence of new variants,
not in-depth description of specific variants.
This is an area of active investigation
and SARS-CoV-2 nomenclature remains fluid,
and at times, confusing.
Please remember to refer to the resources provided
with this module on the toolkit webpage for updated information.
It is possible to quickly identify variant defining
mutations or lineages
by uploading an assembled SARS-CoV-2 genome sequence
to either the Pangolin
or Nextclade web portals using the links provided here
and on the toolkit webpage.
Both are updated regularly to include new variants
as they are identified.
This concludes module 1.4.
Part two of this toolkit contains studies
that review the use of genomics in response to COVID-19.
Please visit the COVID-19 genomic epidemiology toolkit
page where you can find further reading on this topic.
On the toolkit page you can also subscribe to our mailing list
and receive announcements as new modules
and materials are released.
Thank you.