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Redefining viruses: lessons from
Mimivirus
Didier Raoult and Patrick Forterre
Abstract | Viruses are the most abundant living entities and probably had a major role
in the evolution of life, but are still defined using negative criteria. Here, we propose
to divide biological entities into two groups of organisms: ribosome-encoding
organisms, which include eukaryotic, archaeal and bacterial organisms, and capsidencoding organisms, which include viruses. Other replicons (for example, plasmids
and viroids) can be termed ‘orphan replicons’. Based on this suggested classification
system, we propose a new definition for a virus — a capsid-encoding organism that is
composed of proteins and nucleic acids, self-assembles in a nucleocapsid and uses a
ribosome-encoding organism for the completion of its life cycle.
The Darwinian revolution created a new
approach to classification by proposing a
common origin for living organisms. Since
then, scientists have grouped animals and
plants phylogenetically, rather than by gross
appearance. The genetic revolution and our
ability to build trees based on genetic similarities provided support for this method
of classification. Over the past 30 years, the
development of more efficient sequencing
strategies has led to the reclassification of
organisms into a universal tree of life based
on ribosomal RNA sequences1. Viruses,
however, lack ribosomes and have not yet
been incorporated into this universal tree
of life.
Until now, the genetic information that
is encoded by viruses was not thought to
contain sufficient information to allow their
general phylogenetic classification, and
consequently no clear definition of viruses
is currently available. This is unfortunate, as
viruses are the most abundant living entities
on the planet2 and metagenomic studies from
randomly sequenced environmental samples
have revealed that viral genes constitute
the largest part of the genosphere2,3. Recent
research has revealed an important role for
viruses in various evolutionary scenarios,
including the origin of DNA and mammals4–7. Here, based on our knowledge of
archaea, archaeal viruses8 and intracellular
bacteria9, and the recent discovery of the
largest known virus, Mimivirus10–13 (FIG. 1),
we propose a new definition for the virus life
form. Of course, any attempt to redefine an
entire field will be controversial; however, a
debate of this issue, using all of the currently
available data, is needed. We propose a definition of viruses (and cells) that is based on
the hypothesis that viruses are more than just
parasitic nucleic acids and that the presence
of either capsids or ribosomes forms the
basis of the principal classification system in
the living world.
Defining viruses — a history
According to Karl Popper14, definitions
are based on the data and tools that are
available at a specific moment in time. In
the nineteenth century, the word ‘microbes’
was coined by Sedillot15 to define cellular
microorganisms that were only visible using
a microscope. In the middle of the twentieth
century, microorganisms were divided into
two groups, eukaryotes and prokaryotes,
based on cellular structural features16.
Eukaryotic cells have a nucleus and a nuclear
membrane, whereas prokaryotic cells do not
(although Planctomycetes, such as Gemmata
obscuriglobus, are bacteria that have a nucleus
and a nuclear membrane)16. In the last part of
the twentieth century, molecular-biology tools
opened the way for a new classification system
nature reviews | microbiology
for all cellular organisms. Carl Woese17,18
discovered the existence of three different ribosomes in the living world, which
replaced the old prokaryote–eukaryote
dichotomy with a trinity — archaea, bacteria
and eukarya. All cellular organisms could
thus be placed together in a universal tree
of life. Viruses, however, were missing from
this picture.
Unlike most other microorganisms,
viruses are obligate intracellular parasites that
cannot replicate independently. They can
infect organisms from all three domains of
life, and can even parasitize other viruses;
for example, the delta agent (with the
hepatitis B virus19) and satellite viruses
(with an adenovirus or tobacco mosaic
virus (TMV)20,21). Despite their ubiquity
and enormous importance to human
health, viruses have long been neglected by
evolutionary biologists, and are thought to
be derived from cells. Indeed, as a direct
consequence of the cellular theory that
was established in the nineteenth century,
living organisms and cellular organisms are
synonymous to most scientists.
Viruses were initially thought to be
infectious agents that are not visible under
a microscope and can be filtered through
0.22 µm ultrafilters (hence the name
‘ultravirus’)22,23. During the twentieth
century, researchers developed two theories
about viruses. The bacteriologists Felix
d’Herelle, who discovered bacteriophages,
and Macfarlane Burnet, who received the
Nobel Prize in medicine in 1960, believed
that viruses were organisms24,25 (as did Louis
Pasteur), whereas Wendell Stanley26, who
crystallized TMV and received the Nobel
Prize in chemistry in 1946, believed that
viruses were biomolecules. Later, while promoting the eukaryote–prokaryote dichotomy,
Andre Lwoff 22 defined viruses as small (one
dimension smaller than 0.2 µm), infectious,
but not autonomous, agents that cannot
divide by binary fission, and consist of proteins and a single type of nucleic acid. Lwoff
insisted that viruses are not organisms and
maintained that the infectious element of
the virus is the nucleic acid, unlike bacteria
or other pathogens, in which the infectious
agent is the organism itself (although this
theory has been contradicted recently27).
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© 2008 Nature Publishing Group
Perspectives
MV
N
VF
2 µm
Figure 1 | Mimivirus infecting Acanthamoeba polyphaga. Transmission electron microscope image
that shows A. polyphaga infected with Mimivirus. Note the giant virus factory. N, nucleus; VF, virus
Nature Reviews | Microbiology
factory; MV, Mimivirus virions.
Viruses were thus tacitly defined by most
molecular biologists as molecular genetic
parasites that use cellular systems for their
own replication22. Indeed, with such a broad
definition, many types of selfish genetic
elements (such as plasmids, transposons,
retroposons, viroids and virusoids) were
determined to be viruses. For example,
Koonin et al.28,29 recently grouped all infectious-material-containing nucleic acids as
either selfish elements and/or viruses and
used these terms synonymously.
Each of the definitions for viruses has
recently been challenged by the discovery
of viruses that are larger than cellular
organisms10,30. Indeed, both the particle and
genome sizes of viruses now overlap significantly with those of bacteria, eukaryotes
and archaea. Mimivirus, the largest known
virus, is visible with an optical microscope,
contains a 1.2 megabase chromosome that
encodes nearly 1,000 putative genes and
harbours both RNA and DNA11. Moreover,
if exposed to a Gram-stain procedure,
Mimivirus stains Gram-positive, and was
thought for a period to be a ‘Legionella-like
organism’. Interestingly, Mimivirus was
identified as a virus only a few years ago,
when its icosahedral capsid was observed
using an electron microscope13. The size of
Mimivirus challenges the definition of a virus
and even the definition of a microorganism
as a living entity.
Defining organisms and living entities
The general consensus of what constitutes
life can be sampled by consulting a global
resource such as Wikipedia (the largest
free online encyclopaedia; see Further
information), which defines life as ‘‘a
condition that distinguishes organisms
from inorganic objects’’. However, there
is no universal definition of life. The
frequently used ‘reproduction’ criterion
does not apply to sterile organisms. The
distinction between parasites (replicators)
and free-living organisms cannot be used
to distinguish between organisms. There is
now no clear-cut limit between mitochondria, small symbionts, intracellular bacteria
(such as Rickettsia spp. and Candidatus
Carsonella spp.) and free-living bacteria
in size or phylogenetically31. Some recent
definitions of life, such as another from
Wikipedia — “life is a characteristic of self
organizing, self recycling systems consisting of populations of replicators that are
capable of mutation, around most of which
homeostatic, metabolizing organisms
evolve” — clearly include viruses. We can
also paraphrase Engels32 and define life as
“the mode of existence of living organisms”,
which brings us to the problem of organism
definition.
The definition of an organism is a difficult problem in itself and is subject to
controversy. An organism has been defined
316 | april 2008 | volume 6
as “An individual living system such as
animal, plant, fungus or microorganism”
by Wikipedia, “An individual animal, plant
or single-celled life form” by the Oxford
English Dictionary Online and “Any living
structure capable of growth and reproduction” by Chambers Reference Online (see
Further information). The definitions
from Wikipedia and the Oxford English
Dictionary Online exclude intracellular
parasites, symbionts, organelles and viruses.
The definition from Chambers Reference
Online, however, includes viruses and
nucleic acids, as it does not retain the word
cell. Mimivirus changed the perception of
viruses and could also change the definition of an organism. Mimivirus virions
are assembled at the periphery of a large
membrane-bound nucleus-like structure
— the viral factory — within the host cell
(FIG. 1). Although viral factories have been
described for most eukaryotic viruses
(both RNA and DNA)33, the viral factory
of the Mimivirus is especially spectacular12
and, when first observed using an electron
microscope, was initially thought to be the
nucleus of its giant amoebae host. JeanMichel Claverie34 proposed that viruses
are entities that are associated with an
intracellular viral factory, and should not be
confused with virions. Interestingly, from
this view, a virus is similar to an intracellular organism, which therefore further blurs
the boundary between cellular organisms
and viruses.
The virus definition can also be modified by the distinction between a virus
and a virion. A virus can be generated
from synthetic oligonucleotides by wholegenome assembly to produce infectious
virions35. Therefore, we believe that a
virus can be entirely defined by its coding
capacity. As for bacteria, it was recently
shown that genome transplantation from
one species to another is possible, and
that cells which were transplanted with
the genome of Mycoplasma mycoides were
phenotypically identical to M. mycoides27;
here, the genome defined the whole bacterium. Experiments which showed that
synthesized or purified nucleic acids from
either viruses or bacteria can infect hosts
and be replicated, show that there are no
fundamental differences between these living entities. Based on these recent data, we
believe that organisms and living entities
can be defined by genome analysis.
Finally, we retain the more liberal definition of organisms and living entities as it
applies to viruses, and thus reclassify viruses
according to their genome content.
www.nature.com/reviews/micro
© 2008 Nature Publishing Group
Perspectives
J
K
A
L
D
Mimivirus
Nanoarchaeum equitans
Candidatus Carsonella ruddii
Encephalitozoon cuniculi
O
M
N
J
K
A
L
D
O
M
N
P
T
B
U
Z
V
C
G
E
F
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P
Functional gene category
Ribosome-encoding organisms
To determine a natural classification for all
living organisms, we suggest that it is necessary to redefine what is meant by a cellular
organism. We can now compare the genetic
information that is encoded by cellular organisms from the three domains of life as well
as that of a virus of similar proportions30. As
illustrated in FIG. 2, the only significant differences in the distribution of clusters of orthologous groups (COGs) of gene categories
between the smallest cellular organisms —
Candidatus Carsonella ruddii (a bacterium)36,
Nanoarchaeum equitans (an archaeon),
Encephalitozoon cuniculi (a eukaryote) and
Mimivirus — are the number of genes that
are involved in translation, which is much
lower in Mimivirus owing to the lack of
ribosomal proteins, and the lack of any COGs
that are involved in energy production and
conversion in the virus. Although the absence
of these genes is a negative characteristic that
cannot be used to group viruses together, it is
also a positive feature that groups all cellular
organisms. These genes might have been lost
independently many times during a parasitic
mode of life by convergent evolution. Such
convergent evolution was noted for intracellular bacteria that had lost most of the genes
that encode metabolic pathways31, and this is
also the case for mitochondria, chloroplasts
and symbionts. In particular, the genes that
are involved in protein synthesis, specifically
those that encode ribosomal proteins and
ribosomal RNA, are among the few genes
that are conserved in all cellular organisms,
including the smallest intracellular parasites37.
This is because the last universal common
ancestor (LUCA) probably possessed a
sophisticated ribosome that contained at least
34 ribosomal proteins that are shared by all
archaeal, bacterial and eukaryotic organisms.
The descendants of the LUCA (or some of
its predecessors) have superseded all other
cellular life forms that could have used other
mechanisms to synthesize their proteins.
Although some RNA viruses (for example,
arenaviruses) do contain ribosomes within
their capsids, these ribosomes are native
to their hosts, and the absence of genes that
encode ribosomal proteins is common to
all viruses. Thus, we suggest that all cellular
organisms can be adequately defined as ribosome-encoding organisms (REOs), as opposed
to viruses. Interestingly, in contrast to the
view that is advocated by Lwoff 22, mitochondria and chloroplasts would be classified as
REOs based on this definition (instead of as
cellular organelles) because they contain their
own translation apparatus1. There is indeed
no clear difference, either morphologically or
T
B
U
Z
V
C
G
E
F
H
I
Q
Translation
Transcription
RNA processing and modification
Replication, recombination and repair
Cell-cycle control, mitosis and meiosis
Post-translational modification, protein turnover and chaperones
Cell-wall and membrane biogenesis
Cell motility
Inorganic ion transport and metabolism
Signal-transduction mechanisms
Chromatin structure and dynamics
Intracellular trafficking and secretion
Cytoskeleton
Defence mechanisms
Energy production and conversion
Carbohydrate transport and metabolism
Amino acid transport and metabolism
Nucleotide transport and metabolism
Coenzyme transport and metabolism
Lipid transport and metabolism
Secondary metabolite biosynthesis, transport and catabolism
General function (prediction only)
Function unknown
R
S
0
20
40
60
80
100
120
140
160
Number of COGs
Figure 2 | Clusters of orthologous groups (COGs) in Mimivirus and traditional cellular organisms.
Distribution by categories of cluster of orthologous groups’ homologues in Mimivirus, compared
with cellular organisms from the three domains of life that have the smallest currently known
Nature Reviews | Microbiology
genomes: Nanoarchaeum equitans (archaea), Candidatus Carsonella
ruddii (bacteria) and
Encephalitozoon cuniculi (eukarya).
genetically, between mitochondria, symbionts
and intracellular bacteria such as Candidatus
Carsonella spp. and Rickettsia spp.
Capsid-encoding organisms
By analysing all infectious materials other
than REOs, which range from a few hundred
base pairs, such as the single-stranded RNA
molecule that is carried by capsid borrowed
from a helper virus (virusoid and satellite
RNA)19, to the giant Mimivirus, it is clear
that no single common protein exists in the
virosphere. There is no genetic equivalent
in this group to the ribosomal-RNA or
universal proteins that are common to
REOs. Furthermore, virus-specific proteins
are only found in subsets of viral groups.
Consequently, protein phylogenies have only
been useful to tentatively establish a classification for selected virus groups. For example,
according to Iyer et al.38, nucleo–cytoplasmic
large DNA viruses (NCLDVs), such as
nature reviews | microbiology
Mimiviruses, could be classified based on a
set of conserved proteins that are involved in
viral DNA replication and transcription11,38.
Although the viral-factory structure can
be viewed as an ‘organismal’ form of the virus,
it cannot be used to define viruses because,
first, the presence of viral factories has not yet
been demonstrated in archaeal and bacterial
viruses (possibly for methodological reasons
or because the whole cell is transformed into
a viral factory) and, second, it is not known
if all viral factories share a common feature,
although they do disseminate their genetic
information in the same way (through the
linear or exponential multiplication of nucleic
acids and massive production of virions).
We propose that the expression of a capsid
is the only positive determinant that can be
considered to define viruses. The viral capsid
is a necessary structure that is used by the
viral factory to disseminate the virus outside
of the REO host and infect new hosts. Indeed,
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© 2008 Nature Publishing Group
Perspectives
PBCV1 Vp54
PRD1 P3
I
DG
B
I
C
HE F
C′ F′
B′ I′
G′
D′ H′E′
STIV
DG
B C
HE F
B′
C terminus
C terminus
N terminus
B
B′
F′
G′ C′E′
H′
I′ D′
G
D
I
C
B HE F
N terminus
N terminus
B
B′
G′ C′
H′E′ F′
B′ I′ D′
C terminus
B
B′
Figure 3 | Capsid proteins from viruses that infect organisms fromNature
all three
domains of life.
Reviews | Microbiology
Comparison of the major capsid-protein structures from viruses that can infect the three domains of
life: the major capsid protein of virus Paramecium bursaria Chlorella virus 1 (PBCV1) (Vp54; Protein Data
Bank (PDB) code 1M4X), which infects Chlorella-like eukaryotes; the bacteriophage PRD1 coat protein
P3 subunit (PDB code 1cjd), which infects the bacterium Escherichia coli; and the capsid protein of virus
Sulfolobus turreted icosahedral virus (STIV) (PDB code 2BBD), which infects the hyperthermophilic
archaeon Sulfolobus solfataricus P2. These three capsid proteins contain the typical double-jelly-roll
fold (shown in red) that is absent from cellular proteins, which confirms that these structures originated
from a common ancestral protein. Other features shared by these viruses suggest that this protein was
already a capsid protein of an ancestral virus that was present at the time of the last universal common
ancestor, or even earlier. C terminus, carboxyl terminus; N terminus, amino terminus.
the viral capsid has been called the ‘virus
self ’ by Dennis Bamford and colleagues39,
who first identified clear homologous traits
between capsid proteins and the capsid architecture of viruses that were infecting bacteria
(enterobacteria phage PRD1) and eukarya
(an adenovirus)40. Later, it was shown that
the double-jelly-roll fold (which has not been
found in any cellular protein) is also present
in the capsid proteins of Paramecium bursaria
Chlorella virus 1 (PBCV1), an NCLDV that
infects eukaryotic algae41, and Sulfolobus turreted icosahedral virus (STIV), an archaeal
virus that was isolated from a Yellowstone hot
spring42 (FIG. 3). Modelling experiments have
shown that the capsid protein of Mimivirus
contains the same fold, which suggests that it
is present in all NCLDVs43. All these viruses
are double-stranded DNA viruses and have
an internal lipid layer (with the exception of
adenoviruses). These observations favour
the hypothesis that an ancient form of virus
that had this type of capsid predates, or was a
contemporary of, the LUCA43. Interestingly,
the double-jelly-roll fold, which is common
to double-stranded DNA viruses that have
an internal lipid layer, is also present in the
capsid proteins of some single-stranded
RNA viruses, and single-jelly-roll folds are
observed in the capsid proteins of many other
DNA and RNA viruses. It will be important
to determine if, as suggested by Rossmann
and co-workers41, all these jelly-roll folds are
evolutionarily related, which would suggest
a common and ancient origin for some
DNA and RNA viruses. Capsids probably
have multiple origins, as different unique
folds are present in the capsid proteins of
otherwise apparently unrelated viruses (and
again are absent from any cellular proteins)
which links head-and-tailed bacterial viruses
(Caudovirales) and eukaryotic herpesviruses44. Future work should compare the coat
proteins of viruses that have non-icosahedral
morphologies (filamentous, rod-shaped or
pleomorphic) to identify additional folds that
are unique to viral capsids.
Capsids might originally have been storage devices that were designed to protect
nucleic acids that were accidentally released
from lysed cells. These structures could
have been selected within an intracellular
parasite because of their ability to disseminate multiple replication copies by uncoupling replication of the parasite genome from
that of the host genome. Capsids that possess
the associated mechanisms that are used
to exit from one host cell and enter a new
host are specific and complex structures
that could have appeared independently
several times; however, we argue that this
event would not have occurred frequently
over the course of evolutionary time. In
any case, the appearance of capsids was
a crucial event in the early evolution of
life that resulted in divergence among
all subsequent organisms. We therefore
propose to define viruses as capsid encoding organisms (CEOs). The presence of
a capsid defines a group of living entities
that contain nucleic acid and a capsid, and
overlaps one of the trivial virus definitions.
318 | april 2008 | volume 6
In addition to capsids, analyses of the
genomes of viruses and related elements, such
as plasmids, have revealed the existence of
replication proteins, such as the superfamily
III helicases, protein-primed DNA polymerases and rolling-circle initiator proteins, that
have no cellular homologues, but are present
in viruses that infect organisms in different
domains. This suggests that these proteins
were never encoded by cellular genomes or
that they originated in ancient cellular lineages that were wiped out by the descendants
of the LUCA38.
The diversity of viral RNA- and DNAreplication mechanisms and their associated
proteins indicates that various types of
replicons originated in an ancient virosphere
and, possibly, even predate the LUCA4,29.
Consequently, the origin of viruses could
stem from an association between cassettes
of capsid-encoding genes and particular replicons (including an origin of replication and
genes that encoded replication-machinery
proteins which could have used this origin for
self-replication).
Interestingly, most genes that are encoded
by viruses which infect organisms in all three
domains of life have no cellular homologues,
which is in contrast to the traditional view
that viruses are derived from genetic elements that escaped from cells and became
infectious. The persistence of two different
names for viruses — those that are associated
Caspid-encoding organisms
Viruses of Bacteria
Viruses of Eukarya
Viruses of Archaea
Bacteria
Archaea
Eukarya
Ribosome-encoding organisms
Figure 4 | Redefining viruses. Representation
of viruses with their capsids, and the three
Nature Reviews | Microbiology
domains of life that have evolved from the last
universal common ancestor. The three domains
have ribosomes, but lack a capsid. The newly
defined viruses have a capsid, but no ribosome.
Other infectious elements are not shown.
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© 2008 Nature Publishing Group
Perspectives
with bacteria (bacteriophages) and those that
are associated with eukaryotic cells (viruses)
— is, therefore, confusing. In our proposal,
viruses that infect cellular organisms from
all three domains of cellular life should be
unified under a common name, CEOs, and
classified according to their capsids, as previously suggested by Bamford39. For practical
reasons, it will be also useful, in some cases,
to discriminate viruses by the domain of their
host: as bacterioviruses (those that infect bacteria; previously known as bacteriophages),
archaeoviruses (those that infect archaea) or
eukaryoviruses (those that infect eukaryotes).
To summarize, we propose to redefine
viruses as CEOs that are composed of proteins and nucleic acids that self-assemble in
a nucleocapsid, do not multiply by binary
fission and use an REO for the synthesis of
their proteins and production of the energy
and precursor molecules that are required
for their life cycle (FIG. 4).
worlds have evolved in parallel. One form
of life expresses ribosomes and comprises
three domains: archaea, bacteria and eukarya.
The other form of life expresses capsids that
produce virions which infect REOs from each
of these three domains.
Didier Raoult is at the Unité des Rickettsies, IRD-CNRS
UMR 6236, IFR‑48, Faculté de Médecine,
27 Bd Jean Moulin, 13385 Marseille, France.
Patrick Forterre is at the Institut Pasteur, 25 rue du
Docteur Roux, 75015 Paris1, France, and the University
Paris Sud, Institut de Génétique et Microbiologie,
CNRS, UMR 8626 IRF‑115, Centre d’Orsay,
91405 Orsay, France.
Correspondence to D.R.
e‑mail: [email protected]
doi:10.1038/nrmicro1858
Published online 3 March 2008
1.
2.
3.
4.
Orphan replicons
How can we classify infectious genetic elements that do not encode either capsids or
ribosomes (including viroids, virusoids,
RNA satellites, transposons19 and plasmids)?
These replicons could have originated either
from CEOs that had lost their capsid-encoding genes or from ancient RNA (or DNA)
replicons that were unable to obtain capsid
proteins from a CEO for their propagation.
Interestingly, these replicons can parasitize
both REOs and CEOs, and some use capsids
from helper viruses. We suggest that these
elements be grouped together under the term
‘orphan replicons’. The question then arises as
to whether we should consider these elements
as organisms. Because the term organism
implies at least a minimal level of integration (the association of several organs into a
functional unit), we propose to reserve the
term organism for biological entities which
encode both genes that are involved in their
replication (a replicon cassette) and genes that
encode either ribosomes or capsids.
Conclusions
Human beings like dichotomies. In biology,
the animal–plant dichotomy was eventually
replaced by the prokaryote–eukaryote dichotomy. Indeed, this attraction to dichotomies
could partly explain why the prokaryote–
eukaryote division persists, despite the vast
amount of molecular evidence that indicates
the existence of three domains of ribosomeencoding cells1. Here, we propose to reinstall
a primary dichotomy in the classification of
the living world between REOs and CEOs.
We conclude that two connected natural
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Acknowledgements
The authors thank A. Hecker and P.E. Fournier for help with
the figures.
DATABASES
Entrez Genome: http://www.ncbi.nlm.nih.gov/entrez/query.
fcgi?db=genome
PBCV1 | PRD1 | STIV | TMV
Entrez Genome Project: http://www.ncbi.nlm.nih.gov/
entrez/query.fcgi?db=genomeprj
Candidatus Carsonella ruddii | Encephalitozoon cuniculi |
Escherichia coli | Gemmata obscuriglobus | Mycoplasma
mycoides | Nanoarchaeum equitans | Sulfolobus solfataricus P2
FURTHER INFORMATION
Didier Raoult’s homepage: http://ifr48.timone.univ-mrs.fr/
portail2/index.php?option=com_content&task=view&id=78
Chambers Reference Online: http://www.chambersharrap.
co.uk/chambers/features/chref/chref.py/main
NCBI COG s database: http://www.ncbi.nlm.nih.gov/COG /
Oxford English Dictionary Online: http://www.oed.com/
Protein Data Bank: http://www.rcsb.org/pdb/home/home.do
Wikipedia: http://www.wikipedia.org/
All links are active in the online pdf
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