characterization of sars-cov-2 different variants and
TRANSCRIPT
SeyedAlinaghi et al. Eur J Med Res (2021) 26:51 https://doi.org/10.1186/s40001-021-00524-8
REVIEW
Characterization of SARS-CoV-2 different variants and related morbidity and mortality: a systematic reviewSeyedAhmad SeyedAlinaghi1, Pegah Mirzapour1, Omid Dadras2, Zahra Pashaei3, Amirali Karimi4, Mehrzad MohsseniPour1, Mahdi Soleymanzadeh5, Alireza Barzegary6, Amir Masoud Afsahi7, Farzin Vahedi4, Ahmadreza Shamsabadi8, Farzane Behnezhad9, Solmaz Saeidi10, Esmaeil Mehraeen11* and Shayesteh Jahanfar12
Abstract
Introduction: Coronavirus Disease-2019 (SARS-CoV-2) started its devastating trajectory into a global pandemic in Wuhan, China, in December 2019. Ever since, several variants of SARS-CoV-2 have been identified. In the present review, we aimed to characterize the different variants of SARS-CoV-2 and explore the related morbidity and mortality.
Methods: A systematic review including the current evidence related to different variants of SARS-CoV-2 and the related morbidity and mortality was conducted through a systematic search utilizing the keywords in the online databases including Scopus, PubMed, Web of Science, and Science Direct; we retrieved all related papers and reports published in English from December 2019 to September 2020.
Results: A review of identified articles has shown three main genomic variants, including type A, type B, and type C. we also identified three clades including S, V, and G. Studies have demonstrated that the C14408T and A23403G alterations in the Nsp12 and S proteins are the most prominent alterations in the world, leading to life-threatening mutations.The spike D614G amino acid change has become the most common variant since December 2019. From missense mutations found from Gujarat SARS-CoV-2 genomes, C28854T, deleterious mutation in the nucleocapsid (N) gene was significantly associated with patients’ mortality. The other significant deleterious variant (G25563T) is found in patients located in Orf3a and has a potential role in viral pathogenesis.
Conclusion: Overall, researchers identified several SARS-CoV-2 variants changing clinical manifestations and increas-ing the transmissibility, morbidity, and mortality of COVID-19. This should be considered in current practice and interventions to combat the pandemic and prevent related morbidity and mortality.
Keywords: Variants, Strains, Genomic diversity, Characterizations, SARS-CoV-2, COVID-19
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IntroductionIn December 2019, a novel coronavirus (CoV) emerged from Hubei province in China among people visiting the Huanan seafood market in Wuhan. The virus is transmit-ted through human-to-human contact and rapidly spread across the world, and soon turned into a pandemic [1, 2]. Its symptoms can be divided to two main groups of majors (fever, cough, dyspnea) and minors (anosmia,
Open Access
European Journalof Medical Research
*Correspondence: [email protected] Department of Health Information Technology, Khalkhal University of Medical Sciences, 1419733141 Khalkhal, IranFull list of author information is available at the end of the article
Page 2 of 20SeyedAlinaghi et al. Eur J Med Res (2021) 26:51
dysgeusia, headache, gastrointestinal symptoms, skin lesions) [3–6]. Ever since, it has caused worldwide social and economic disruption. There are no universally recog-nized clinically useful antiviral drugs against COVID-19 so far (actually remdesivir showed good efficacy in many trials, but it needs to be discussed more). Although there are several effective vaccines to prevent infection with SARS-CoV-2, efforts to develop medications and vac-cines are continuing [7].
It appeared that there are several variants of SARS-CoV-2. Since the beginning of the pandemic; there have been tremendous efforts to determine the genetic diver-sity of virus and discover the variations such as immune targets change (such as the spike glycoprotein), primer-binding and probe-binding sites change (which can reduce the sensitivity of diagnostic tests), and genetic variations (which might affect transmissibility and viru-lence) [8–11].
SARS-CoV-2 genome consists of approximately 29,903 nucleotides and organized in the following order from 5’ to 3’: open reading frame (ORF) 1ab (replicas), structural spike glycoprotein (S), ORF3a protein, a structural enve-lope protein (E), structural membrane glycoprotein (M), ORF6 protein, ORF7a protein, ORF7b protein, ORF8 protein, structural nucleocapsid-phosphoprotein (N), and ORF10 protein. ORF1ab is a large polyprotein (∼ 21,291 nucleotides) encoding sixteen non-structural pro-teins: leader protein, nsp2, nsp3, nsp4, 3C-like protein-ase, nsp6, nsp7, nsp8, nsp9, nsp10, RNA-dependent RNA polymerase (RdRp), helicase, 3’–5’ exonuclease, endoR-NAse, 2’-o-ribose methyltransferase, and nsp11 [12].
Different variants have been discovered besides the wild-type, with a certain amount of nucleotide dele-tion in the ORF8 (which is the biological function of the ORF8 protein in SARS-CoV-2 remains unclear). The most known one is the ∆382 variant, a 382-nucleotide deletion in the ORF7b and ORF8, removing its transcrip-tion-regulatory sequence (this omission stops ORF8 tran-scription). This variant was successfully early transmitted during the epidemic, but was unknown until March 2020. These different variants have been found around the world in countries such as Bangladesh (345 nucleotides), Australia (138 nucleotides), and Spain (62 nucleotides). An identical Δ382 variant was also detected in February 2020 in a traveler who returned from Wuhan, China, to Taiwan [13, 14].
In the last pandemic of 2002–2003, the SARS-CoV was responsible for zoonotic transmission from civ-ets to humans. After a short time, the virus’s wild-type mutated, and a new variant emerged, which had a 29-nucleotide deletion in the ORF8, known as the Δ29. Subsequently, there were some reports of 82-nucleotide deletion and 415-nucleotide deletions in the same region.
The influence of these deletions on the pandemic is still unknown. But some in vitro studies have shown that Δ29 replicates less efficiently and causes milder clinical illness than the wild-type [15, 16].
The relations between the magnitude of nucleotide deletion in ORF8 with its virulence and the ORF8 func-tion are still unknown. However, a recent study suggested that ORF8 mediates immune evasion by downregulating MHC-I molecules. In vitro studies have also shown that these deletions do not affect replicative fitness, but it can affect the transcription of some essential and defensive regions such as ORF6 and N genes (known as SARS-CoV interferon antagonists); thus, it can create a more fragile variant compared to the wild-type [17–19].
Besides ORF8, other genome parts can be affected by the mutations, and new variants could emerge. Studies have revealed that the highly mutable spike (S) protein of the virus is associated with the elevated human-to-human transmission rate through interaction with the host’s ACE2 receptor. S protein is one of the well-charac-terized proteins of the Coronaviridae family; this ∼ 1255 amino acid transmembrane protein helps the virus to attach and enter the host [12, 20].
There are also reports about the mutations in other parts such as nsp2 and nsp12 (RdRp). The SARS-CoV-2 nsp12 is RNA-dependent RNA polymerase (RdRp) con-sisting of 932 amino acids located in the polyprotein, from 4393 to 5324 aa. Structurally, the SARS-CoV-2 nsp12 protein is categorized into N-terminal (1–397aa) and a polymerase domain (398–919aa). These mutations have been observed in patients from India, Germany, and Iran [20].
In this article, we aimed to report on and compare the morbidity and mortality of the different variants of SARS-CoV-2 with that of the wild-type to realize whether they could be an immense threat to humans.
MethodsThis study is a systematic review of current evidence con-ducted in September 2020. The authors aimed to study the effect of different variants of SARS-CoV-2 on mor-tality and morbidity. Our study is consistent with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist to ensure reported results’ reliability and validity.
Sources of dataWe retrieved all the relevant papers and reports pub-lished in English from December 2019 to September 2020 through a systematic search using keywords in the online databases of PubMed, Web of Science, Scopus,
Page 3 of 20SeyedAlinaghi et al. Eur J Med Res (2021) 26:51
and Science Direct. We updated our search on late Feb-ruary 2021. Our search strategy employed multiple com-binations of keywords, as follows:
• "SARS-CoV-2" OR "Coronavirus" OR "COVID-19" OR "2019-nCoV" OR "Novel Coronavirus"[Title/abstract]
• "Variants "OR "Variation" OR "Strains" OR "Types" OR "Minority Variants" OR "Genomic Variants" OR "Genetic Variation" OR "Genomic Diversity"OR "Characterizations" [Title/abstract]
• [A] and [B]
Selection of the studyThree independent investigators reviewed the extracted papers’ full text and selected the most pertinent papers according to the eligibility criteria. Then we pulled the relevant data and organized them in some tables. We included the original and peer-reviewed English papers fulfilling the eligibility criteria in the final report. Besides, the following exclusion criteria were applied in the pre-sent study:
• Non-human studies, including animal experiments, in vitro observations, or papers with a limited report on COVID-19, and those without reference to this review’s keywords.
• Papers with inaccessibility to their full texts.• Any duplicated and suspicious outcomes in data-
bases.
Extraction of dataThe authors’ names, publication date, article types (e.g., case reports), country of origin, sample size, gender, age, and clinical symptoms were recorded in an information sheet. This information was collected by two independ-ent researchers and subsequently organized in tables. All authors cross-checked the selected articles to avoid any duplications or overlap in the content.
Assessment of qualityThis study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist to ensure the quality and accuracy of selected papers and outcomes. Two independent researchers examined the quality of the articles and the probable risk of bias. A third researcher addressed any disagreement.
The full text of selected articles was read, and the key findings are summarized in tables.
ResultsWe identified a total of 56 relevant articles by title and abstract. Of 56 articles, 50 were related to the genomic variations in SARS-CoV-2. The included studies were conducted in 16 countries, and one of the articles was a report on multinational scientific collaborations [1] (Table 1 illustrates a summary of the findings). We sum-marized each study’s main findings in the two categories: genomic variants and other results.
Studies have revealed that the highly mutable spike (S) protein of the virus is associated with the elevated human-to-human transmission rate through interaction with the host’s ACE2 receptor. A review of identified articles has shown three main genomic variants, includ-ing type A, type B, and type C. we also identified three clades including S, V, and G. Studies have demonstrated that the C14408T and A23403G alterations in the Nsp12 and S proteins are the most prominent alterations in the world, leading to miserable mutations.The spike D614G amino acid change has become the most common variant since December 2019. From missense mutations found from Gujarat SARS-CoV-2 genomes, C28854T, del-eterious mutation in the nucleocapsid (N) gene was sig-nificantly associated with patients’ mortality. The other significant deleterious variant (G25563T) is found in patients located in Orf3a and has a potential role in viral pathogenesis.
DiscussionSince the emergence of COVID-19, understanding the virus behavior has been received much attention from the scientific community. The different viral behav-ior has been attributed to the virus’s difference in types and strains [75]. Therefore, in the present review, we characterized the different variants of SARS-CoV-2 and discussed the findings in four sections, including the different types of SARS-CoV-2 variants, their effects on viral transmission, clinical manifestations, morbidity as well as mortality, and the other relevant findings.
Different variants and strainsThis review has focused on the different variations of SARS-CoV-2 and their impact on virus behavior. Alter-nation of the SARS-CoV-2 genome, through mutation and recombination, potentially leads to changes in the viral life cycle, including transitivity, cellular tropism, and severity of the disease. The diverse clinical outcomes in COVID-19 patients happen due to SARS-CoV-2 genome
Page 4 of 20SeyedAlinaghi et al. Eur J Med Res (2021) 26:51
Tabl
e 1
Com
preh
ensi
ve d
etai
ls o
f the
incl
uded
art
icle
s
Vari
ants
of C
OVI
D-1
9
IDTh
e fir
st a
utho
r (re
fere
nce)
Type
of s
tudy
Coun
try
Stud
y po
pula
tion
Gen
omic
var
iant
sO
ther
1A
loua
ne [2
1]Re
sear
ch a
rtic
leM
oroc
coSA
RS-C
oV-2
gen
omes
ORF
1, R
ecep
tor b
indi
ng d
omai
n (R
BD),
D61
4G, Q
57H
, T26
5IA
tota
l of 3
206
varia
nt s
ites
wer
e de
tect
ed c
ompa
red
to th
e re
fere
nce
geno
me
Wuh
an-H
u-1/
2019
. For
eac
h cl
uste
r, w
e id
entifi
ed d
iffer
ent
clad
es: c
lust
er o
ne c
onta
inin
g tw
o m
ain
clad
es A
1a a
nd B
1 ha
rbor
ing
mai
nly
stra
ins
from
Asi
a, N
orth
Am
eric
a, a
nd A
sia
Euro
pe, r
espe
ctiv
ely.
H
owev
er, c
lust
er 2
har
bore
d th
ree
clad
es: B
2, A
2, A
2a w
ithou
t a s
peci
fic
patt
ern
2A
l-Taw
fiq Ja
ffar [
22]
Lett
er to
the
edito
rU
SACO
VID
-19
patie
nts
Ther
e w
ere
thre
e ge
nom
ic v
ari-
ants
, ter
med
A, B
, and
C, b
ased
on
am
ino
acid
cha
nges
–
3A
rmen
gaud
[23]
Opi
nion
Fran
ceCO
VID
-19
patie
nts
–A
s ex
pect
ed fo
r any
RN
A v
irus,
over
tim
e, in
divi
dual
s ar
e in
fect
ed w
ith
SARS
-CoV
-2 v
aria
nts
that
typi
cally
dis
play
som
e de
gree
of g
enet
ic d
rift,
com
pare
d w
ith th
e fir
st is
olat
es o
f the
viru
s ob
tain
ed in
Wuh
an. T
he s
tudy
of
vira
l evo
lutio
n in
dica
tes
that
gen
etic
drif
t, m
ainl
y de
rived
from
gen
omic
de
letio
ns, w
ill a
lmos
t ine
vita
bly
atte
nuat
e th
e pa
thog
enic
ity o
f viru
ses
give
n en
ough
tim
e. T
he o
nly
hint
at a
tten
uatio
n co
mes
from
an
obse
rva-
tion
in S
inga
pore
, whe
re s
ome
SARS
-CoV
-2 is
olat
es tu
rned
out
to h
ave
a 38
2-nu
cleo
tide
dele
tion
in O
RF8
of th
e vi
ral g
enom
e. T
his
findi
ng is
of
part
icul
ar in
tere
st b
ecau
se o
f the
om
issi
on o
f 29
nucl
eotid
es in
ORF
8 du
r-in
g th
e ea
rly s
prea
ding
of S
ARS
-CoV
-1 in
200
3. T
his
29-n
ucle
otid
e de
letio
n w
as d
emon
stra
ted
to a
tten
uate
vira
l rep
licat
ion
whe
n in
trod
uced
in a
n in
fect
ious
clo
ne g
ener
ated
by
reve
rse
gene
tics
4Ba
jaj [
24]
Scie
ntifi
c co
r-re
spon
denc
eIn
dia
COVI
D-1
9 pa
tient
s–
The
initi
al s
tudi
es id
entifi
ed tw
o m
ajor
type
s of
viru
lent
SA
RS-C
oV-2
circ
ulat
-in
g am
ong
the
Chi
nese
pop
ulat
ion.
The
agg
ress
ive
form
’s pr
eval
ence
de
crea
sed
afte
r ear
ly Ja
nuar
y 20
20, a
nd th
e m
ilder
type
has
bec
ome
stan
dard
due
to s
elec
tive
hum
an in
terv
entio
n. T
wo
geno
mes
ava
ilabl
e fro
m In
dia
show
ed c
lust
erin
g cl
oser
to th
e st
rain
s pr
eval
ent i
n C
hina
to
date
. How
ever
, a u
niqu
e m
utat
ion
2435
1C (A
930V
(T))
in th
e sp
ike
surf
ace
glyc
opro
tein
of I
ndia
n SA
RS-C
oV-2
gen
ome
is a
bsen
t in
othe
r str
ains
from
W
uhan
, Ita
ly, U
SA, a
nd N
epal
is re
port
ed
5Bh
owm
ik [2
0]Re
sear
ch a
rtic
leIn
dia
COVI
D-1
9 pa
tient
sTw
o gr
oups
(A a
nd B
) and
furt
her
subg
roup
ing
(C, D
and
E) o
f the
si
gnifi
cant
gro
up A
SARS
-CoV
-2 g
enom
e is
aro
und
29,9
03 n
ucle
otid
es a
nd o
rgan
ized
in th
e fo
l-lo
win
g or
der f
rom
5’ t
o 3’
: ORF
1ab
(repl
icas
), st
ruct
ural
spi
ke g
lyco
prot
ein
(S),
ORF
3a p
rote
in, a
str
uctu
ral e
nvel
ope
prot
ein
(E),
stru
ctur
al m
embr
ane
glyc
opro
tein
(M),
ORF
6 pr
otei
n, O
RF7a
pro
tein
, ORF
7b p
rote
in, O
RF8
prot
ein,
str
uctu
ral n
ucle
ocap
sid-
phos
phop
rote
in (N
) and
ORF
10 p
rote
in.
Stud
ies
have
reve
aled
that
the
high
ly m
utab
le s
pike
(S) p
rote
in o
f the
vi
rus
is a
ssoc
iate
d w
ith th
e el
evat
ed h
uman
-to-
hum
an tr
ansm
issi
on ra
te
thro
ugh
inte
ract
ion
with
the
host
’s A
CE2
rece
ptor
6Bi
swas
[25]
Lett
er to
the
edito
rBa
ngla
desh
COIV
D-1
9 pa
tient
sTh
is s
tudy
ana
lyze
d 95
SA
RS-C
oV-2
co
mpl
ete
geno
me
sequ
ence
s ob
tain
ed fr
om G
en B
ank,
foun
d 15
6 va
riant
s in
tota
l and
116
un
ique
var
iant
s
Ano
ther
ana
lysi
s of
86
geno
mic
seq
uenc
es o
btai
ned
from
the
GIS
AID
dat
a-ba
se (h
ttps
:// w
ww
. gis
aid.
org/
) ide
ntifi
ed th
ree
dele
tions
in th
e ge
nom
es
of S
ARS
-CoV
-2 fr
om Ja
pan,
USA
, and
Aus
tral
ia, a
nd 9
3 m
utat
ions
ove
r the
en
tire
SARS
-CoV
-2 g
enom
es [3
]. Se
vera
l of t
hese
mut
atio
ns w
ere
loca
ted
in th
e re
cept
or-b
indi
ng d
omai
n (R
BD) o
f the
spi
ke s
urfa
ce g
lyco
prot
ein
7Bi
swas
[26]
Lett
er to
the
edito
rBa
ngla
desh
SARS
-CoV
-2 g
enom
esRe
cept
or b
indi
ng d
omai
n (R
BD),
RNA
-dep
ende
nt R
NA
pol
ymer
-as
e (R
dRp)
Seve
ral s
tudi
es h
ave
so fa
r bee
n co
nduc
ted
utili
zing
seq
uenc
ing
data
of
SARS
-CoV
-2 o
btai
ned
from
pub
licly
ava
ilabl
e re
posi
torie
s. O
ne s
uch
stud
y,
anal
yzed
95
SARS
-CoV
-2 c
ompl
ete
geno
me
sequ
ence
s ob
tain
ed fr
om
Gen
Ban
k, fo
und
156
varia
nts
in to
tal a
nd 1
16 u
niqu
e va
riant
s
Page 5 of 20SeyedAlinaghi et al. Eur J Med Res (2021) 26:51
Tabl
e 1
(con
tinue
d)
Vari
ants
of C
OVI
D-1
9
IDTh
e fir
st a
utho
r (re
fere
nce)
Type
of s
tudy
Coun
try
Stud
y po
pula
tion
Gen
omic
var
iant
sO
ther
8Bl
acks
tone
[27]
Com
men
tary
USA
COIV
D-1
9 pa
tient
s–
If a
path
ogen
str
ain
repl
icat
es to
o ra
pidl
y, th
e tr
ansm
issi
on m
ight
not
occ
ur
befo
re th
e ho
st is
deb
ilita
ted.
Fas
t-re
plic
atin
g pa
thog
en s
trai
ns m
ay th
us
face
ext
inct
ion.
Slo
w-r
eplic
atin
g st
rain
s th
at c
ause
mild
or i
napp
aren
t di
seas
e m
ay a
llow
a lo
nger
tran
smis
sion
win
dow
and
per
sist
in th
e ho
st
popu
latio
n
9Ca
o [2
8]Re
sear
ch a
rtic
leC
hina
COIV
D-1
9 pa
tient
sTy
pes
A a
nd C
wer
e on
ly fo
und
outs
ide
East
Asi
a, i.
e., E
urop
e an
d A
mer
ica,
whe
reas
type
B
was
the
mos
t com
mon
type
in
East
Asi
a
Resu
lts s
how
ed th
at m
ainl
and
Chi
na s
trai
ns’ g
enom
es w
ere
mos
tly d
istr
ib-
uted
in C
lade
B a
nd C
lade
und
efine
d in
the
phyl
ogen
etic
tree
, with
onl
y 3.
47%
(5/1
44) f
ound
in C
lade
A. A
lso,
Cla
des
A2
(one
cas
e) a
nd A
2a (1
12
inst
ance
s) c
onta
ined
no
mai
nlan
d C
hina
cas
es. I
n th
ese
clad
es, a
ll ca
ses
cam
e fro
m 1
6 re
gion
s, m
ainl
y th
e N
ethe
rland
s (6
5 ca
ses)
, Sw
itzer
land
(13
case
s, an
d U
K 13
cas
es),
with
onl
y on
e ca
se re
port
ed fr
om T
aiw
an. F
urth
er
anal
ysis
dem
onst
rate
d th
at a
min
o ac
id v
aria
tion
of th
e S
prot
ein
at 6
14
(QH
D43
416.
1: p
.614
D >
G),
i.e.,
the
subs
titut
ion
of g
luta
mic
aci
d (D
) with
gl
ycin
e (G
) in
the
mut
ant p
rote
in, w
as fo
und
in s
trai
ns w
ithin
Cla
des
A2
and
A2a
10Ca
still
o [2
9]Re
sear
ch a
rtic
leC
hile
Chi
lean
CO
VID
-19
patie
nts
Thre
e va
riant
s: S
varia
nt, G
var
iant
, V
varia
ntA
ccor
ding
to p
reva
lent
SN
Ps, a
ll ge
nom
es h
ave
been
cla
ssifi
ed b
y am
ino
acid
cha
nges
in s
peci
fic O
RFs.
The
first
thre
e ca
ses
(20–
1891
820–
1930
320–
1930
5) a
re c
lass
ified
as
"S" t
ype
for t
he C
hile
an s
trai
ns. M
ean-
whi
le, t
he fo
urth
cas
e (2
0–19
731)
is a
"G" t
ype,
acc
ordi
ng to
nuc
leot
ide
subs
titut
ions
in th
e po
sitio
ns 2
8 14
4 an
d 23
403
11Ev
eret
t [30
]Re
sear
ch a
rtic
leU
SACO
IVD
-19
patie
nts
D61
4G, R
NA
-dep
ende
nt R
NA
po
lym
eras
e (R
dRp)
loca
ted
on
ORF
1b
The
D61
4G s
ubst
itutio
n ha
s be
en p
ropo
sed
to p
rom
ote
infe
ctio
n of
hu
man
cel
ls, a
nd th
is v
aria
nt h
as s
prea
d gl
obal
ly a
t the
exp
ense
of o
ther
ge
noty
pes
12Fo
rni [
31]
Orig
inal
art
icle
Italy
SARS
-CoV
-2 g
enom
esD
614G
Rece
nt s
tudi
es h
ave
indi
cate
d th
at th
e D
614G
var
iant
, whi
ch is
now
pre
va-
lent
wor
ldw
ide,
enh
ance
s vi
ral i
nfec
tivity
13Fo
rste
r [32
]Re
sear
ch a
rtic
leG
erm
any
COVI
D-1
9 pa
tient
sTh
ree
cent
ral v
aria
nts:
A v
aria
nt B
va
riant
C v
aria
ntN
ode
B is
der
ived
from
A b
y tw
o m
utat
ions
: the
syn
onym
ous
mut
atio
n T8
782C
and
the
non-
syno
nym
ous
mut
atio
n C
2814
4T c
hang
ing
a le
ucin
e to
a s
erin
e. T
ype
C d
iffer
s fro
m it
s pa
rent
type
B b
y th
e no
n-sy
nony
mou
s m
utat
ion
G26
144T
, whi
ch c
hang
es a
gly
cine
to a
val
ine
14G
ómez
-Car
balla
[33]
Rese
arch
art
icle
Spai
nSA
RS-C
oV-2
gen
omes
C87
82T,
C18
060T
, T28
144C
, C
2909
5TSu
b-ha
plog
roup
A2
mos
t lik
ely
orig
inat
ed in
Eur
ope
from
an
Asi
an a
nces
tor
and
gave
rise
to s
ub-c
lade
A2a
, whi
ch re
pres
ents
the
maj
or n
on-A
sian
ou
tbre
ak, e
spec
ially
in A
frica
and
Eur
ope
15G
oren
[34]
Lett
er to
the
edito
rU
SACO
IVD
-19
patie
nts
TMPR
SS2
Both
SA
RS-C
oV-2
and
influ
enza
are
dep
ende
nt o
n TM
PRSS
2 fo
r inf
ectiv
ity,
it is
like
ly th
at S
ARS
-CoV
-2 w
ill h
ave
a si
mila
r sea
sona
l cyc
le; t
hus,
the
fall
and
win
ter a
re li
kely
to s
ee a
n in
crea
se in
CO
VID
-19
case
s
16G
raud
enzi
[35]
Rese
arch
art
icle
Italy
COIV
D-1
9 pa
tient
s–
Seve
ral m
utat
ions
link
ed to
low
-rat
e m
utat
iona
l pro
cess
es a
ppea
r to
tran
sit
to c
lona
lity
in th
e po
pula
tion,
eve
ntua
lly le
adin
g to
the
defin
ition
of n
ew
vira
l gen
otyp
es a
nd to
an
incr
ease
of o
vera
ll ge
nom
ic d
iver
sity
17Is
lam
[36]
Orig
inal
art
icle
Bang
lade
shCO
VID
-19
patie
nts
Thre
e ce
ntra
l var
iant
s A
var
iant
B
varia
nt C
var
iant
Cla
de S
Cla
de
V C
lade
G
–
Page 6 of 20SeyedAlinaghi et al. Eur J Med Res (2021) 26:51
Tabl
e 1
(con
tinue
d)
Vari
ants
of C
OVI
D-1
9
IDTh
e fir
st a
utho
r (re
fere
nce)
Type
of s
tudy
Coun
try
Stud
y po
pula
tion
Gen
omic
var
iant
sO
ther
18Ja
in [3
7]Re
sear
ch a
rtic
leIn
dia
COIV
D-1
9 pa
tient
s–
SARS
-CoV
-2 v
aria
nts
impa
ct R
T-PC
R effi
cien
cy in
det
ectio
n. A
tota
l of 2
9 gl
obal
SA
RS-C
oV-2
gen
etic
var
iant
s ha
d a
frequ
ency
≥ 1
%. T
he th
erm
ody-
nam
ic s
tabi
lity
of th
e vi
rus–
prim
ers
com
plex
get
s pe
rtur
bed.
A n
umbe
r of
reco
mm
ende
d pr
imer
or p
robe
seq
uenc
es h
ad h
igh
varia
nt fr
eque
ncy
19Ja
y [8
]Re
sear
ch a
rtic
leFr
ance
COVI
D-1
9 pa
tient
sG
enom
ic d
iver
sity
of S
ARS
-CoV
-2
by n
ext-
gene
ratio
n se
quen
c-in
g (N
GS)
For t
he fi
rst t
ime,
min
ority
vira
l pop
ulat
ions
repr
esen
ted
up to
1%
dur
ing
SARS
-CoV
-2 in
fect
ion.
Sub
spec
ies
wer
e di
ffere
nt fr
om o
ne d
ay to
the
next
an
d be
twee
n an
atom
ical
site
s, su
gges
ting
that
in v
ivo,
this
new
cor
onav
i-ru
s ap
pear
s as
a c
ompl
ex a
nd d
ynam
ic d
istr
ibut
ion
of v
aria
nts
20Jo
shi [
38]
Rese
arch
art
icle
Indi
aCO
VID
-19
patie
nts
C28
854T
and
G25
563T
From
mis
sens
e m
utat
ions
foun
d fro
m G
ujar
at S
ARS
-CoV
-2 g
enom
es,
C28
854T
, del
eter
ious
mut
atio
n in
the
nucl
eoca
psid
(N) g
ene
was
si
gnifi
cant
ly a
ssoc
iate
d w
ith m
orta
lity
in p
atie
nts.
The
othe
r sig
nific
ant
dele
terio
us v
aria
nt (G
2556
3T) i
s fo
und
in p
atie
nts
loca
ted
in O
rf3a
and
has
a
pote
ntia
l rol
e in
vira
l pat
hoge
nesi
s. SA
RS-C
oV-2
gen
omes
from
Guj
arat
ar
e fo
rmin
g di
stin
ct c
lust
ers
unde
r the
GH
cla
de o
f GIS
AID
21Ju
nejo
[39]
Revi
ew a
rtic
lePa
kist
anCO
VID
-19
patie
nts
AC
E2, I
L-10
, TN
F, VE
GF
Elev
ated
leve
ls o
f cyt
okin
es a
nd c
hem
okin
es in
CO
VID
-19
patie
nts
incl
udin
g IL
1 β,
IL1R
A, I
L7, I
L8, I
L9, I
L10,
bas
ic F
GF2
, GC
SF, G
MC
SF, I
FN γ
, IP1
0, M
CP1
, M
IP1
α, M
IP1
β, P
DG
FB, T
NF
α, a
nd V
EGFA
wer
e ob
serv
ed. T
he in
crea
sed
pro-
infla
mm
ator
y cy
toki
nes,
incl
udin
g IL
2, IL
7, IL
10, G
CSF
, IP1
0, M
CP1
, M
IP1
α, a
nd T
NF
α, w
ere
resp
onsi
ble
for d
isea
se s
ever
ity. M
any
cand
idat
e ge
nes,
i.e.,
AC
E2, I
L-10
, TN
F, VE
GF,
are
belie
ved
to b
e as
soci
ated
with
ARD
S de
velo
pmen
t or o
utco
me.
In a
dditi
on, t
he in
crea
sed
leve
ls o
f IL-
6 an
d IL
-8
wer
e co
nfirm
ed to
be
asso
ciat
ed w
ith A
RDS.
Dat
a co
llect
ed o
n ge
netic
ev
olut
ion,
rece
ptor
-bin
ding
, and
pat
hoge
nesi
s ha
ve s
how
n th
at b
ats
mos
t lik
ely
caus
e SA
RS-C
oV b
y se
quen
tial r
ecom
bina
tion
of b
at S
ARS
-CoV
s
22Ko
rber
[11]
Rese
arch
art
icle
USA
COVI
D-1
9 pa
tient
sD
614G
An
A-t
o-G
nuc
leot
ide
mut
atio
n ca
uses
the
Spik
e D
614G
am
ino
acid
cha
nge
at p
ositi
on 2
3,40
3 in
the
Wuh
an re
fere
nce
stra
in. T
hree
oth
er m
utat
ions
al
mos
t alw
ays
acco
mpa
ny th
e D
614G
cha
nge:
a C
-to-
T m
utat
ion
in th
e 5′
U
TR (p
ositi
on 2
41 re
lativ
e to
the
Wuh
an re
fere
nce
sequ
ence
), a
sile
nt C
-to-
T m
utat
ion
at p
ositi
on 3
,037
, and
a C
-to-
T m
utat
ion
at p
ositi
on 1
4,40
8 th
at re
sults
in a
n am
ino
acid
cha
nge
in R
NA
-dep
ende
nt R
NA
pol
ymer
ase
(RdR
p P3
23L)
. The
hap
loty
pe c
ompr
isin
g th
ese
four
gen
etic
ally
link
ed
mut
atio
ns is
now
the
glob
ally
dom
inan
t for
m
23Ko
urib
a [4
0]Re
sear
ch a
rtic
leA
frica
COIV
D-1
9 pa
tient
sM
0025
93 a
nd M
0026
59A
naly
sis
show
s th
at b
oth
the
early
A (1
9B) a
nd th
e la
ter o
bser
ved
B (2
0A/C
) cl
ade
are
pres
ent i
n M
ali,
indi
catin
g m
ultip
le a
nd in
depe
nden
t int
rodu
c-tio
ns o
f SA
RS-C
oV-2
to th
e Sa
hel r
egio
n
24Ko
yam
a [4
1]Re
sear
ch a
rtic
leU
SACO
VID
-19
patie
nts
D61
4G, L
84S,
L36
06F,
D44
8del
and
G
392D
Seve
ral v
aria
nts
of th
e SA
RS-C
oV-2
gen
ome
exis
t, an
d th
at th
e D
614G
cl
ade
has
beco
me
the
mos
t com
mon
var
iant
sin
ce D
ecem
ber 2
019.
The
au
thor
s id
entifi
ed s
ix s
igni
fican
t cla
des
(tha
t is,
basa
l, D
614G
, L84
S, L
3606
F, D
448d
el, a
nd G
392D
) and
14
subc
lade
s. Re
gard
ing
the
base
cha
nges
, the
C
> T
mut
atio
n w
as th
e m
ost c
omm
on d
istin
ct v
aria
nts
25Ko
zlov
skay
a [4
2]Re
sear
ch a
rtic
leRu
ssia
COVI
D-1
9 pa
tient
sA
min
o ac
id s
ubst
itutio
nsA
spe
cific
set
of s
even
nuc
leot
ide
mut
atio
ns u
sing
am
ino
acid
sub
stitu
tions
in
spi
ke p
rote
in S
and
nuc
leop
rote
in N
, pos
sibl
y aff
ectin
g th
eir p
rope
rtie
s
Page 7 of 20SeyedAlinaghi et al. Eur J Med Res (2021) 26:51
Tabl
e 1
(con
tinue
d)
Vari
ants
of C
OVI
D-1
9
IDTh
e fir
st a
utho
r (re
fere
nce)
Type
of s
tudy
Coun
try
Stud
y po
pula
tion
Gen
omic
var
iant
sO
ther
26La
ha [2
5]Re
sear
ch a
rtic
leIn
dia
COVI
D-1
9 pa
tient
sN
ucle
otid
e an
d am
ino
acid
se
quen
ces
of O
RF1a
b, O
RF3a
, O
RF6,
ORF
7a, O
RF8,
ORF
10,
enve
lop
(E),
mem
bran
e (M
), nu
cleo
caps
id (N
), an
d su
rfac
e gl
ycop
rote
in (S
)
The
surf
ace
glyc
opro
tein
, nuc
leoc
apsi
d, O
RF1a
b, a
nd O
RF8
show
ed fr
eque
nt
mut
atio
ns, w
hile
env
elop
e, m
embr
ane,
ORF
6, O
RF7a
, and
ORF
7b s
how
ed
cons
erva
tion
in te
rms
of a
min
o ac
id s
ubst
itutio
ns. S
ome
of th
e m
utat
ions
ac
ross
diff
eren
t pro
tein
s sh
owed
co-
occu
rren
ces,
sugg
estin
g th
eir s
truc
-tu
ral a
nd/o
r fun
ctio
nal i
nter
actio
n am
ong
diffe
rent
SA
RS-C
OV-
2 pr
otei
ns
and
thei
r inv
olve
men
t in
adap
tabi
lity
and
vira
l tra
nsm
issi
on. A
naly
sis
of
prot
ein
stru
ctur
e st
abili
ty o
f sur
face
gly
copr
otei
n m
utan
ts in
dica
ted
the
viab
ility
of s
peci
fic v
aria
nts
and
are
mor
e pr
one
to b
e te
mpo
rally
and
sp
atia
lly d
istr
ibut
ed a
cros
s th
e gl
obe
27La
tini [
43]
Rese
arch
art
icle
Italy
COVI
D-1
9 pa
tient
sA
CE2
, TM
PRSS
2, P
CSK
3, D
PP4,
and
BS
G g
enes
It is
kno
wn
that
AC
E2 a
cts
as a
rece
ptor
for t
his
path
ogen
, but
the
vira
l ent
ry
into
the
targ
et c
ell a
lso
depe
nds
on o
ther
pro
tein
s. In
the
PCSK
3 ge
ne, w
e ob
serv
ed a
mis
sens
e va
riant
(c.8
93G
> A
) sta
tistic
ally
mor
e fre
quen
t com
-pa
red
to th
e EU
R G
nom
AD
refe
renc
e po
pula
tion
and
a m
isse
nse
mut
atio
n (c
.190
6A >
G) n
ot fo
und
in th
e G
nom
AD
dat
abas
e. In
the
TMPR
SS2
gene
, th
e au
thor
s ob
serv
ed a
sig
nific
ant d
iffer
ence
in c
.331
G >
A, c
.23G
> T,
and
c.
589G
> A
var
iant
alle
les
in C
OVI
D-1
9 pa
tient
s, co
mpa
red
to th
e co
r-re
spon
ding
alle
lic fr
eque
ncy
in G
nom
AD
. Gen
etic
var
iant
s in
thes
e ge
nes
coul
d in
fluen
ce th
e en
try
of th
e SA
RS-C
oV-2
. The
se d
ata
also
sup
port
the
hypo
thes
is th
at h
ost g
enet
ic v
aria
bilit
y m
ay c
ontr
ibut
e to
the
varia
bilit
y in
in
fect
ion
susc
eptib
ility
and
sev
erity
28La
u [4
4]Re
sear
ch a
rtic
leC
hina
COVI
D-1
9 pa
tient
sVe
ro-E
6 ce
llsTh
e pr
esen
ce o
f a d
istin
ct m
otif
in th
e S1
/S2
junc
tion
regi
on s
ugge
sts
the
poss
ible
acq
uisi
tion
of th
e cl
eava
ge s
ite(s
) in
the
spik
e pr
otei
n th
at
prom
oted
cro
ss-s
peci
es tr
ansm
issi
on. T
hrou
gh p
laqu
e pu
rifica
tion
of
Vero
-E6
cultu
red
SARS
-CoV
-2, w
e fo
und
a se
ries
of v
aria
nts
that
con
tain
15
–30-
bp d
elet
ions
(Del
–mut
) or p
oint
mut
atio
ns, r
espe
ctiv
ely,
at t
he S
1/S2
junc
tion.
The
uni
que
clea
vage
mot
if pr
omot
ing
SARS
-CoV
-2 in
fect
ion
in h
uman
s m
ay b
e un
der i
nten
se s
elec
tive
pres
sure
, giv
en th
at re
plic
atio
n in
per
mis
sive
Ver
o-E6
cel
ls le
ads
to th
e lo
ss o
f thi
s ad
aptiv
e fu
nctio
n
29Le
e [4
5]Re
sear
ch a
rtic
leJa
pan
COIV
D-1
9 pa
tient
sA
CE2
, TM
PRSS
2, T
LR7
Gen
ome‐
wid
e as
soci
atio
n st
udie
s ha
ve id
entifi
ed g
enet
ic ri
sk fa
ctor
s fo
r se
vere
CO
VID‐1
9 ca
ses
in a
seg
men
t of c
hrom
osom
e 3
that
invo
lves
six
ge
nes
enco
ding
thre
e im
mun
e‐re
gula
tory
che
mok
ine
rece
ptor
s an
d an
othe
r thr
ee m
olec
ules
. The
risk
hap
loty
pe s
eem
ed to
be
inhe
rited
fro
m N
eand
erth
als,
sugg
estin
g ge
netic
ada
ptat
ion
agai
nst p
atho
gens
in
mod
ern
hum
an e
volu
tion.
The
refo
re, S
ARS‐C
oV‐2
use
s hi
ghly
con
serv
ed
mol
ecul
es a
s its
viri
on in
tera
ctio
n, w
here
as it
s im
mun
e‐re
spon
se a
ppea
rs
to b
e ge
netic
ally
bia
sed
in in
divi
dual
s to
som
e ex
tent
30Li
u [4
6]Re
sear
ch a
rtic
leU
SACO
VID
-19
patie
nts
Sing
le-n
ucle
otid
e va
riant
s (S
NVs
)Fo
ur s
igna
ture
gro
ups
of fr
eque
ntly
occ
urre
d si
ngle
-nuc
leot
ide
varia
nts
(SN
Vs) w
ere
iden
tified
in o
ver t
wen
ty-e
ight
thou
sand
hig
h-qu
ality
and
hi
gh-c
over
age
SARS
-CoV
-2 c
ompl
ete
geno
me
sequ
ence
s, re
pres
ent-
ing
diffe
rent
vira
l str
ains
. Int
eres
tingl
y nu
cleo
tide
subs
titut
ions
am
ong
SARS
-CoV
-2 g
enom
es te
nded
to s
witc
h be
twee
n ba
t RaT
G13
cor
onav
irus
sequ
ence
and
Wuh
an-H
u-1
geno
me,
indi
catin
g th
e hi
gher
gen
etic
inst
a-bi
lity
or to
lera
nce
of m
utat
ions
on
thos
e si
tes
or s
ugge
stin
g th
at m
ajor
vi
ral s
trai
ns m
ight
exi
st b
etw
een
Wuh
an-H
u-1
and
RaTG
13 c
oron
aviru
s
Page 8 of 20SeyedAlinaghi et al. Eur J Med Res (2021) 26:51
Tabl
e 1
(con
tinue
d)
Vari
ants
of C
OVI
D-1
9
IDTh
e fir
st a
utho
r (re
fere
nce)
Type
of s
tudy
Coun
try
Stud
y po
pula
tion
Gen
omic
var
iant
sO
ther
31Lo
kman
[47]
Rese
arch
art
icle
Bang
lade
shCO
VID
-19
patie
nts
N-t
erm
inal
dom
ain
(NTD
) and
re
cept
or-b
indi
ng d
omai
n (R
BD)
and
angi
oten
sin-
conv
ertin
g en
zym
e 2
(AC
E2)
Spik
e gl
ycop
rote
in is
one
of t
he m
ajor
targ
ets
to b
e ex
plor
ed b
ecau
se o
f its
ro
le d
urin
g co
rona
viru
ses’
entr
y in
to h
ost c
ells
. Var
iatio
ns lo
cate
d at
the
N-t
erm
inal
dom
ain
(NTD
) and
the
rece
ptor
-bin
ding
dom
ain
(RBD
) mig
ht
alte
r the
inte
ract
ion
of S
pro
tein
with
the
host
rece
ptor
ang
iote
nsin
-co
nver
ting
enzy
me
2 (A
CE2
)
32M
uham
mad
Ans
ari [
48]
Rese
arch
art
icle
Indo
nesi
aCO
VID
-19
patie
nts
SARS
-CoV
-2 s
pike
gly
copr
otei
n ge
ne s
eque
nces
Ther
efor
e, th
e co
rona
viru
s sp
ike
glyc
opro
tein
med
iate
s m
embr
ane
fusi
on
and
vira
l ent
ry in
to h
ost c
ells
and
is th
e pr
imar
y ta
rget
for m
any
neut
ral-
izin
g an
tibod
ies.
The
spik
e gl
ycop
rote
in h
as tw
o do
mai
ns, S
1 an
d S2
, w
here
S1
is re
spon
sibl
e fo
r bin
ding
the
virio
n to
AC
E2 o
n th
e ho
st c
ell
mem
bran
e 21
. Sev
eral
ant
ivira
l dru
gs a
nd v
acci
nes
have
bee
n de
velo
ped
whi
ch ta
rget
the
spik
e gl
ycop
rote
in. T
here
was
no
sign
ifica
nt d
iffer
ence
be
twee
n th
e SA
RS-C
oV-2
spi
ke g
lyco
prot
ein
gene
seq
uenc
es fo
und
in
Indo
nesi
a an
d th
e W
uhan
-Hu-
1 is
olat
e fro
m C
hina
33M
ukhe
rjee
[49]
Rese
arch
art
icle
Indi
aCO
VID
-19
patie
nts
SARS
-CoV
-2 g
enom
e se
quen
ceTh
is s
tudy
sug
gest
ed a
pos
sibl
e cr
oss-
talk
bet
wee
n ho
st R
BPs-
miR
NA
s an
d vi
ral U
TR v
aria
nts
in S
ARS
-Cov
-2 in
fect
ion.
The
var
iatio
ns in
the
UTR
re
gion
s an
d bi
ndin
g of
hos
t RBP
to th
em re
mai
n m
ostly
una
ltere
d, w
hich
fu
rthe
r infl
uenc
ed s
peci
fic m
iRN
As’
func
tioni
ng
34Pa
chet
ti [5
0]Re
view
art
icle
Italy
COVI
D-1
9 pa
tient
sSA
RS-C
oV-2
gen
ome
sequ
ence
, Rd
Rp g
ene
The
viru
s is
evo
lvin
g, a
nd E
urop
ean,
Nor
th A
mer
ican
, and
Asi
an s
trai
ns
mig
ht c
oexi
st, e
ach
of th
em c
hara
cter
ized
by
a di
ffere
nt m
utat
ion
pat-
tern
. The
con
trib
utio
n of
the
mut
ated
RdR
p to
this
phe
nom
enon
nee
ds
to b
e in
vest
igat
ed. T
o da
te, s
ever
al d
rugs
targ
etin
g Rd
Rp e
nzym
es a
re
bein
g em
ploy
ed fo
r SA
RS-C
oV-2
infe
ctio
n tr
eatm
ent.
Som
e of
them
ha
ve a
pre
dict
ed b
indi
ng m
oiet
y in
a S
ARS
-CoV
-2 R
dRp
hydr
opho
bic
clef
t adj
acen
t to
the
14,4
08 m
utat
ions
we
iden
tified
. Con
sequ
ently
, it i
s im
port
ant t
o st
udy
and
char
acte
rize
SARS
-CoV
-2 R
dRp
mut
atio
n to
ass
ess
poss
ible
dru
g-re
sist
ance
vira
l phe
noty
pes.
It is
als
o im
port
ant t
o re
cogn
ize
whe
ther
the
pres
ence
of s
ome
mut
atio
ns m
ight
cor
rela
te w
ith d
iffer
ent
SARS
-CoV
-2 m
orta
lity
rate
s
35Pa
nchi
n [5
1]Re
sear
ch a
rtic
leRu
ssia
COVI
D-1
9 pa
tient
sSi
ngle
-nuc
leot
ide
varia
tions
Mut
atio
n pa
tter
ns o
f SA
RS-C
oV-2
hav
e ch
ange
d af
ter t
rans
mis
sion
to
hum
ans.
Ther
e ar
e tw
o re
mar
kabl
e ob
serv
atio
ns re
gard
ing
the
exce
ss o
f G
–U tr
ansv
ersi
ons
in S
ARS
-CoV
-2. O
ne is
the
chan
ge in
SA
RS-C
oV-2
mut
a-tio
n ra
tes
afte
r zoo
notic
tran
sfer
to h
uman
s si
nce
the
prop
ortio
n of
G–U
su
bstit
utio
ns m
easu
red
betw
een
the
SARS
-CoV
-2 a
nd th
e ba
t cor
onav
irus
RaTG
13 is
unr
emar
kabl
e. T
he s
econ
d re
mar
kabl
e fe
atur
e is
that
this
exc
ess
of m
utat
ions
is a
sym
met
ric: t
here
is n
o si
mila
r effe
ct fo
r C–A
mut
atio
ns
36Pa
rdo-
Seco
[52]
Lett
er to
the
edito
rSp
ain
COIV
D-1
9 pa
tient
sC
8782
T–T2
8144
CBa
rcod
es b
ased
on
wor
ldw
ide
data
base
s in
evita
bly
prio
ritiz
e va
riant
s lo
cate
d at
the
basa
l nod
es o
f the
phy
loge
ny, s
uch
that
mos
t rep
rese
nta-
tive
geno
mes
in th
ese
ance
stra
l nod
es a
re n
o lo
nger
in c
ircul
atio
n.
Cons
eque
ntly
, cor
onav
irus
phyl
odyn
amic
s ca
nnot
be
prop
erly
cap
ture
d by
uni
vers
al g
enom
ic b
arco
des
beca
use
mos
t SA
RS-C
oV-2
var
iatio
n is
ge
nera
ted
in g
eogr
aphi
cally
rest
ricte
d ar
eas
by th
e co
ntin
uous
intr
oduc
-tio
n of
dom
estic
var
iant
s
Page 9 of 20SeyedAlinaghi et al. Eur J Med Res (2021) 26:51
Tabl
e 1
(con
tinue
d)
Vari
ants
of C
OVI
D-1
9
IDTh
e fir
st a
utho
r (re
fere
nce)
Type
of s
tudy
Coun
try
Stud
y po
pula
tion
Gen
omic
var
iant
sO
ther
37Pa
rlika
r [53
]Re
sear
ch a
rtic
leIn
dia
COIV
D-1
9 pa
tient
s–
SARS
-CoV
-2 s
trai
ns fo
rm a
mon
ophy
letic
cla
de d
istin
ct fr
om S
ARS
-CoV
and
Pa
ngol
in C
oV th
at th
ey a
re c
lose
st to
the
Bat C
oV R
aTG
13 s
trai
n fo
llow
ed
by P
ango
lin C
oV, s
ugge
stin
g th
at S
ARS
-CoV
-2 e
volv
ed fr
om a
com
mon
an
cest
or p
utat
ivel
y re
sidi
ng in
bat
or p
ango
lin h
osts
. 44
prot
ein-
codi
ng
regi
ons
cons
titut
e th
e pa
n-ge
nom
e fo
r nin
etee
n ge
nus
Beta
coro
navi
rus
stra
ins.
Mor
eove
r, th
eir p
an-g
enom
e is
ope
n, h
ighl
ight
ing
the
wid
e di
vers
ity p
rovi
ded
by n
ewly
iden
tified
nov
el s
trai
ns. E
ven
mem
bers
of
subg
enus
Sar
beco
viru
s ar
e di
vers
e re
lativ
e to
eac
h ot
her d
ue to
the
rela
tive
pres
ence
of u
niqu
e pr
otei
n-co
ding
regi
ons
orf3
b, o
rf7b
, orf
8 an
d or
f9b
and
orf1
0
38Pe
ñarr
ubia
[54]
Rese
arch
art
icle
Spai
nCO
VID
-19
patie
nts
The
anno
tate
d si
ngle
-nuc
leot
ide
varia
tions
Giv
en th
at g
enet
ic v
aria
bilit
y in
the
SARS
-CoV
-2 g
enom
e is
exp
ecte
d to
in
crea
se b
ased
on
the
natu
ral v
iral m
utat
ion
and
reco
mbi
natio
n ra
tes,
our
resu
lts s
how
that
the
com
bina
tion
of m
ore
than
one
ass
ay ta
rget
in re
al-
time
RT-P
CR
SARS
-CoV
-2 p
anel
s ca
n m
itiga
te th
e ris
k of
loss
of s
ensi
tivity
or
spe
cific
ity
39Pe
ñarr
ubia
[55]
Rese
arch
art
icle
Spai
nSA
RS-C
oV-2
gen
omes
Gen
omic
var
iant
s de
tect
ed in
co
mpl
emen
tary
bin
ding
regi
ons
of e
arlie
st a
vaila
ble
SARS
-CoV
-2
RT-P
CR
assa
ys
Com
bina
tion
of m
ore
than
one
ass
ay ta
rget
in re
al-t
ime
RT-P
CR
SARS
-Co
V-2
pane
ls c
an m
itiga
te th
e ris
k of
loss
of s
ensi
tivity
or s
peci
ficity
. In
this
rega
rd, c
ontin
uous
mon
itorin
g of
gen
omic
var
iatio
ns is
ess
entia
l to
prov
ide
a ra
pid
resp
onse
in c
ase
assa
y re
-des
ign
is n
eede
d
40Po
rtel
li [5
6]Co
mm
enta
ryA
ustr
alia
stru
ctur
al d
istr
ibut
ion
of g
enet
ic v
ari-
atio
n in
SA
RS-C
oV-2
obt
aine
d fro
m
GIS
AID
and
CO
G-U
K
SARS
-CoV
-2 s
pike
pro
tein
’s A
CE2
-re
cept
or-b
indi
ng d
omai
ns
(QH
D43
416
p). A
sp61
4Gly
), SA
RS-C
oV-2
mai
n pr
otei
nase
do
mai
ns (Q
HD
4341
5_5)
That
stu
dy d
evel
oped
a c
ompr
ehen
sive
onl
ine
reso
urce
, CO
VID
-3D
, to
enab
le th
e an
alys
is a
nd in
terp
reta
tion
of v
aria
nts
dete
cted
in m
ore
than
12
5,00
0 SA
RS-C
oV-2
gen
omic
seq
uenc
es. T
he S
ARS
-CoV
-2 s
pike
pro
tein
bi
nds
h-A
CE2
, whi
ch m
edia
tes
cell
entr
y. S
ubse
quen
tly, t
he s
pike
pro
tein
’s A
CE2
-rec
epto
r-bi
ndin
g do
mai
n ha
s be
en th
e m
ain
targ
et o
f mos
t vac
cine
pr
ogra
ms.
Mea
sure
s of
sel
ectiv
e pr
essu
re s
ugge
st th
at th
e sp
ike
prot
ein
is o
ne o
f the
vira
l pro
tein
s m
ost t
oler
ant o
f int
rodu
cing
mut
atio
ns. C
lose
r in
spec
tion
indi
cate
s th
at s
ubst
antia
l var
iatio
n ca
n be
see
n ac
ross
the
prot
ein
surf
ace,
incl
udin
g in
pre
dict
ed e
pito
pe re
gion
s in
the
rece
ptor
-bi
ndin
g do
mai
n. O
f the
se v
aria
nts,
QH
D43
416
p.A
sp61
4Gly
is p
rese
nt
in tw
o-th
irds
of th
e se
quen
ced
stra
ins,
alth
ough
its
actu
al im
port
ance
re
mai
ns u
ncle
ar, d
espi
te in
itial
sug
gest
ions
that
it m
ay in
crea
se tr
ansm
issi
-bi
lity.
It is
iden
tified
sev
eral
gen
es u
nder
str
ong
purif
ying
sel
ectio
n. T
hese
in
clud
e th
e ge
nes
enco
ding
hel
icas
e, R
NA
pol
ymer
ase,
NSP
4, N
SP9,
and
Ex
oN, w
hich
may
ser
ve a
s no
vel,
prom
isin
g dr
ug ta
rget
s w
ith fe
w c
ircul
at-
ing
varia
nts
seen
nea
r the
dru
ggab
le p
ocke
ts
Page 10 of 20SeyedAlinaghi et al. Eur J Med Res (2021) 26:51
Tabl
e 1
(con
tinue
d)
Vari
ants
of C
OVI
D-1
9
IDTh
e fir
st a
utho
r (re
fere
nce)
Type
of s
tudy
Coun
try
Stud
y po
pula
tion
Gen
omic
var
iant
sO
ther
41Po
teric
o [5
7]Re
sear
ch a
rtic
lePe
ru69
1 SA
RS-C
oV-2
com
plet
e vi
ral
geno
mes
wor
ldw
ide,
incl
udin
g 30
ge
nom
es fr
om S
outh
Am
eric
an
coun
trie
s in
the
GIS
AID
dat
abas
e
ORF
1a (G
392D
in n
sp1,
T70
8I in
ns
p2, A
876T
and
A10
43V
in
nsp3
, N28
94D
and
F30
71Y
in
nsp4
, G33
34S
in n
sp5,
L36
06F
in
nsp6
), O
RF1b
(P31
4L in
nsp
12),
Spik
e pr
otei
n (D
614G
, E12
07V
), O
RF3a
(Q57
H, G
196V
, G25
1V),
Mem
bran
e ge
ne (T
175M
), O
RF8
(L84
S), N
gen
e (D
103Y
, R19
1C,
S197
L, G
238C
, R20
3K, G
204R
)
Our
resu
lts p
ortr
ay c
ircul
atin
g SA
RS‐C
oV‐2
Sou
th A
mer
ican
str
ains
com
ing
from
Eur
ope,
Nor
th A
mer
ica,
and
Oce
ania
; and
mos
tly b
elon
gs to
Cla
de
G. I
nfec
tivity
and
pat
hoge
nici
ty o
f SA
RS‐C
oV‐2
is re
late
d to
S p
rote
in,
mai
nly
due
to th
e h‐
AC
E2 b
indi
ng ri
dge
stru
ctur
al c
hang
es o
f the
RB
D d
omai
n, o
n re
sidu
es 4
82 to
485
: Gly
, Val
, Glu
, and
Gly
. Our
repo
rt
high
light
s tw
o st
rain
s w
ith n
ovel
var
iant
s on
the
S re
gion
, with
no
amin
o ac
id c
hang
e in
nt2
4022
(E12
07E)
, whe
reas
ano
ther
non
-syn
onym
ous
alte
ratio
n in
nt2
5182
(E12
07V
), fo
r Per
u (E
PI_I
SL_4
1578
7) a
nd E
cuad
or
(EPI
_ISL
_417
482)
, res
pect
ivel
y. H
owev
er, t
hese
cha
nges
see
m fa
r aw
ay
from
the
criti
cal r
egio
n of
S p
rote
in fo
r h‐A
CE2
affi
nity
. Due
to it
s pr
eva-
lenc
e, C
lade
G s
trai
ns c
ould
be
mor
e co
ntag
ious
than
oth
er s
ubty
pes
due
to n
ucle
otid
e ch
ange
s in
ORF
1ab
(nt8
750)
and
N (n
t290
63) g
enes
that
en
hanc
e vi
ral r
eplic
atio
n. W
e fo
und
8 (8
/30)
var
iatio
ns in
bot
h of
nt8
782
and
nt28
144
posi
tions
. Con
vers
ely,
oth
er re
gion
s se
em to
be
hots
pots
in
Sou
th A
mer
ican
str
ains
, with
11(
36.6
7%) o
f the
se p
ortr
ayin
g ch
ange
s at
5′U
TR (n
t241
), ns
p3 (n
t303
7), n
sp12
(nt1
4408
), an
d N
/ORF
9 (n
t288
81,
nt28
882,
and
nt2
8883
) reg
ions
. Thi
s is
par
amou
nt b
ecau
se c
hang
es in
ns
p1, n
sp3,
and
nsp
5 co
uld
be re
late
d to
som
e fu
nctio
ns o
f the
vira
l inc
u-ba
tion
perio
d an
d im
mun
e re
spon
se e
vasi
on o
f SA
RS‐C
oV‐2
. Am
ino
acid
al
tera
tions
in b
oth
of th
ese
regi
ons,
such
as
G39
2D (n
sp1)
, A87
6T, A
1043
(n
sp3)
, and
nsp
5 (G
3334
S); a
nd s
houl
d be
test
ed in
furt
her s
tudi
es. S
trik
-in
gly,
we
iden
tified
four
cha
nges
—nt
1532
4 in
ORF
1ab
(RdR
p), n
t261
44
in E
gen
e, n
t285
80, a
nd n
t286
57 in
the
nucl
eoca
psid
gen
e—in
the
sugg
este
d re
gion
s fo
r prim
er a
nnea
ling
for S
ARS‐C
oV‐2
spe
cific
frag
men
ts
iden
tifica
tion,
acc
ordi
ng to
real
-tim
e RT‐P
CR
reco
mm
enda
tions
from
the
WH
O. M
oreo
ver,
vira
l gen
omes
with
alte
ratio
ns o
n 14
408
and
23
403
posi
tions
hav
e be
en c
orre
late
d w
ith m
ore
mut
atio
ns (3
–4 p
er g
enom
e)
than
thei
r cou
nter
part
s w
ithou
t it.
All
Sout
h A
mer
ican
viru
ses
of C
lade
G
anal
yzed
in th
is re
port
hav
e m
utat
ions
con
com
itant
ly o
n 14
408
and
23
403
nucl
eotid
ic p
ositi
ons
42Ro
mer
o [5
8]Co
mm
enta
ryPe
ruSo
uth
Am
eric
an S
ARS‐C
oV‐2
gen
ome
sequ
ence
s in
the
SRA
dat
abas
em
utat
ion
N28
94D
in n
sp4,
non
-sy
nony
mou
s m
utat
ion
E120
7E
in th
e S
gene
The
de n
ovo
reas
sem
bly
and
map
ped
read
s pr
ovid
ed in
depe
nden
t ev
iden
ce to
val
idat
e Po
teric
o an
d M
esta
nza’s
mut
atio
ns b
ased
on
the
Peru
vian
SA
RS‐C
oV‐2
gen
ome.
Firs
t, m
utat
ion
N28
94D
in n
sp4
(Tab
le 1
in
ref.
1) c
orre
spon
ding
to a
cha
nge
from
A to
G in
the
nucl
eotid
e po
sitio
n 89
45 o
ccur
s on
ly in
few
read
s (4
out
of 3
3 m
appe
d re
ads)
. It i
s no
t con
-si
dere
d in
the
cons
ensu
s se
quen
ce in
the
de n
ovo
reas
sem
bly.
Thu
s, w
e sh
ould
be
caut
ious
in c
onsi
derin
g th
is m
utat
ion
as a
real
var
iant
. Sec
ond,
th
e au
thor
s re
port
ed a
non
-syn
onym
ous
mut
atio
n E1
207E
in th
e S
gene
; th
is c
orre
spon
ds to
T to
C in
the
nucl
eotid
e po
sitio
n 24
,022
. Aga
in, t
his
mut
atio
n oc
curr
ed o
nly
in 4
of 2
9 m
appe
d re
ads,
and
it is
not
pre
sent
in
the
cons
ensu
s se
quen
ce. T
his
evid
ence
sup
port
s th
e ne
cess
ity o
f usi
ng
orig
inal
seq
uenc
e re
ads
to v
erify
if th
e pr
evio
usly
des
crib
ed m
utat
ions
in
SA
RS‐C
oV‐2
gen
omes
are
acc
urat
e, a
ssem
bly
artif
acts
, or s
eque
ncin
g er
rors
Page 11 of 20SeyedAlinaghi et al. Eur J Med Res (2021) 26:51
Tabl
e 1
(con
tinue
d)
Vari
ants
of C
OVI
D-1
9
IDTh
e fir
st a
utho
r (re
fere
nce)
Type
of s
tudy
Coun
try
Stud
y po
pula
tion
Gen
omic
var
iant
sO
ther
43Sa
pova
l [59
]Re
sear
ch a
rtic
leU
SA69
28 S
ARS
-CoV
-2, 4
2 SA
RS-C
oV-1
, and
53
MER
S ge
nom
e da
tase
ts in
add
i-tio
n to
RN
A-s
eq d
atas
ets
from
151
CO
VID
-19
posi
tive
patie
nts
Intr
a-ho
st s
ingl
e-nu
cleo
tide
varia
nts
(iSN
Vs),
cons
ensu
s-le
vel
sing
le-n
ucle
otid
e po
lym
or-
phis
ms
(SN
Ps) a
nd s
truc
tura
l va
riant
s (S
Vs) i
n th
ree
clad
es V
, S
and
G
Thou
gh R
NA
viru
ses
mut
ate
mor
e ra
pidl
y th
an D
NA
viru
ses,
ther
e ar
e a
rela
-tiv
ely
smal
l num
ber o
f SN
Ps th
at d
iffer
entia
te th
e m
ain
SARS
-CoV
-2 c
lade
s th
at h
ave
spre
ad th
roug
hout
the
wor
ld. F
irst,
the
mut
atio
nal p
rofil
e of
SA
RS-C
oV-2
hig
hlig
hts
iSN
V an
d SN
P si
mila
rity,
alb
eit w
ith h
igh
varia
bilit
y in
C >
T ch
ange
s. G
enes
NSP
6 an
d N
SP10
are
par
ticul
arly
enr
iche
d fo
r T >
C
mut
atio
ns, w
hile
NSP
7 ha
s an
enr
ichm
ent o
f A >
C S
NVs
. Sec
ond,
iSN
V an
d SN
P pa
tter
ns in
SA
RS-C
oV-2
are
mor
e si
mila
r to
MER
S-Co
V th
an S
ARS
-Co
V-1;
exc
ept f
or s
igni
fican
tly la
rger
pro
port
ion
of G
> T
chan
ges
in b
oth
iSN
Vs a
nd S
NPs
. Thi
rd, a
sig
nific
ant f
ract
ion
of s
mal
l ind
els
fuel
the
gene
tic
dive
rsity
of S
ARS
-CoV
-2. F
ourt
h, th
e m
utat
iona
l spe
ctra
of t
he S
NPs
and
iS
NVs
indi
cate
that
ther
e is
a c
ompl
ex in
terp
lay
betw
een
endo
geno
us
SARS
-CoV
-2 m
utat
iona
l pro
cess
es a
nd h
ost-
depe
nden
t RN
A e
ditin
g. T
his
obse
rvat
ion
is in
line
with
sev
eral
rece
nt s
tudi
es th
at p
ropo
se A
POBE
C
and
AD
AR
deam
inas
e ac
tivity
as
a lik
ely
driv
er o
f the
C >
T ch
ange
s in
the
SARS
-CoV
-2 g
enom
es. T
he s
tudy
sho
wed
hig
h se
quen
ce c
onse
rvat
ion
with
in th
e N
SP3
regi
on, a
regi
on th
at is
one
of t
he m
ost d
iver
ged
from
SA
RS-C
oV-1
and
MER
S-Co
V. T
he lo
wer
NSP
3 m
utat
ions
are
due
to it
s es
sent
ial f
unct
iona
l im
plic
atio
ns in
vira
l rep
licat
ion,
thus
pro
mis
ing
NSP
3 as
a g
ood
targ
et fo
r dru
g de
velo
pmen
t. A
num
ber o
f con
verg
ent fi
ndin
gs
sugg
est d
e-m
ono-
AD
P-rib
osyl
atio
n of
STA
T1 b
y th
e SA
RS-C
oV-2
NSP
3 as
a
puta
tive
caus
e of
the
cyto
kine
sto
rm o
bser
ved
in th
e m
ost s
ever
e ca
ses
of
COVI
D-1
9. A
lso,
one
del
etio
n (a
t 282
45 b
p) w
as p
rese
nt in
10
sam
ples
(AF:
6%
) in
ORF
8, a
pot
entia
lly im
port
ant g
ene
for v
iral a
dapt
atio
n to
hum
ans
44Sa
rkar
[60]
Rese
arch
art
icle
Indi
a83
7 In
dian
SA
RS-C
oV-2
str
ains
33 d
iffer
ent m
utat
ions
; 18
of
whi
ch th
ese
wer
e un
ique
to
Indi
a: S
gly
copr
otei
n (L
54F,
K77M
, R78
M, D
294D
, E58
3D,
Q67
7H),
NSP
3 (G
716I
, T74
9I,
A99
4D, D
1121
G, S
1197
R), R
dRP
(A97
V, L
329I
, G57
1S, V
880I
), N
SP2
(S30
1F, G
339S
), an
d N
(S
194L
)
Non
-syn
onym
ous
mut
atio
ns w
ere
foun
d to
be
3.07
tim
es m
ore
prev
alen
t th
an s
ynon
ymou
s m
utat
ions
. The
A2a
cla
de w
as fo
und
to b
e do
min
ant i
n In
dia
(71.
34%
), fo
llow
ed b
y A
3 (2
3.29
%) a
nd B
(5.3
6%),
but a
het
erog
ene-
ous
dist
ribut
ion
was
obs
erve
d am
ong
vario
us g
eogr
aphi
cal r
egio
ns.
The
A2a
cla
de w
as h
ighl
y pr
edom
inan
t in
East
Indi
a, W
este
rn In
dia,
and
Ce
ntra
l Ind
ia, w
here
as th
e A
2a a
nd A
3 cl
ades
wer
e ne
arly
equ
al in
pre
va-
lenc
e in
Sou
th a
nd N
orth
Indi
a. D
614G
/S, a
cha
ract
eris
tic m
utat
ion
of th
e A
2 cl
ade
that
was
firs
t rep
orte
d in
Ger
man
y, h
as b
een
foun
d to
cor
rela
te
stro
ngly
with
hig
h in
fect
ivity
45Sh
en [6
1]Re
sear
ch a
rtic
leC
hina
Bron
choa
lveo
lar l
avag
e flu
id s
ampl
es
from
8 p
atie
nts
with
SA
RS-C
oV-2
, an
d 25
pat
ient
s w
ith c
omm
unity
-ac
quire
d pn
eum
onia
(CA
P), a
nd 2
0 he
alth
y co
ntro
ls fo
r com
paris
on
ORF
1a, O
RF1b
, S, O
RF3a
, E, M
, O
RF6,
ORF
7a, O
RF8,
N, O
RF10
m
utat
ions
The
med
ian
num
ber o
f int
ra-h
ost v
aria
nts
was
1–4
in S
ARS
-CoV
-2-in
fect
ed
patie
nts,
rang
ed fr
om 0
to 5
1 in
diff
eren
t sam
ples
, sug
gest
ing
a hi
gh e
vo-
lutio
n ra
te o
f the
viru
s. Th
e di
strib
utio
n of
var
iant
s on
gen
es w
as s
imila
r to
thos
e ob
serv
ed in
the
popu
latio
n da
ta. H
owev
er, v
ery
few
intr
a-ho
st
varia
nts
wer
e ob
serv
ed in
the
popu
latio
n as
pol
ymor
phis
ms,
impl
ying
ei
ther
a b
ottle
neck
or p
urify
ing
sele
ctio
n in
volv
ed in
the
tran
smis
sion
of
the
viru
s or
a c
onse
quen
ce o
f the
lim
ited
dive
rsity
repr
esen
ted
in th
e cu
r-re
nt p
olym
orph
ism
dat
a. A
lthou
gh re
cent
evi
denc
e di
d no
t sup
port
the
tran
smis
sion
of i
ntra
-hos
t var
iant
s in
a p
ossi
ble
pers
on-t
o-pe
rson
spr
ead,
th
e ris
k sh
ould
not
be
over
look
ed. M
icro
biot
a in
SA
RS-C
oV-2
-infe
cted
pa
tient
s w
ere
sim
ilar t
o th
ose
in C
AP,
eith
er d
omin
ated
by
the
path
ogen
s or
with
ele
vate
d le
vels
of o
ral a
nd u
pper
resp
irato
ry c
omm
ensa
l bac
teria
. SA
RS-C
oV-2
evo
lves
in v
ivo
afte
r inf
ectio
n, a
ffect
ing
its v
irule
nce,
infe
ctiv
-ity
, and
tran
smis
sibi
lity
Page 12 of 20SeyedAlinaghi et al. Eur J Med Res (2021) 26:51
Tabl
e 1
(con
tinue
d)
Vari
ants
of C
OVI
D-1
9
IDTh
e fir
st a
utho
r (re
fere
nce)
Type
of s
tudy
Coun
try
Stud
y po
pula
tion
Gen
omic
var
iant
sO
ther
46Si
ngh
[62]
Rese
arch
art
icle
Indi
a1,
325
com
plet
e dr
aft g
enom
ic
sequ
ence
s of
SA
RS-C
oV-2
and
ad
ditio
nal 2
79 C
DS
havi
ng p
artia
l ge
nom
es c
odin
g sp
ike
prot
ein
from
N
CBI
dat
abas
e
RBD
(A34
8V, V
367F
, A41
9S, T
323I
, A
344S
, R40
8I, G
476S
, V48
3A,
H51
9Q, A
520S
, A52
2S, K
529E
, T3
23I,
A34
4S, V
367F
, A41
9S,
A52
2S, a
nd K
529E
)
The
sign
ifica
nt v
aria
tions
in th
e pr
edic
ted
epito
pes
show
ing
high
ant
igen
ic-
ity w
ere
A34
8V, V
367F
, and
A41
9S in
the
rece
ptor
-bin
ding
dom
ain
(RBD
). O
ther
mut
atio
ns o
bser
ved
with
in R
BD e
xhib
iting
low
ant
igen
icity
wer
e T3
23I,
A34
4S, R
408I
, G47
6S, V
483A
, H51
9Q, A
520S
, A52
2S, a
nd K
529E
. The
RB
D T
323I
, A34
4S, V
367F
, A41
9S, A
522S
, and
K52
9E a
re n
ovel
mut
atio
ns
repo
rted
for t
he fi
rst t
ime
in th
is s
tudy
. Mor
eove
r, A
930V
and
D93
6Y m
uta-
tions
wer
e ob
serv
ed in
the
hept
ad re
peat
dom
ain,
and
one
mut
atio
n,
D11
68H
, was
not
ed in
hep
tad
repe
at d
omai
n 2.
S p
rote
in is
the
prim
ary
targ
et fo
r vac
cine
dev
elop
men
t, bu
t sev
eral
mut
atio
ns w
ere
pred
icte
d in
S
prot
ein’
s an
tigen
ic e
pito
pes
acro
ss a
ll ge
nom
es a
vaila
ble
glob
ally
. The
em
erge
nce
of v
ario
us m
utat
ions
with
in a
sho
rt p
erio
d m
ight
resu
lt in
con
-fo
rmat
iona
l cha
nges
in th
e pr
otei
n st
ruct
ure,
sug
gest
ing
that
dev
elop
ing
a un
iver
sal v
acci
ne m
ay b
e a
chal
leng
ing
task
47Ta
boad
a [6
3]Re
sear
ch a
rtic
leM
exic
oCo
vid-
19 p
atie
nts
pres
ent t
he fu
ll ge
nom
e se
quen
ce
for 1
7 SA
RS-C
oV-2
isol
ates
co
rres
pond
ing
to th
e ea
rlies
t sa
mpl
ed c
ases
in M
exic
o
The
auth
ors
repo
rted
that
the
initi
al v
irus
stra
ins
intr
oduc
ed in
Mex
ico
cam
e fro
m E
urop
e an
d th
e U
nite
d St
ates
. The
viru
s w
as c
ircul
atin
g lo
cally
in th
e co
untr
y as
ear
ly a
s m
id-M
arch
. The
y al
so fo
und
evid
ence
for e
arly
loca
l tr
ansm
issi
on o
f str
ains
with
an
H49
Y m
utat
ion
in th
e Sp
ike
prot
ein,
whi
ch
coul
d be
furt
her u
sed
as a
mol
ecul
ar m
arke
r to
follo
w v
iral s
prea
d w
ithin
th
e co
untr
y an
d th
e re
gion
48Th
iele
n [6
4]Re
sear
ch a
rtic
leU
SA62
0 sa
mpl
es fr
om th
e Jo
hns
Hop
kins
H
ealth
Sys
tem
col
lect
ed b
etw
een
Mar
ch 1
1–31
, 202
0; 1
43 o
f whi
ch
was
seq
uenc
ed, g
ener
atin
g 11
4 co
mpl
ete
vira
l gen
omes
Iden
tified
a to
tal o
f 153
uni
que,
un
ambi
guou
s si
ngle
-nuc
leot
ide
varia
nts
acro
ss a
ll se
quen
ces
(54
syno
nym
ous
varia
nts,
91
non-
syn
onym
ous
varia
nts,
8 no
ncod
ing
varia
nts)
com
pare
d to
the
Wuh
an-H
u-1
SARS
-CoV
-2
refe
renc
e ge
nom
e
Thes
e ge
nom
es b
elon
g to
all
five
maj
or N
ext s
trai
n-de
fined
cla
des,
sugg
est-
ing
mul
tiple
intr
oduc
tions
into
the
regi
on a
nd u
nder
scor
ing
the
dive
rsity
of
the
regi
onal
epi
dem
ic. W
e al
so fo
und
that
clin
ical
ly s
ever
e ca
ses
had
geno
mes
bel
ongi
ng to
all
of th
ese
clad
es. W
e fo
und
no c
lear
cor
rela
tion,
bu
t wer
e lim
ited
by s
ampl
e si
ze. S
imila
rly, p
atie
nt p
heno
type
s in
clud
ing
sex,
race
, rec
ent t
rave
l, sy
mpt
oms,
and
com
orbi
ditie
s w
ere
repr
esen
ted
acro
ss a
ll fiv
e m
ajor
phy
loge
netic
cla
des,
sugg
estin
g th
at s
usce
ptib
ility
w
as in
depe
nden
t of c
lade
. The
wid
ely
exam
ined
mut
atio
n in
the
vira
l sp
ike
prot
ein
(D61
4G) 2
8–30
is o
ne o
f the
key
mut
atio
ns d
iffer
entia
ting
the
19 a
nd 2
0 cl
ades
. Not
ably
, we
see
seve
re c
ases
in b
oth
of th
ese
clad
es,
thou
gh o
ur d
atas
et is
und
erpo
wer
ed to
sho
w s
igni
fican
t cor
rela
tions
be
twee
n vi
ral g
enom
e m
utat
ions
and
dis
ease
sev
erity
. The
div
ersi
ty o
f vi
rus
gene
tics,
clin
ical
sym
ptom
s, an
d pa
tient
out
com
es s
ugge
sts
that
vi
ral m
utat
ions
are
not
the
mai
n dr
iver
of c
linic
al p
rese
ntat
ion
49To
yosh
ima
[65]
Rese
arch
art
icle
Japa
nCo
vid-
19 p
atie
nts
One
thou
sand
two
hund
red
thirt
y-fo
ur m
utat
ions
by
com
parin
g w
ith th
e re
fere
nce
SARS
-CoV
-2
sequ
ence
All
repl
icat
ing
viru
ses,
incl
udin
g co
rona
viru
s, co
ntin
uous
ly a
ccum
ulat
e ge
nom
ic m
utat
ions
that
per
sist
due
to n
atur
al s
elec
tions
. The
se m
utat
ions
co
ntrib
ute
to th
e en
hanc
emen
t of t
he a
bilit
y of
vira
l pro
lifer
atio
n an
d in
fect
ion
and
an e
scap
e fro
m h
ost i
mm
une
atta
ck
50U
gure
l [66
]Re
sear
ch a
rtic
leTu
rkey
Covi
d-19
pat
ient
sVa
riatio
ns in
SA
RS-C
oV-2
gen
ome
Des
pite
som
e va
riatio
ns b
eing
in lo
w-fr
eque
ncy
rate
in s
ome
cont
inen
ts,
C14
408T
and
A23
403G
var
iatio
ns o
n N
sp12
and
S p
rote
in, r
espe
ctiv
ely,
w
ere
obse
rved
to b
e th
e m
ost p
rom
inen
t var
iatio
ns a
ll ov
er th
e w
orld
, in
gene
ral,
and
both
cau
se m
isse
nse
mut
atio
ns. I
t is
also
not
able
that
mos
t is
olat
es c
arry
C14
408T
and
A23
403
varia
tions
sim
ulta
neou
sly,
and
als
o ne
arly
all
isol
ates
car
ryin
g th
e G
2556
3T v
aria
tion
on O
RF3a
, als
o ca
rry
C14
408T
and
A23
403
varia
tions
, alth
ough
thei
r loc
atio
n di
strib
utio
ns a
re
not s
imila
r
Page 13 of 20SeyedAlinaghi et al. Eur J Med Res (2021) 26:51
Tabl
e 1
(con
tinue
d)
Vari
ants
of C
OVI
D-1
9
IDTh
e fir
st a
utho
r (re
fere
nce)
Type
of s
tudy
Coun
try
Stud
y po
pula
tion
Gen
omic
var
iant
sO
ther
51va
n D
orp
[67]
Rese
arch
art
icle
UK
7710
SA
RS-C
oV-2
ass
embl
ies
flagg
ed
as “c
ompl
ete
(> 2
9,00
0 bp
)”, “h
igh
cove
rage
onl
y”, “
low
cov
erag
e ex
cl”
wer
e do
wnl
oade
d fro
m th
e G
ISA
ID
Initi
ativ
e Ep
iCoV
pla
tform
as
of A
pril
19 2
020
Iden
tified
198
hom
opla
sy
posi
tions
in th
e SA
RS-C
oV-2
ge
nom
e al
ignm
ent (
0.67
% o
f all
site
s) w
hich
was
ass
ocia
ted
with
29
0 am
ino
acid
cha
nges
acr
oss
all g
enom
es; 2
32 n
on-s
ynon
-ym
ous
and
58 s
ynon
ymou
s m
utat
ions
. Tw
o no
n-sy
nony
-m
ous
mut
atio
ns in
volv
ed th
e in
trod
uctio
n or
rem
oval
of s
top
codo
ns w
ere
foun
d (*
1340
2Y,
*261
52G
)
One
of t
he s
tron
gest
hom
opla
sies
lies
at s
ite 1
1,08
3 in
the
SARS
-CoV
-2
geno
mes
in a
regi
on o
f Orf
1a e
ncod
ing
Nsp
6. T
his
site
pas
sed
our
strin
gent
filte
ring
crite
ria a
nd w
as a
lso
pres
ent i
n ou
r ana
lysi
s of
the
SRA
dat
aset
. Int
eres
tingl
y, th
is re
gion
ove
rlaps
a p
utat
ive
imm
unog
enic
pe
ptid
e pr
edic
ted
to re
sult
in b
oth
CD
4+ a
nd C
D8+
T c
ell r
eact
ivity
. Mor
e m
inor
hom
opla
sies
am
ong
our t
op c
andi
date
s, id
entifi
ed w
ithin
Orf
3a,
also
map
to a
pre
dict
ed C
D4
T ce
ll ep
itope
of n
ote,
we
also
iden
tify
a st
rong
recu
rren
t mut
atio
n in
nuc
leot
ide
posi
tion
21,5
75, c
orre
spon
ding
to
the
SARS
-CoV
-2 s
pike
pro
tein
(cod
on 5
). W
hile
the
spik
e pr
otei
n is
the
know
n m
edia
tor o
f hos
t cel
l ent
ry, o
ur d
etec
ted
hom
opla
sy fa
lls o
utsi
de
of th
e N
-ter
min
al a
nd re
cept
or-b
indi
ng d
omai
ns
52W
ang
[68]
Rese
arch
art
icle
Chi
naCo
vid-
19 p
atie
nts
Ana
lyze
d se
quen
ce v
aria
tions
al
ong
the
SARS
-CoV
-2 g
enom
eTh
ere
may
be
sele
ctiv
e m
utat
ions
in S
ARS
-CO
V-2,
and
it is
nec
essa
ry to
av
oid
cert
ain
regi
ons
whe
n de
sign
ing
prim
ers
and
prob
es. T
he e
stab
lish-
men
t of t
he re
fere
nce
sequ
ence
for S
ARS
-CoV
-2 c
ould
ben
efit n
ot o
nly
the
biol
ogic
al s
tudy
of t
his
viru
s bu
t als
o di
agno
sis,
clin
ical
mon
itorin
g,
and
inte
rven
tion
of S
ARS
-CoV
-2 in
fect
ion
in th
e fu
ture
53Xi
ao [6
9]Re
sear
ch a
rtic
leC
hina
Clin
ical
spe
cim
ens
(incl
udin
g th
roat
sw
ab, n
asal
sw
ab, a
n an
al s
wab
, and
sp
utum
) obt
aine
d fro
m c
onfir
med
CO
VID
-19
case
s at
the
Firs
t Affi
liate
d H
ospi
tal o
f Gua
ngzh
ou M
edic
al
Uni
vers
ity
SARS
-CoV
-2 g
enom
e se
quen
ces
This
wor
k off
ers
prac
tical
gui
danc
e fo
r gen
ome
sequ
enci
ng a
nd a
naly
ses
of S
ARS
-CoV
-2 a
nd o
ther
em
ergi
ng v
iruse
s. W
e de
mon
stra
ted
that
bot
h am
plic
on a
nd c
aptu
re m
etho
ds e
ffici
ently
enr
iche
d SA
RS-C
oV-2
con
tent
fro
m c
linic
al s
ampl
es, w
hile
the
enric
hmen
t effi
cien
cy o
f am
plic
on o
utra
n th
at o
f cap
ture
in m
ore
chal
leng
ing
sam
ples
54Ya
p [7
0]Re
sear
ch a
rtic
leSo
uthe
ast
Asi
a co
un-
trie
s
142
com
plet
e se
quen
ces
of S
ARS
-Co
V-2
from
six
of t
he S
EA c
ount
ries,
incl
udin
g Ca
mbo
dia
(n =
1),
Mal
aysi
a (n
= 1
6), t
he P
hilip
pine
s/Ph
ilipp
ines
(n
= 1
2), S
inga
pore
(n =
74)
, Tha
iland
(n
= 3
1) a
nd V
ietn
am (n
= 8
)
ORF
1a, O
RF1b
, S, M
, E, O
RF3a
, O
RF6,
ORF
7a, O
RF8,
ORF
10Th
e au
thor
s fo
cuse
d on
mut
atio
ns th
at h
ave
emer
ged
mul
tiple
tim
es a
nd
iden
tified
22
recu
rren
t mut
atio
ns in
the
SEA
SA
RS-C
oV-2
gen
omes
. The
y al
so n
ote
that
nea
rly 7
5% o
f the
hits
als
o ov
erla
p w
ith c
andi
date
mut
a-tio
ns, w
hich
may
affe
ct th
e ph
enot
ype
of S
ARS
-CoV
-2 id
entifi
ed b
y Va
n D
orp
et a
l. The
cur
rent
gen
omes
stu
died
sho
wed
phy
loge
netic
rela
tion
with
com
mon
recu
rren
t mut
atio
ns. C
lust
er I
exhi
bite
d co
mm
on re
curr
ent
mut
atio
n at
878
2C >
T in
ORF
1ab
(n =
35)
. For
ster
et a
l. ob
serv
ed th
at th
e an
cest
ral S
var
iant
with
thes
e tw
o m
utat
ions
at 8
782C
> T
and
2814
4 T
> C
w
as p
redo
min
antly
iden
tified
in E
ast A
sia.
Stil
l, th
is v
aria
nt o
utsi
de o
f Asi
a w
as o
bser
ved
with
str
ikin
g, lo
ng m
utat
iona
l bra
nch
leng
ths.
The
G v
aria
nt
was
rare
ly s
ampl
ed in
Asi
a bu
t cor
resp
onde
d to
the
mos
t fre
quen
t var
iant
in
Eur
ope.
In th
is s
tudy
, G v
aria
nts
wer
e id
entifi
ed in
str
ains
pre
dom
inan
tly
from
Tha
iland
, fol
low
ed b
y Si
ngap
ore
and
Viet
nam
. Clu
ster
III b
elon
ged
to c
lade
s ou
tsid
e th
e re
port
ed S
, G, a
nd V
sha
red
mut
atio
ns d
istin
guis
hed
clad
es, a
nd a
t 631
2C >
A, 1
1083
G >
T, 1
3730
C >
T, a
nd 1
9524
C >
T in
O
RF1a
b, 2
3929
C >
T in
spi
ke, a
nd 2
8311
C >
T in
the
N p
rote
in (n
= 3
8). T
his
varia
nt w
as o
bser
ved
in s
trai
ns fr
om M
alay
sia,
the
Phili
ppin
es, a
nd S
inga
-po
re fr
om m
id-M
arch
onw
ards
. On
Apr
il 19
, 202
0, a
new
clu
ster
em
erge
d fro
m s
tude
nts
retu
rnin
g to
Mal
aysi
a fro
m In
done
sia
Page 14 of 20SeyedAlinaghi et al. Eur J Med Res (2021) 26:51
Tabl
e 1
(con
tinue
d)
Vari
ants
of C
OVI
D-1
9
IDTh
e fir
st a
utho
r (re
fere
nce)
Type
of s
tudy
Coun
try
Stud
y po
pula
tion
Gen
omic
var
iant
sO
ther
55Zh
ang
[18]
Rese
arch
art
icle
Chi
na97
com
plet
e ge
nom
es o
f CO
VID
-19
sam
ples
from
GIS
AID
Thre
e ty
pe-s
peci
fic v
aria
nts
cor-
resp
ond
to th
e ge
nom
ic p
osi-
tions
875
0, 2
8112
, and
290
63,
resp
ectiv
ely;
the
coor
dina
tes
are
refe
rred
to a
s th
e se
quen
ce
MN
9383
84.1
COVI
D-1
9 st
rain
s fo
rm tw
o w
ell-s
uppo
rted
cla
des
(gen
otyp
e I,
or T
ype
I, an
d Ty
pe II
). Th
e tw
o ty
pes’
geno
mes
mai
nly
diffe
r at t
hree
site
s, w
hich
ar
e 87
5028
112
and
2906
3, b
ased
on
MN
9383
84.1
’s ge
nom
e co
ordi
nate
s. Sp
ecifi
cally
, the
nuc
leot
ides
at t
he th
ree
area
s ar
e T,
C, a
nd T
/C in
Typ
e I,
and
C, T
, and
C in
Typ
e II,
resp
ectiv
ely.
Bas
ed o
n th
e nu
cleo
tide
at th
e si
te
2906
3, th
e Ty
pe I
stra
ins
can
be fu
rthe
r div
ided
into
Typ
e IA
and
IB. T
he
num
ber o
f gen
omes
bel
ongi
ng to
type
IA, I
B, a
nd is
10
18 a
nd 6
9. T
ype
II st
rain
s w
ere
likel
y ev
olve
d fro
m T
ype
I and
are
mor
e pr
eval
ent t
han
Type
I am
ong
infe
cted
pat
ient
s (6
8 Ty
pe II
str
ains
vs.
29 T
ype
I str
ains
in to
tal).
The
ou
tbre
ak o
f typ
e II
COVI
D-1
9 lik
ely
occu
rred
in th
e H
uana
n m
arke
t, w
hile
th
e in
itial
tran
smis
sion
of t
he ty
pe I
viru
s to
hum
ans
prob
ably
hap
pene
d at
a d
iffer
ent l
ocat
ion
in W
uhan
. By
anal
yzin
g th
e th
ree
geno
mic
site
s di
stin
guis
hing
Typ
e I a
nd T
ype
II st
rain
s, th
ey fo
und
that
the
syno
nym
ous
chan
ges
at tw
o of
the
thre
e si
tes
conf
er h
ighe
r pro
tein
tran
slat
iona
l effi
-ci
enci
es in
Typ
e II
stra
ins
than
in T
ype
I str
ains
, whi
ch m
ight
exp
lain
why
Ty
pe II
str
ains
are
mor
e pr
eval
ent,
impl
ying
that
Typ
e II
is m
ore
cont
agio
us
(tra
nsm
issi
ble)
than
Typ
e I
56Zh
u [7
1]Re
sear
ch a
rtic
leC
hina
27,3
88 fu
ll-le
ngth
CO
VID
-19
geno
mes
(c
olle
cted
from
Dec
embe
r, 20
19 to
M
ay, 2
020
from
GIS
AID
, NC
BI, C
oVdb
an
d Vi
ral Z
one
9 ne
w m
utat
ions
; SN
P-24
1 C
> T,
SN
P-30
37 C
> T,
SN
P-87
82 C
> T,
SN
P-14
408
C >
T, S
NP-
2340
3 A
> G
, SN
P-28
144
T >
C, S
NP-
2888
1 G
> A
, SN
P-28
882
G >
A
and
SNP-
2888
3 G
> C
; whe
re th
e ge
nom
e of
the
stra
in M
N90
8947
is
use
d as
the
refe
renc
e
The
9 ne
wly
evo
lved
SA
RS-C
oV-2
sin
gle-
nucl
eotid
e po
lym
orph
ism
(SN
P)
alle
les
repo
rted
, und
erw
ent a
rapi
d in
crea
se(7
cas
es) 0
or d
ecre
ase
(2
case
s) in
thei
r fre
quen
cy fo
r 30–
80%
in th
e in
itial
four
mon
ths,
whi
ch a
re
furt
her c
onfir
med
by
intr
a-ho
st s
ingl
e-nu
cleo
tide
varia
tion
(iSN
V) a
naly
sis
usin
g ra
w s
eque
nce
data
incl
udin
g 82
17 s
ampl
es. T
he 9
SN
Ps a
re m
ostly
(8
/9) l
ocat
ed in
the
codi
ng re
gion
and
are
mai
nly
(6/9
) non
-syn
onym
ous
subs
titut
ions
. The
y sh
ow a
com
plet
e lin
kage
in S
NP
pairs
and
bel
ong
to
3 di
ffere
nt li
nkag
e gr
oups
, nam
ed L
G_1
–LG
_3. A
naly
ses
in p
opul
atio
n ge
netic
s sh
ow s
igna
ture
s of
ada
ptiv
e se
lect
ion
tow
ard
the
mut
ants
in
LG_1
, but
no
sign
al o
f sel
ectio
n fo
r LG
_2. P
opul
atio
n ge
netic
ana
lysi
s re
sults
on
LG_3
sho
w g
eolo
gica
l diff
eren
tiatio
n. A
naly
ses
on g
eogr
aphi
c CO
VID
-19
case
s an
d pu
blis
hed
clin
ical
dat
a pr
ovid
e ev
iden
ce th
at th
e m
utan
ts in
LG
_1 a
nd L
G_3
ben
efit v
irus
repl
icat
ion
and
thos
e in
LG
_1
have
a p
ositi
ve c
orre
latio
n w
ith th
e di
seas
e se
verit
y in
CO
VID
-19-
infe
cted
pa
tient
s. Th
e m
utan
ts in
LG
_2 s
how
a b
ias
tow
ard
mild
ness
of t
he d
isea
se
base
d on
ava
ilabl
e pu
blic
clin
ical
dat
a
Nov
azzi
[72]
Case
repo
rtIta
ly66
-yea
r-ol
d Ita
lian
mal
e w
ho te
sted
po
sitiv
e fo
r B.1
.351
. Aft
er re
turn
ing
from
Mal
awi (
Afri
ca)
B.1.
351
in P
AN
GO
LIN
phy
loge
ny
or 2
0H/5
01Y.
V2 in
Nex
tStr
ain
phyl
ogen
y
Des
pite
sig
nific
ant r
esis
tanc
e to
con
vale
scen
t pla
sma
and
seve
ral m
Abs
, se
ra fr
om h
uman
sub
ject
s va
ccin
ated
with
mRN
A-1
273
led
to 2
.7 a
nd
a 6.
4-fo
ld g
eom
etric
mea
n re
duct
ion
in n
eutr
aliz
atio
n (b
ut s
till 1
:190
) ag
ains
t K41
7N +
E48
4K +
N50
1Y +
D61
4G o
r ful
l B.1
.351
Spi
ke p
seu-
dovi
rus,
resp
ectiv
ely,
whe
n co
mpa
red
to th
e D
614G
VSV
pse
udov
irus.
Sim
ilarly
, ser
a fro
m h
uman
sub
ject
s va
ccin
ated
with
BN
T162
b2 le
d to
0.
81- t
o a
1.46
-fold
geo
met
ric m
ean
redu
ctio
n in
neu
tral
izat
ion
agai
nst
an E
484K
+ N
501Y
+ D
614G
spi
ke p
seud
oviru
s fin
ally
, ser
a fro
m p
erso
ns
vacc
inat
ed w
ith o
ne o
f 2 C
hine
se v
acci
nes
(BBI
BP-C
orV
or re
com
bina
nt
dim
eric
RBD
vac
cine
ZF2
001)
larg
ely
pres
erve
d ne
utra
lizin
g tit
res,
with
a
slig
ht re
duct
ion,
aga
inst
501
Y.V2
aut
hent
ic v
irus
Page 15 of 20SeyedAlinaghi et al. Eur J Med Res (2021) 26:51
mutations. The mutation of single-stranded RNA viruses is much faster than the human genome’s mutation rate, about 10–6–10–4 and 10–8, respectively [76, 77]. This leads to numerous quasi-species in each infected one, which may justify the observed difference in symptoms and disease severity [78]. Altered ACE2 binding interactions or shifted tissue tropism may happen due to a mutation among viral progeny that causes aggressive and immense infections [20].
Evolutionary benefits such as changing a primary epitope to escape from the host immune system or changing virulence factors to enhance transmission of the virus can occur due to gene mutations. Natural selection or vaccine selective pressure can cause these mutations and subsequently lead to new viral strains [79]. Prelimi-nary studies at the beginning of the outbreak identified two major genotypes of SARS-CoV-2 among a Chinese population, type Ι, and type ΙΙ [18]. The prevalence of the aggressive form had decreased in the early months due to the start of treatment, and its mild form became the common variant [24].
Further studies reported the identification of three major variant types (A, B, C) of SARS-CoV-2, based on amino acid changes [22]. Forster et al. confirmed those three major variant types by phylogenetic analysis of 160 viral genomes [32]. Interestingly, variant A is the conventional type; type B viruses prevailed in East Asia, while both type A and C viruses have been dominant in America and Europe. After two mutations, including the synonymous mutation T8782C and the non-synonymous mutation C28144T, by replacing serine with leucine in type A, type B is formed. Type C is also derived from type B by the non-synonymous mutation G26144T, in which valine replaces glycine [32, 80, 81]. In other words, the S variant (Type A) with two mutations at 8782C>T and 28144 T>C was mainly identified in East Asia. Still, out-side Asia, significant and long mutations were observed with the length of the branches. The G variant was domi-nant in Europe and was rare in Asia [70]. Bhowmik et al. reported two D and E subgrouping of the influential group A. Moreover, they stated that the SARS-CoV-2 genome is around 29,903 nucleotides. The highly muta-ble spike (S) protein of the virus is probably related to the increased human-to-human transmission rate through interaction with the host’s ACE2 receptor [20]. Ugurel et al. reported C14408T variant on Nsp12 and A23403G variation on S protein, and both cause significant muta-tions and changes in virus variants worldwide [66].
Recent studies around the world have identified eight strains of SARS-CoV-2. However, they have a signifi-cant sequence similarity [50]. Also, Liu et al. have been recognized four distinct groups of common mononu-cleotide types (SNVs) in more than 28,000 high-quality, Ta
ble
1 (c
ontin
ued)
Vari
ants
of C
OVI
D-1
9
IDTh
e fir
st a
utho
r (re
fere
nce)
Type
of s
tudy
Coun
try
Stud
y po
pula
tion
Gen
omic
var
iant
sO
ther
Faria
[73]
Repo
rts
Braz
ilCo
vid-
19 p
atie
nts
P.1Li
neag
e P.1
, acq
uire
d 17
mut
atio
ns, i
nclu
ding
a tr
io in
the
spik
e pr
otei
n (K
417T
, E48
4K, a
nd N
501Y
) ass
ocia
ted
with
incr
ease
d bi
ndin
g to
the
hum
an A
CE2
rece
ptor
Ferr
eira
[74]
Rese
arch
art
icle
UK,
Indi
aCo
vid-
19 p
atie
nts
B.1.
617
The
defin
ing
mut
atio
ns in
B.1
.617
.1 s
pike
are
L45
2R a
nd E
484Q
in th
e RB
D
that
inte
ract
s w
ith A
CE2
and
is th
e ta
rget
of n
eutr
aliz
ing
antib
odie
s
Page 16 of 20SeyedAlinaghi et al. Eur J Med Res (2021) 26:51
high-coverage SARS-CoV-2 complete genome sequences, demonstrating different viral strains [46]. These reports are consistent with the findings of two studies in Italy and the United States, where about 4–10 non-synonymous stable mutations were reported in the SARS genome [11, 50]. Eke, one of the mutations in S protein (D614G), has been seen repeatedly in Europe and the United States since the onset of the infection, apparently because it has dramatically increased the transmission ability of SARS-CoV-2. Thus, it became the most common variant [41, 56].
Although the mutation of the SARS-CoV-2 appears to be stable, consecutive consideration of virus mutations remains essential. A large study by Poterico and col-leagues characterized two novel mutations in the S region across 691 complete viral genomes of SARS-CoV-2 from around the world. They also highlighted that the virus had acquired about 27 mutations, and most of South American countries’ trains are nearly related to Euro-pean viral isolates [57]. Meanwhile, a unique mutation 24351C (A930V (T)) in the spike surface glycoprotein was reported in one of the Wuhan strains in India [24]. In a study conducted in Singapore, the cause of SARS attenuation was attributed to the 382-nucleotide deletion in ORF8 of the viral genome [23]. In a survey conducted in mid-March in Mexico, evidence of local translocation of strains with an H49Y mutation in Spike protein strains was reported [63]. According to the findings of Castello et al., the first three cases of ORF amino acid are classi-fied as S type in position 28 144; nevertheless, the fourth case is a G type in position 23 403 [29].
The effect of the variants on the viral transmissionSeveral studies have reported the association between the transmissibility and different variants and mutations [18, 20, 25, 27, 44, 51, 56, 57, 63, 75]. Some mutations facilitate the transmission of SARS-CoV-2 between ani-mal species and humans. The G-U transversion excess might play a role in the bat to human transmission [51]. Besides, the S1/S2 junction region’s specific motif may have caused the viral exchange between species [44].
Regarding the viral transmission between humans, some fundamental facts are noteworthy. The rapid viral replication might cause rapid morbidity and mortal-ity and hinder the viral passage to healthy individuals. Viruses causing slower replications and asymptomatic or mild disease can allow the transmission for a more extended period [27]. Furthermore, mutations alter-ing viral structure might increase virulence or help-ing the pathogen escape the immune system, resulting in higher transmission rates [75]. Type II SARS-CoV-2 strains possibly spreading through the Huanan seafood market were also considered more prevalent than type I
viruses, probably due to being more contagious [18]. Sev-eral mutations are proposed to increase transmissibility [20, 57, 63, 75]. Variants possessing immensely mutable S proteins might be more contagious due to their inter-action with the host ACE2 [20]. Concurrently, a spe-cific mutation (D614G) in the S protein might speed up the viral transmission [75, 82]. The role of QHD43416 p.Asp614Gly variant in many strains is controversial and not fully understood [56, 82]. H49Y mutation in the S protein may also be responsible for local transmissions in earlier stages. It was proposed as a potential marker to trace the viral spreading between the countries and regions [63]. ORF1ab (nt8750) and N (nt29063) are also the identified responsible genes for the higher transmis-sibility of clade G strain [57].
Variant effects on symptoms, morbidity, and mortalityPneumonia and lung involvement is often the main clini-cal sign of COVID-19. Recent evidence also demonstrates gastrointestinal symptoms and asymptomatic infections [83]. The percentage of people infected with the corona-virus who remain asymptomatic during infection has not yet been accurately assessed and reported. Symptomatic patients often have clinical symptoms of fatigue, cough, nasal congestion, fever, and other signs of upper respira-tory tract infections that usually appear after a week. The condition can develop into severe disease with dyspnea and severe chest symptoms [84, 85], and the respiratory tract infections are known as the primary clinical signs of COVID-19 [86].
In COVID-19, pneumonia usually manifests in the sec-ond or third week of symptomatic infection. Prominent signs of viral pneumonia include reduced oxygen satura-tion, blood gas deviations. Changes can be seen through chest X-rays and other imaging techniques, leading to the deterioration of vital signs and death. Lymphope-nia (abnormally low level of lymphocytes in the blood) is common in these patients, and inflammatory mark-ers (C-reactive protein and pro-inflammatory cytokines) could also increase [85, 87]. Furthermore, specific genetic mutations in the coronavirus can even increase mortality [85, 87].
Other relevant findingsCOVID-19 mortality rates differ substantially depending on the country. This difference in mortality rates depends on various factors in each country, including the ade-quacy of health care delivery, political decisions, and epi-demiological characteristics of the affected population. The frequency of diagnostic and screening measures in asymptomatic or mildly symptomatic patients may also affect morbidity and mortality [88, 89].
Page 17 of 20SeyedAlinaghi et al. Eur J Med Res (2021) 26:51
Studies have demonstrated a steadfast and transpar-ent pattern of age-based exponential enhancement in mortality, regardless of geographic area, in patients with COVID-19. Age-related mortality changes are relatively common for COVID-19 because other significant causes of mortality, especially chronic diseases such as cardio-vascular disease, could also be increased by advanced ages [90]. Promislow et al. have shown that the mortality rate doubling time (MRDT) of all-cause fatality 9 years in the United States was close to that of COVID-19 in New York City [91]. In other words, there is no significant relationship between age and increased death in patients with COVID-19. However, many scientists and the media have paid particular attention to age as a risk factor for mortality in COVID-19. Nonetheless, the age-related pattern of death from COVID-19 is different from other respiratory viral infections. The pattern of morbidity and mortality is higher in the elderly than in young people [90].
LimitationsAlthough this systematic review produces valuable knowledge regarding the COVID-19 variants and related morbidity and mortality, there were some shortcomings. First, the number of published reports is still limited. The knowledge regarding the different strains and variants and their effects on the symptoms, morbidity, and mor-tality is not entirely described yet. Furthermore, various countries ought to report their data to identify the world-wide distribution of these variants. Researchers might also strive to discover various novel mutations resulting in different viral behaviors in the future.
ConclusionOverall, researchers identified several SARS-CoV-2 vari-ants changing clinical manifestations and increasing the transmissibility, morbidity, and mortality of COVID-19; however, many observations produced controversial results. Variants with asymptomatic disease or milder disease can increase their transmission by extending the duration of contact between sick and healthy peo-ple. Mutations causing increased virulence and immune escapes might also cause an elevated transmissibility level. As the vaccine inoculations are increasing world-wide, we encourage researching for potential mutations that might escape vaccine-induced immunity. The cur-rent practice and interventions should consider these findings to combat the COVID-19 pandemic and prevent related morbidity and mortality.
AcknowledgementsThe present study was conducted in collaboration with Khalkhal University of Medical Sciences, Iranian Institute for Reduction of High-Risk Behaviors, Tehran University of Medical Sciences, and Department of Global Health and Socioepidemiology, Kyoto University.
Authors’ contributionsThe conception and design of the study: EM, SS. Acquisition of data: AK, ZP, OD. Analysis and interpretation of data: PM, FV, AB. Drafting the article: EM, MM, AMA, MH. Revising it critically for important intellectual content: MS, AS, FB, SS. Final approval of the version to be submitted: EM, OD, SJ. All authors read and approved the final manuscript.
FundingThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Availability of data and materialsThe authors stated that all information provided in this article could be shared.
Declarations
Ethics approval and consent to participateThe present study was extracted from the research project with code IR.KHALUMS.REC.1399.001 entitled "Investigation of effective drugs for people affected by Coronavirus disease 2019 (COVID-19) in Imam Khomeyni hospital " conducted at Khalkhal University of Medical Sciences in 2020. We thank all the participants for taking the time to contribute to the study.
Consent for publicationNot applicable.
Competing interestsThe authors declare that there is no conflict of interests regarding the publica-tion of this manuscript.
Author details1 Iranian Research Center for HIV/AIDS, Iranian Institute for Reduction of High Risk Behaviors, Tehran University of Medical Sciences, Tehran, Iran. 2 Depart-ment of Global Health and Socioepidemiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. 3 Chronic Respiratory Disease Research Center, Masih Daneshvari Hospital, Tehran, Iran. 4 School of Medicine, Tehran Uni-versity of Medical Sciences, Tehran, Iran. 5 Ophthalmology Resident at Farabi Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. 6 School of Medicine, Islamic Azad University, Tehran, Iran. 7 Department of Radiology, School of Medicine, University of California, San Diego, CA, USA. 8 Department of Health Information Technology, Esfarayen Faculty of Medical Sciences, Esfarayen, Iran. 9 Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran. 10 Department of Nurs-ing, Khalkhal University of Medical Sciences, Khalkhal, Iran. 11 Department of Health Information Technology, Khalkhal University of Medical Sciences, 1419733141 Khalkhal, Iran. 12 Department of Public Health and Community Medicine, Tufts University School of Medicine, Boston, MA, USA.
Received: 9 February 2021 Accepted: 28 May 2021
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