In genetics, a mutagen is a physical or chemical agent that permanently changes genetic material, usually DNA, in an organism and thus increases the frequency of mutations above the natural background level. As many mutations can cause cancer in animals, such mutagens can therefore be carcinogens, although not all necessarily are. All mutagens have characteristic mutational signatures with some chemicals becoming mutagenic through cellular processes.
The process of DNA becoming modified is called mutagenesis. Not all mutations are caused by mutagens: so-called "spontaneous mutations" occur due to spontaneous hydrolysis, errors in DNA replication, repair and recombination.
Discovery
The first mutagens to be identified were carcinogens, substances that were shown to be linked to cancer. Tumors were described more than 2,000 years before the discovery of chromosomes and DNA; in 500 B.C., the Greek physicianHippocrates named tumors resembling a crab karkinos (from which the word "cancer" is derived via Latin), meaning crab. In 1567, Swiss physician Paracelsus suggested that an unidentified substance in mined ore (identified as radon gas in modern times) caused a wasting disease in miners, and in England, in 1761, John Hill made the first direct link of cancer to chemical substances by noting that excessive use of snuff may cause nasal cancer. In 1775, Sir Percivall Pott wrote a paper on the high incidence of scrotal cancer in chimney sweeps, and suggested chimney soot as the cause of scrotal cancer. In 1915, Yamagawa and Ichikawa showed that repeated application of coal tar to rabbit's ears produced malignant cancer. Subsequently, in the 1930s the carcinogen component in coal tar was identified as a polyaromatic hydrocarbon (PAH), benzo[a]pyrene.
Polyaromatic hydrocarbons are also present in soot, which was suggested
to be a causative agent of cancer over 150 years earlier.
The association of exposure to radiation and cancer had been
observed as early as 1902, six years after the discovery of X-ray by Wilhelm Röntgen and radioactivity by Henri Becquerel. Georgii Nadson and German Filippov were the first who created fungi mutants under ionizing radiation in 1925. The mutagenic property of mutagens was first demonstrated in 1927, when Hermann Muller discovered that x-rays can cause genetic mutations in fruit flies, producing phenotypic mutants as well as observable changes to the chromosomes, visible due to the presence of enlarged "polytene" chromosomes in fruit fly salivary glands. His collaborator Edgar Altenburg also demonstrated the mutational effect of UV radiation in 1928. Muller went on to use x-rays to create Drosophila mutants that he used in his studies of genetics. He also found that X-rays not only mutate genes in fruit flies, but also have effects on the genetic makeup of humans. Similar work by Lewis Stadler also showed the mutational effect of X-rays on barley in 1928, and ultraviolet (UV) radiation on maize in 1936.
The effect of sunlight had previously been noted in the nineteenth
century where rural outdoor workers and sailors were found to be more
prone to skin cancer.
Chemical mutagens were not demonstrated to cause mutation until the 1940s, when Charlotte Auerbach and J. M. Robson found that mustard gas can cause mutations in fruit flies. A large number of chemical mutagens have since been identified, especially after the development of the Ames test in the 1970s by Bruce Ames that screens for mutagens and allows for preliminary identification of carcinogens.Early studies by Ames showed around 90% of known carcinogens can be
identified in Ames test as mutagenic (later studies however gave lower
figures), and ~80% of the mutagens identified through Ames test may also be carcinogens.
Difference between mutagens and carcinogens
Mutagens are not necessarily carcinogens, and vice versa. Sodium azide for example may be mutagenic (and highly toxic), but it has not been shown to be carcinogenic.
Meanwhile, compounds which are not directly mutagenic but stimulate
cell growth which can reduce the effectiveness of DNA repair and
indirectly increase the chance of mutations, and therefore that of
cancer. One example of this would be anabolic steroids, which stimulate growth of the prostate gland and increase the risk of prostate cancer among others. Other carcinogens may cause cancer through a variety of mechanisms without producing mutations, such as tumour promotion, immunosuppression that reduces the ability to fight cancer cells or pathogens that can cause cancer, disruption of the endocrine system (e.g. in breast cancer), tissue-specific toxicity, and inflammation (e.g. in colorectal cancer).
Difference between mutagens and DNA damaging agents
A DNA damaging agent is an agent that causes a change in the structure of DNA that is not itself replicated when the DNA is replicated. Examples of DNA damage include a chemical addition or disruption of a nucleotide
base in DNA (generating an abnormal nucleotide or nucleotide fragment),
or a break in one or both strands in DNA. When duplex DNA containing a
damaged base is replicated, an incorrect base may be inserted in the
newly synthesized strand opposite the damaged base in the complementary
template strand, and this can become a mutation
in the next round of replication. Also a DNA double-strand break may
be repaired by an inaccurate process leading to an altered base pair, a
mutation. However, mutations and DNA damages differ in a fundamental
way: mutations can, in principle, be replicated when DNA replicates,
whereas DNA damages are not necessarily replicated. Thus DNA damaging
agents often cause mutations as a secondary consequence, but not all DNA
damages lead to mutation and not all mutations arise from a DNA damage. The term genotoxic means toxic (damaging) to DNA.
Mutagens can cause changes to the DNA and are therefore genotoxic.
They can affect the transcription and replication of the DNA, which in
severe cases can lead to cell death. The mutagen produces mutations in
the DNA, and deleterious mutation can result in aberrant, impaired or
loss of function for a particular gene, and accumulation of mutations
may lead to cancer. Mutagens may therefore be also carcinogens. However,
some mutagens exert their mutagenic effect through their metabolites,
and therefore whether such mutagens actually become carcinogenic may be
dependent on the metabolic processes of an organism, and a compound
shown to be mutagenic in one organism may not necessarily be
carcinogenic in another.
Different mutagens act on DNA differently. Powerful mutagens may result in chromosomal instability, causing chromosomal breakages and rearrangement of the chromosomes such as translocation, deletion, and inversion. Such mutagens are called clastogens.
Mutagens may also modify the DNA sequence; the changes in nucleic acid sequences by mutations include substitution of nucleotidebase-pairs and insertions and deletions
of one or more nucleotides in DNA sequences. Although some of these
mutations are lethal or cause serious disease, many have minor effects
as they do not result in residue changes that have significant effect on
the structure and function of the proteins. Many mutations are silent mutations,
causing no visible effects at all, either because they occur in
non-coding or non-functional sequences, or they do not change the amino-acid sequence due to the redundancy of codons.
Some mutagens can cause aneuploidy and change the number of chromosomes in the cell. They are known as aneuploidogens.
In Ames test, where the varying concentrations of the chemical
are used in the test, the dose response curve obtained is nearly always
linear, suggesting that there may be no threshold for mutagenesis.
Similar results are also obtained in studies with radiations, indicating
that there may be no safe threshold for mutagens. However, the no-threshold model is disputed with some arguing for a dose rate dependent threshold for mutagenesis. Some have proposed that low level of some mutagens may stimulate the DNA repair
processes and therefore may not necessarily be harmful. More recent
approaches with sensitive analytical methods have shown that there may
be non-linear or bilinear dose-responses for genotoxic effects, and that
the activation of DNA repair pathways can prevent the occurrence of
mutation arising from a low dose of mutagen.
Types
Mutagens
may be of physical, chemical or biological origin. They may act
directly on the DNA, causing direct damage to the DNA, and most often
result in replication error. Some however may act on the replication
mechanism and chromosomal partition. Many mutagens are not mutagenic by
themselves, but can form mutagenic metabolites through cellular
processes, for example through the activity of the cytochrome P450 system and other oxygenases such as cyclooxygenase. Such mutagens are called promutagens.
Ultraviolet radiations with wavelength above 260 nm are absorbed strongly by bases, producing pyrimidine dimers, which can cause error in replication if left uncorrected.
Chemical mutagens either directly or indirectly damage DNA. On this basis, they are of 2 types:
Directly acting chemical mutagens
They
directly damage DNA, but may or may not undergo metabolism to produce
promutagens (metabolites that can have higher mutagenic potential than
their substrates).
Reactive oxygen species (ROS) – These may be superoxide, hydroxyl radicals and hydrogen peroxide,
and large number of these highly reactive species are generated by
normal cellular processes, for example as a by-products of mitochondrial
electron transport, or lipid peroxidation.
As an example of the latter, 15-hydroperoxyeicosatetraenoic acid, a
natural product of cellular cyclooxygenases and lipoxygenases, breaks
down to form 4-hydroxy-2(E)-nonenal, 4-hydroperoxy-2(E)-nonenal, 4-oxo-2(E)-nonenal, and cis-4,5-epoxy-2(E)-decanal;
these bifunctional electophils are mutagenic in mammalian cells and may
contribute to the development and/or progression of human cancers (see 15-Hydroxyicosatetraenoic acid).
A number of mutagens may also generate these ROS. These ROS may result
in the production of many base adducts, as well as DNA strand breaks and
crosslinks.
Alkylating agents such as ethylnitrosourea.
The compounds transfer methyl or ethyl group to bases or the backbone
phosphate groups. Guanine when alkylated may be mispaired with thymine.
Some may cause DNA crosslinking and breakages. Nitrosamines
are an important group of mutagens found in tobacco, and may also be
formed in smoked meats and fish via the interaction of amines in food
with nitrites added as preservatives. Other alkylating agents include mustard gas and vinyl chloride.
Aromatic amines and amides have been associated with carcinogenesis since 1895 when German physician Ludwig Rehn observed high incidence of bladder cancer among workers in German synthetic aromatic amine dye industry. 2-Acetylaminofluorene,
originally used as a pesticide but may also be found in cooked meat,
may cause cancer of the bladder, liver, ear, intestine, thyroid and
breast.
Alkaloid from plants, such as those from Vinca species, may be converted by metabolic processes into the active mutagen or carcinogen.
Bromine and some compounds that contain bromine in their chemical structure.
Sodium azide, an azide salt that is a common reagent in organic synthesis and a component in many car airbag systems
Psoralen combined with ultraviolet radiation causes DNA cross-linking and hence chromosome breakage.
Benzene, an industrial solvent and precursor in the production of drugs, plastics, synthetic rubber and dyes.
Chromium trioxide, a highly toxic and oxidizing substance used in electroplating.
Indirectly acting chemical mutagens
They
are not necessarily mutagenic by themselves, but they produce
promutagens mutagenic compounds through metabolic processes in cells.
Some chemical mutagens additionally require UV or visible light activation for their mutagenic effect. These are the photomutagens, which include furocoumarins and limettin.
Base analogs
Base analog, which can substitute for DNA bases during replication and cause transition mutations. Some examples are 5-bromouracil and 2-aminopurine.
Many metals, such as arsenic, cadmium, chromium, nickel and their compounds may be mutagenic, but they may act, however, via a number of different mechanisms.
Arsenic, chromium, iron, and nickel may be associated with the
production of ROS, and some of these may also alter the fidelity of DNA
replication. Nickel may also be linked to DNA hypermethylation and histone deacetylation, while some metals such as cobalt, arsenic, nickel and cadmium may also affect DNA repair processes such as DNA mismatch repair, and base and nucleotide excision repair.
Biological agents
Transposons,
a section of DNA that undergoes autonomous fragment
relocation/multiplication. Its insertion into chromosomal DNA disrupts
functional elements of the genes.
Oncoviruses
– Virus DNA may be inserted into the genome and disrupts genetic
function. Infectious agents have been suggested to cause cancer as early
as 1908 by Vilhelm Ellermann and Oluf Bang, and 1911 by Peyton Rous who discovered the Rous sarcoma virus.
Bacteria – some bacteria such as Helicobacter pylori
cause inflammation during which oxidative species are produced, causing
DNA damage and reducing efficiency of DNA repair systems, thereby
increasing mutation.
Antioxidants are an important group of anticarcinogenic compounds that may help remove ROS or potentially harmful chemicals. These may be found naturally in fruits and vegetables. Examples of antioxidants are vitamin A and its carotenoid precursors, vitamin C, vitamin E, polyphenols, and various other compounds. β-Carotene is the red-orange colored compounds found in vegetables like carrots and tomatoes. Vitamin C may prevent some cancers by inhibiting the formation of mutagenic N-nitroso compounds (nitrosamine). Flavonoids, such as EGCG in green tea,
have also been shown to be effective antioxidants and may have
anti-cancer properties. Epidemiological studies indicate that a diet
rich in fruits and vegetables is associated with lower incidence of some
cancers and longer life expectancy, however, the effectiveness of antioxidant supplements in cancer prevention in general is still the subject of some debate.
Other chemicals may reduce mutagenesis or prevent cancer via
other mechanisms, although for some the precise mechanism for their
protective property may not be certain. Selenium,
which is present as a micronutrient in vegetables, is a component of
important antioxidant enzymes such as gluthathione peroxidase. Many
phytonutrients may counter the effect of mutagens; for example, sulforaphane in vegetables such as broccoli has been shown to be protective against prostate cancer. Others that may be effective against cancer include indole-3-carbinol from cruciferous vegetables and resveratrol from red wine.
An effective precautionary measure an individual can undertake to
protect themselves is by limiting exposure to mutagens such as UV
radiations and tobacco smoke. In Australia, where people with pale skin
are often exposed to strong sunlight, melanoma is the most common cancer diagnosed in people aged 15–44 years.
In 1981, human epidemiological analysis by Richard Doll and Richard Peto indicated that smoking caused 30% of cancers in the US.
Diet is also thought to cause a significant number of cancer
fatalities, and it has been estimated that around 32% of cancer deaths
may be avoidable by modification to the diet. Mutagens identified in food include mycotoxins from food contaminated with fungal growths, such as aflatoxins which may be present in contaminated peanuts and corn; heterocyclic amines
generated in meat when cooked at high temperature; PAHs in charred meat
and smoked fish, as well as in oils, fats, bread, and cereal; and nitrosamines generated from nitrites used as food preservatives in cured meat such as bacon (ascorbate, which is added to cured meat, however, reduces nitrosamine formation). Overly-browned starchy food such as bread, biscuits and potatoes can generate acrylamide, a chemical shown to cause cancer in animal studies. Excessive alcohol consumption has also been linked to cancer; the possible mechanisms for its carcinogenicity include formation of the possible mutagen acetaldehyde, and the induction of the cytochrome P450 system which is known to produce mutagenic compounds from promutagens.
For certain mutagens, such as dangerous chemicals and radioactive
materials, as well as infectious agents known to cause cancer,
government legislations and regulatory bodies are necessary for their
control.
Test systems
Many different systems for detecting mutagen have been developed.
Animal systems may more accurately reflect the metabolism of human,
however, they are expensive and time-consuming (may take around three
years to complete), they are therefore not used as a first screen for
mutagenicity or carcinogenicity.
Ames test – This is the most commonly used test, and Salmonella typhimurium strains deficient in histidine
biosynthesis are used in this test. The test checks for mutants that
can revert to wild-type. It is an easy, inexpensive and convenient
initial screen for mutagens.
Resistance to 8-azaguanine in S. typhimurium – Similar to Ames test, but instead of reverse mutation, it checks for forward mutation that confer resistance to 8-Azaguanine in a histidine revertant strain.
Escherichia coli systems – Both forward and reverse mutation detection system have been modified for use in E. coli. Tryptophan-deficient
mutant is used for the reverse mutation, while galactose utility or
resistance to 5-methyltryptophan may be used for forward mutation.
DNA repair – E. coli and Bacillus subtilis strains deficient in DNA repair may be used to detect mutagens by their effect on the growth of these cells through DNA damage.
Yeast
Systems similar to Ames test have been developed in yeast. Saccharomyces cerevisiae is generally used. These systems can check for forward and reverse mutations, as well as recombinant events.
Drosophila
Sex-Linked Recessive Lethal Test
– Males from a strain with yellow bodies are used in this test. The
gene for the yellow body lies on the X-chromosome. The fruit flies are
fed on a diet of test chemical, and progenies are separated by sex. The
surviving males are crossed with the females of the same generation, and
if no males with yellow bodies are detected in the second generation,
it would indicate a lethal mutation on the X-chromosome has occurred.
Mammalian cell lines such as Chinese hamster V79 cells, Chinese hamster ovary (CHO) cells or mouse lymphoma cells may be used to test for mutagenesis. Such systems include the HPRT assay for resistance to 8-azaguanine or 6-thioguanine, and ouabain-resistance (OUA) assay.
Rat primary hepatocytes may also be used to measure DNA repair
following DNA damage. Mutagens may stimulate unscheduled DNA synthesis
that results in more stained nuclear material in cells following
exposure to mutagens.
Chromosome check systems
These
systems check for large scale changes to the chromosomes and may be
used with cell culture or in animal test. The chromosomes are stained
and observed for any changes. Sister chromatid exchange is a
symmetrical exchange of chromosome material between sister chromatids
and may be correlated to the mutagenic or carcinogenic potential of a
chemical. In micronucleus Test, cells are examined for
micronuclei, which are fragments or chromosomes left behind at anaphase,
and is therefore a test for clastogenic agents that cause chromosome
breakages. Other tests may check for various chromosomal aberrations
such as chromatid and chromosomal gaps and deletions, translocations,
and ploidy.
Animal test systems
Rodents are usually used in animal test. The chemicals under
test are usually administered in the food and in the drinking water, but sometimes by dermal application, by gavage,
or by inhalation, and carried out over the major part of the life span
for rodents. In tests that check for carcinogens, maximum tolerated
dosage is first determined, then a range of doses are given to around 50
animals throughout the notional lifespan of the animal of two years.
After death the animals are examined for sign of tumours. Differences in
metabolism between rat and human however means that human may not
respond in exactly the same way to mutagen, and dosages that produce
tumours on the animal test may also be unreasonably high for a human,
i.e. the equivalent amount required to produce tumours in human may far
exceed what a person might encounter in real life.
Mice with recessive mutations for a visible phenotype may also be
used to check for mutagens. Females with recessive mutation crossed
with wild-type males would yield the same phenotype as the wild-type,
and any observable change to the phenotype would indicate that a
mutation induced by the mutagen has occurred.
Mice may also be used for dominant lethal assays where
early embryonic deaths are monitored. Male mice are treated with
chemicals under test, mated with females, and the females are then
sacrificed before parturition and early fetal deaths are counted in the uterine horns.
Transgenic mouse assay using a mouse strain infected with a viral shuttle vector
is another method for testing mutagens. Animals are first treated with
suspected mutagen, the mouse DNA is then isolated and the phage segment
recovered and used to infect E. coli. Using similar method as the blue-white screen, the plaque formed with DNA containing mutation are white, while those without are blue.
In anti-cancer therapy
Many
mutagens are highly toxic to proliferating cells, and they are often
used to destroy cancer cells. Alkylating agents such as cyclophosphamide and cisplatin, as well as intercalating agent such as daunorubicin and doxorubicin may be used in chemotherapy.
However, due to their effect on other cells which are also rapidly
dividing, they may have side effects such as hair loss and nausea.
Research on better targeted therapies may reduce such side-effects.
Ionizing radiations are used in radiation therapy.
Diagram illustrating the development process of avian flu vaccine by reverse genetics techniques
Reverse genetics is a method in molecular genetics that is used to help understand the function(s) of a gene by analysing the phenotypic effects caused by genetically engineering specific nucleic acid sequences within the gene. The process proceeds in the opposite direction to forward genetic screens of classical genetics. While forward genetics seeks to find the genetic basis of a phenotype or trait, reverse genetics seeks to find what phenotypes are controlled by particular genetic sequences.
Automated DNA sequencing generates large volumes of genomic sequence data
relatively rapidly. Many genetic sequences are discovered in advance of
other, less easily obtained, biological information. Reverse genetics
attempts to connect a given genetic sequence with specific effects on
the organism. Reverse genetics systems can also allow the recovery and generation of infectious or defective viruses with desired mutations. This allows the ability to study the virus in vitro and in vivo.
Techniques used
In
order to learn the influence a sequence has on phenotype, or to
discover its biological function, researchers can engineer a change or
disrupt the DNA. After this change has been made a researcher can look for the effect of such alterations in the whole organism. There are several different methods of reverse genetics:
Wild-type Physcomitrella patens and knockout mosses: Deviating phenotypes induced in gene-disruption library transformants. Physcomitrella wild-type and transformed plants were grown on minimal Knop medium to induce differentiation and development of gametophores.
For each plant, an overview (upper row; scale bar corresponds to 1 mm)
and a close-up (bottom row; scale bar equals 0.5 mm) are shown. A:
Haploid wild-type moss plant completely covered with leafy gametophores
and close-up of wild-type leaf. B–E: Different mutants.
Alternatively, the technique can be used to create null alleles so that the gene is not functional. For example, deletion of a gene by gene targeting (gene knockout) can be done in some organisms, such as yeast, mice and moss. Unique among plants, in Physcomitrella patens, gene knockout via homologous recombination to create knockout moss (see figure) is nearly as efficient as in yeast. In the case of the yeast model system directed deletions have been created in every non-essential gene in the yeast genome. In the case of the plant model system huge mutant libraries have been created based on gene disruption constructs. In gene knock-in, the endogenous exon is replaced by an altered sequence of interest.
In some cases conditional alleles can be used so that the gene
has normal function until the conditional allele is activated. This
might entail 'knocking in' recombinase
sites (such as lox or frt sites) that will cause a deletion at the gene
of interest when a specific recombinase (such as CRE, FLP) is induced.
Cre or Flp recombinases can be induced with chemical treatments, heat
shock treatments or be restricted to a specific subset of tissues.
Another technique that can be used is TILLING. This is a method that combines a standard and efficient technique of mutagenesis with a chemical mutagen such as ethyl methanesulfonate (EMS) with a sensitive DNA-screening technique that identifies point mutations in a target gene.
In the field of virology, reverse-genetics techniques can be used
to recover full-length infectious viruses with desired mutations or
insertions in the viral genomes or in specific virus genes. Technologies
that allow these manipulations include circular polymerase extension
reaction (CPER) which was first used to generate infectious cDNA for
Kunjin virus a close relative of West Nile virus. CPER has also been successfully utilised to generate a range of positive-sense RNA viruses such as SARS-CoV-2, the causative agent of COVID-19.
Gene silencing
The discovery of gene silencing using double stranded RNA, also known as RNA interference (RNAi), and the development of gene knockdown using Morpholino
oligos, have made disrupting gene expression an accessible technique
for many more investigators. This method is often referred to as a gene knockdown since the effects of these reagents are generally temporary, in contrast to gene knockouts which are permanent.
RNAi creates a specific knockout effect without actually mutating the DNA of interest. In C. elegans,
RNAi has been used to systematically interfere with the expression of
most genes in the genome. RNAi acts by directing cellular systems to
degrade target messenger RNA (mRNA).
RNAi interference, specifically gene silencing, has become a
useful tool to silence the expression of genes and identify and analyze
their loss-of-function phenotype. When mutations occur in alleles, the
function which it represents and encodes also is mutated and lost; this
is generally called a loss-of-function mutation.
The ability to analyze the loss-of-function phenotype allows analysis
of gene function when there is no access to mutant alleles.
While RNA interference
relies on cellular components for efficacy (e.g. the Dicer proteins,
the RISC complex) a simple alternative for gene knockdown is Morpholino
antisense oligos. Morpholinos bind and block access to the target mRNA
without requiring the activity of cellular proteins and without
necessarily accelerating mRNA degradation. Morpholinos are effective in
systems ranging in complexity from cell-free translation in a test tube
to in vivo studies in large animal models.
Interference using transgenes
A molecular genetic approach is the creation of transgenic organisms that overexpress a normal gene of interest. The resulting phenotype may reflect the normal function of the gene.
Alternatively it is possible to overexpress mutant forms of a gene that interfere with the normal (wildtype)
gene's function. For example, over-expression of a mutant gene may
result in high levels of a non-functional protein resulting in a dominant negative
interaction with the wildtype protein. In this case the mutant version
will out compete for the wildtype proteins partners resulting in a
mutant phenotype.
Other mutant forms can result in a protein that is abnormally
regulated and constitutively active ('on' all the time). This might be
due to removing a regulatory domain or mutating a specific amino residue
that is reversibly modified (by phosphorylation, methylation, or ubiquitination). Either change is critical for modulating protein function and often result in informative phenotypes.
Vaccine synthesis
Reverse genetics plays a large role in vaccine
synthesis. Vaccines can be created by engineering novel genotypes of
infectious viral strains which diminish their pathogenic potency enough
to facilitate immunity in a host. The reverse genetics approach to
vaccine synthesis utilizes known viral genetic sequences to create a
desired phenotype: a virus with both a weakened pathological potency and
a similarity to the current circulating virus strain. Reverse genetics
provides a convenient alternative to the traditional method of creating inactivated vaccines, viruses which have been killed using heat or other chemical methods.
Vaccines created through reverse genetics methods are known as attenuated vaccines,
named because they contain weakened (attenuated) live viruses.
Attenuated vaccines are created by combining genes from a novel or
current virus strain with previously attenuated viruses of the same
species.
Attenuated viruses are created by propagating a live virus under novel
conditions, such as a chicken's egg. This produces a viral strain that
is still live, but not pathogenic to humans,
as these viruses are rendered defective in that they cannot replicate
their genome enough to propagate and sufficiently infect a host.
However, the viral genes are still expressed in the host's cell through a
single replication cycle, allowing for the development of an immunity.
Influenza vaccine
A
common way to create a vaccine using reverse genetic techniques is to
utilize plasmids to synthesize attenuated viruses. This technique is
most commonly used in the yearly production of influenza vaccines, where an eight plasmid system can rapidly produce an effective vaccine. The entire genome of the influenza A virus consists of eight RNA segments, so the combination of six attenuated viral cDNA
plasmids with two wild-type plasmids allow for an attenuated vaccine
strain to be constructed. For the development of influenza vaccines, the
fourth and sixth RNA segments, encoding for the hemagglutinin and neuraminidase
proteins respectively, are taken from the circulating virus, while the
other six segments are derived from a previously attenuated master
strain. The HA and NA proteins exhibit high antigen
variety, and therefore are taken from the current strain for which the
vaccine is being produced to create a well matching vaccine.
The plasmid used in this eight-plasmid system contains three
major components that allow for vaccine development. Firstly, the
plasmid contains restriction sites
that will enable the incorporation of influenza genes into the plasmid.
Secondly, the plasmid contains an antibiotic resistance gene, allowing
the selection of merely plasmids containing the correct gene. Lastly,
the plasmid contains two promotors, human pol 1 and pol 2 promotor that
transcribe genes in opposite directions.
cDNA sequences of viral RNA are synthesized from attenuated master strains by using RT-PCR.
This cDNA can then be inserted between an RNA polymerase I (Pol I)
promoter and terminator sequence through restriction enzyme digestion.
The cDNA and pol I sequence is then, in turn, surrounded by an RNA
polymerase II (Pol II) promoter and a polyadenylation site.
This entire sequence is then inserted into a plasmid. Six plasmids
derived from attenuated master strain cDNA are cotransfected into a
target cell, often a chicken egg, alongside two plasmids of the
currently circulating wild-type influenza strain. Inside the target
cell, the two "stacked" Pol I and Pol II enzymes transcribe the viral
cDNA to synthesize both negative-sense viral RNA and positive-sense
mRNA, effectively creating an attenuated virus.
The result is a defective vaccine strain that is similar to the current
virus strain, allowing a host to build immunity. This synthesized
vaccine strain can then be used as a seed virus to create further
vaccines.
Advantages and disadvantages
Vaccines
engineered from reverse genetics carry several advantages over
traditional vaccine designs. Most notable is speed of production. Due to
the high antigenic variation in the HA and NA glycoproteins,
a reverse-genetic approach allows for the necessary genotype (i.e. one
containing HA and NA proteins taken from currently circulating virus
strains) to be formulated rapidly. Additionally, since the final product of a reverse genetics attenuated vaccine production is a live virus, a higher immunogenicity is exhibited than in traditional inactivated vaccines,
which must be killed using chemical procedures before being transferred
as a vaccine. However, due to the live nature of attenuated viruses,
complications may arise in immunodeficient patients.
There is also the possibility that a mutation in the virus could result
the vaccine to turning back into a live unattenuated virus.
A genetic screen or mutagenesis screen is an experimental technique used to identify and select individuals who possess a phenotype of interest in a mutagenized population. Hence a genetic screen is a type of phenotypic screen. Genetic screens can provide important information on gene function as well as the molecular events that underlie a biological process or pathway. While genome projects
have identified an extensive inventory of genes in many different
organisms, genetic screens can provide valuable insight as to how those
genes function.
Basic screening
Forward genetics
(or a forward genetic screen) starts with a phenotype and then attempts
to identify the causative mutation and thus gene(s) responsible for the
phenotype. For instance, the famous screen by Christiane Nüsslein-Volhard and Eric Wieschaus mutagenized fruit flies and then set out to find the genes causing the observed mutant phenotypes.
Successful forward genetic screens often require a defined
genetic background and a simple experimental procedure. That is, when
multiple individuals are mutagenized they should be genetically
identical so that their wild-type phenotype is identical too and mutant
phenotypes are easier to identify. A simple screening method allows for
a larger number of individuals to be screened, thereby increasing the
probability of generating and identifying mutants of interest.
Since natural allelic mutations are rare prior to screening geneticists often mutagenize a population of individuals by exposing them to a known mutagen, such as a chemical or radiation, thereby generating a much higher frequency of chromosomal mutations. In some organisms mutagens are used to perform saturation screens, that is, a screen used to uncover all genes involved in a particular phenotype. Christiane Nüsslein-Volhard and Eric Wieschaus were the first individuals to perform this type of screening procedure in animals.
Reverse genetics
(or a reverse genetic screen), starts with a known gene and assays the
effect of its disruption by analyzing the resultant phenotypes. For
example, in a knock-out screen, one or more genes are completely deleted
and the deletion mutants are tested for phenotypes. Such screens have
been done for all genes in many bacteria and even complex organisms,
such as C. elegans. A reverse genetic screen typically begins with a gene sequence followed by targeted inactivation. Moreover, it induces mutations in model organisms to learn their role in disease.
Reverse genetics is also used to provide extremely accurate statistics
on mutations that occur in specific genes. From these screens you are
able to determine how fortuitous the mutations are, and how often the
mutations occur.
Screening variations
Many screening variations have been devised to elucidate a gene that leads to a mutant phenotype of interest.
Enhancer
An enhancer screen
begins with a mutant individual that has an affected process of
interest with a known gene mutation. The screen can then be used to
identify additional genes or gene mutations that play a role in that
biological or physiological process. A genetic enhancer screen
identifies mutations that enhance a phenotype of interest in an already
mutant individual. The phenotype of the double mutant (individual with
both the enhancer and original background mutation) is more prominent
than either of the single mutant phenotypes. The enhancement must
surpass the expected phenotypes of the two mutations on their own, and
therefore each mutation may be considered an enhancer of the other.
Isolating enhancer mutants can lead to the identification of interacting
genes or genes which act redundantly with respect to one another.
Suppressor
A suppressor screen is used to identify suppressor mutations that alleviate or revert the phenotype of the original mutation, in a process defined as synthetic viability.
Suppressor mutations can be described as second mutations at a site on
the chromosome distinct from the mutation under study, which suppress
the phenotype of the original mutation. If the mutation is in the same gene as the original mutation it is known as intragenic suppression, whereas a mutation located in a different gene is known as extragenic suppression or intergenic suppression.
Suppressor mutations are extremely useful to define the functions of
biochemical pathways within a cell and the relationships between
different biochemical pathways.
Temperature sensitive
A temperature-sensitive screen
involves performing temperature shifts to enhance a mutant phenotype. A
population grown at low temperatures would have a normal phenotype;
however, the mutation in the particular gene would make it unstable at a
higher temperature. A screen for temperature sensitivity in fruit
flies, for example, might involve raising the temperature
in the cage until some flies faint, then opening a portal to let the
others escape. Individuals selected in a screen are liable to carry an
unusual version of a gene involved in the phenotype of interest. An advantage of alleles found in this type of screen is that the mutant phenotype is conditional and can be activated by simply raising the temperature. A null mutation
in such a gene may be lethal to the embryo and such mutants would be
missed in a basic screen. A famous temperature-sensitive screen was
carried out independently by Lee Hartwell and Paul Nurse to identify mutants defective in the cell cycle in S. cerevisiae and S. pombe, respectively.
RNAi
An overview of RNA interference (RNAi) embryonic injection method
RNA interference (RNAi)
screen is essentially a forward genetics screen using a reverse
genetics technique. Similar to classical genetic screens in the past,
large-scale RNAi surveys success depends on a careful development of
phenotypic assays and their interpretation. In Drosophila,
RNAi has been applied in cultured cells or in vivo to investigate gene
functions and to effect the function of single genes on a genome-wide
scale. RNAi is used to silence gene expression in Drosophila by
injecting dsRNA into early embryos, and interfering with Frizzled and Frizzled2 genes creating defects in embryonic patterning that mimic loss of wingless function.
CRISPR
Cas12a in complex with crRNA and target DNA – the key tool for CRISPR screens
CRISPR/Cas
is primarily used for reverse genetic screens. CRISPR has the ability
to create libraries of thousands of precise genetic mutations and can
identify new tumors as well as validate older tumors in cancer research.
Genome-scale CRISPR-Cas9 knockout (GeCKO)
library targeting 18,080 genes with 64,751 unique guide sequences
identify genes essential for cell viability in cancer. Bacterial CRISPR–Cas9
system for engineering both loss of function (LOF) and gain of function
(GOF) mutations in untransformed human intestinal organoids in order to
demonstrate a model of Colorectal cancer (CRC). It can also be used to study functional consequences of mutations in vivo by enabling direct genome editing in somatic cells.
Mapping mutants
By the classical genetics approach, a researcher would then locate (map) the gene on its chromosome by crossbreeding with individuals that carry other unusual traits
and collecting statistics on how frequently the two traits are
inherited together. Classical geneticists would have used phenotypic
traits to map the new mutant alleles. With the advent of genomic sequences for model systems such as Drosophila melanogaster,Arabidopsis thaliana and C. elegans many single nucleotide polymorphisms (SNPs) have now been identified that can be used as traits for mapping. In fact, the Heidelberg screen, allowing mass testing of mutants and developed in 1980 by Nüsslein-Volhard and Wieschaus, cleared the way for future scientists in this field.
SNPs are the preferred traits for mapping since they are very frequent,
on the order of one difference per 1000 base pairs, between different
varieties of organism. Mutagens such as random DNA insertions by transformation or active transposons
can also be used to generate new mutants. These techniques have the
advantage of tagging the new alleles with a known molecular (DNA) marker that can facilitate the rapid identification of the gene.
Positional cloning
Positional
cloning is a method of gene identification in which a gene for a
specific phenotype is identified only by its approximate chromosomal
location (but not the function); this is known as the candidate region. Initially, the candidate region can be defined using techniques such as linkage analysis,
and positional cloning is then used to narrow the candidate region
until the gene and its mutations are found. Positional cloning
typically involves the isolation of partially overlapping DNA segments
from genomic libraries to progress along the chromosome toward a
specific gene. During the course of positional cloning, one needs to
determine whether the DNA segment currently under consideration is part
of the gene.
Tests used for this purpose include cross-species hybridization, identification of unmethylated CpG islands, exon trapping, direct cDNA
selection, computer analysis of DNA sequence, mutation screening in
affected individuals, and tests of gene expression. For genomes in which
the regions of genetic polymorphisms
are known, positional cloning involves identifying polymorphisms that
flank the mutation. This process requires that DNA fragments from the
closest known genetic marker are progressively cloned and sequenced,
getting closer to the mutant allele with each new clone. This process
produces a contig map of the locus and is known as chromosome walking. With the completion of genome sequencing projects such as the Human Genome Project, modern positional cloning can use ready-made contigs from the genome sequence databases directly.
For each new DNA clone a polymorphism is identified and tested in the mapping population for its recombination
frequency compared to the mutant phenotype. When the DNA clone is at or
close to the mutant allele, the recombination frequency should be close
to zero. If the chromosome walk proceeds through the mutant allele,
the new polymorphisms will start to show increase in recombination
frequency compared to the mutant phenotype. Depending on the size of
the mapping population, the mutant allele can be narrowed down to a
small region (<30 Kb). Sequence comparison between wild type and mutant DNA in that region is then required to locate the DNA mutation that causes the phenotypic difference.
Modern positional cloning can more directly extract information
from genomic sequencing projects and existing data by analyzing the
genes in the candidate region. Potential disease genes from the
candidate region can then be prioritized, potentially reducing the
amount of work involved. Genes with expression patterns consistent with
the disease phenotype, showing a (putative) function related to the
phenotype, or homologous to another gene linked to the phenotype are all
priority candidates. Generalization of positional cloning techniques
in this manner is also known as positional gene discovery.
Positional cloning is an effective method to isolate disease
genes in an unbiased manner and has been used to identify disease genes
for Duchenne muscular dystrophy, Huntington's disease, and cystic fibrosis. However, complications in the analysis arise if the disease exhibits locus heterogeneity.
The West as a geographical area is unclear and undefined. There is
some disagreement about which nations should or should not be included
in the category, when, and why. Certainly related conceptual terminology
has changed over time in scope, meaning, and use. The term "western"
draws on an affiliation with, or a perception of, a shared philosophy, worldview, political, and religious heritage grounded in the Greco-Roman world, the legacy of the Roman Empire, and medieval concepts of Christendom. For example, whether the Eastern Roman Empire (anachronistically/controversially referred to as the Byzantine Empire),
or those countries heavily influenced by its legacy, should be counted
as "Western" is an example of the possible ambiguity of the term. These
questions[which?] can be traced back to the affiliation between the culture of ancient Rome and that of Classical Greece, a persistent Greek East and Latin West language-split within the Roman Empire, and an eventual permanent splitting of the Roman Empire in 395 into Western and Eastern halves. And perhaps, at its worst, culminating in Pope Leo III's transfer of the Roman Empire from the Eastern Roman Empire to the Frankish King Charlemagne in the form of the Holy Roman Empire in 800, the Great Schism of 1054, and the devastating Fourth Crusade of 1204.
Conversely, traditions of scholarship around Plato, Aristotle, and Euclid had been forgotten in the Catholic west and were rediscovered by Italians from scholars fleeing the 1453 fall of the Eastern Roman Empire.[16] The subsequent Renaissance,
a conscious effort by Europeans to revive and surpass the ideas and
achievements of the Greco-Roman world, eventually encouraged the Age of Discovery, the Scientific Revolution, Age of Enlightenment, and the subsequent Industrial Revolution.
Similarly, complicated relationships between virtually all the
countries and regions within a broadly defined "West" can be discussed
in the light of a persistently fragmented political landscape resulting
in a lack of uniformity and significant diversity between the various
cultures affiliating with this shared socio-cultural heritage. Thus,
those cultures identifying with the West and with what it means to be
"western" change over time as the geopolitical circumstances of a place
changes and what is meant by the terminology changes.
It is difficult to determine which individuals or places or
trends fit into which category, and the East–West contrast is sometimes
criticized as relativistic and arbitrary.
Globalization has spread Western ideas so widely that almost all modern
cultures are, to some extent, influenced by aspects of Western culture.
Stereotypical views of "the West" have been labeled "Occidentalism", paralleling "Orientalism"—the term for the 19th-century stereotyped views of "the East".
Some philosophers have questioned whether Western culture can be considered a historically sound, unified body of thought. For example, Kwame Anthony Appiah pointed out in 2016 that many of the fundamental influences on Western culture – such as those of Greek philosophy – are also shared by the Islamic world to a certain extent. Appiah argues that the origin of the Western and European identity can be traced back to the 8th-century Muslim invasion of Europe via Iberia, when Christians would start to form a common Christian or European identity. Contemporary Latin chronicles from Spain referred to the victors in the Frankish victory over the Umayyads at the 732 Battle of Tours as "Europeans" according to Appiah, denoting a shared sense of identity.
A former, now less-acceptable synonym for "Western civilisation" was "the white race".
As Europeans discovered the extra-European world, old concepts adapted. The area that had formerly been considered the Orient ("the East") became the Near East as the interests of the European powers interfered with Meiji Japan and Qing China for the first time in the 19th century. Thus the Sino-Japanese War in 1894–1895 occurred in the "Far East" while troubles surrounding the decline of the Ottoman Empire occurred simultaneously in the Near East. The term "Middle East" in the mid-19th century included the territory east of the Ottoman Empire but west of China—Greater Persia and Greater India—but is now used synonymously with "Near East" in most languages.
Phoenician
mercantilism and the introduction of the Alphabetic script boosted
state formation in the Aegean and current-day Italy and current-day
Spain, spawning civilizations in the Mediterranean such as Ancient Carthage, Ancient Greece, Etruria, and Ancient Rome.
During the Greco-Roman world, North Africa and the Western regions of the Middle East were integral parts of the Western civilization, due to Hellenization
and the direct cultural impact of the conquests of the Roman Empire.
After the Roman conquests, the whole Mediterranean become essentially a
Roman inland sea.
While the concept of a "West" did not exist until the emergence of the Roman Republic, the roots of the concept can be traced back to Ancient Greece. Since Homeric literature (the Trojan Wars), through the accounts of the Persian Wars of Greeks against Persians by Herodotus, and right up until the time of Alexander the Great, there was a paradigm of a contrast between Greeks and other civilizations. Greeks felt they were the most civilized and saw themselves (in the formulation of Aristotle) as something between the advanced civilizations of the Near East (who they viewed as soft and slavish) and the wild barbarians of most of Europe to the north. During this period writers like Herodotus and Xenophon
would highlight the importance of freedom in the Ancient Greek world,
as opposed to the perceived slavery of the so-called barbaric world.
Alexander's conquests led to the emergence of a Hellenistic civilization, representing a synthesis of Greek and Near-Eastern cultures in the Eastern Mediterranean region. The Near-Eastern civilizations of Ancient Egypt and the Levant, which came under Greek rule, became part of the Hellenistic world. The most important Hellenistic centre of learning was Ptolemaic Egypt, which attracted Greek, Egyptian, Jewish, Persian, Phoenician and even Indian scholars. Hellenistic science, philosophy, architecture, literature and art later provided a foundation embraced and built upon by the Roman Empire as it swept up Europe and the Mediterranean world, including the Hellenistic world in its conquests in the 1st century BCE.
Following the Roman conquest of the Hellenistic world, the
concept of a "West" arose, as there was a cultural divide between the Greek East and Latin West.
The Latin-speaking Western Roman Empire consisted of Western Europe and
Northwest Africa, while the Greek-speaking Eastern Roman Empire
consisted of the Balkans, Asia Minor, Egypt and Levant. The "Greek" East was generally wealthier and more advanced than the "Latin" West.With the exception of Italia,
the wealthiest provinces of the Roman Empire were in the East,
particularly Roman Egypt which was the wealthiest Roman province outside
of Italia. Nevertheless, the Celts in the West created some significant literature
in the ancient world whenever they were given the opportunity (an
example being the poet Caecilius Statius), and they developed a large amount of scientific knowledge themselves (as seen in their Coligny Calendar).
The Maison Carrée in Nîmes, one of the best-preserved Roman templesThe Roman Empire (red) and its client states (pink) at its greatest extent in 117 AD under emperor TrajanThe
Roman Empire in 330. The area in red shows the zone of influence of the
Latin West, while the area in blue shows the eastern Greek part.
For about five hundred years, the Roman Empire maintained the Greek East
and consolidated a Latin West, but an east–west division remained,
reflected in many cultural norms of the two areas, including language.
Eventually, the empire became increasingly split into a Western and
Eastern part, reviving old ideas of a contrast between an advanced East,
and a rugged West.
From the time of Alexander the Great (the Hellenistic period), Greek civilization came in contact with Jewish civilization. Christianity would eventually emerge from the syncretism of Hellenic culture, Roman culture, and Second Temple Judaism, gradually spreading across the Roman Empire and eclipsing its antecedents and influences.
The Greek and Roman paganism was gradually replaced by Christianity, first with its legalisation with the Edict of Milan and then the Edict of Thessalonica which made it the State church of the Roman Empire. Catholic
Christianity, served as a unifying force in Christian parts of Europe,
and in some respects replaced or competed with the secular authorities.
The Jewish Christian tradition out of which it had emerged was all but extinguished, and antisemitism became increasingly entrenched or even integral to Christendom. Much of art and literature, law, education, and politics were preserved in the teachings of the Church.
In a broader sense, the Middle Ages, with its fertile encounter between Greek philosophical reasoning and Levantine monotheism
was not confined to the West but also stretched into the old East. The
philosophy and science of Classical Greece were largely forgotten in
Europe after the collapse of the Western Roman Empire, other than in
isolated monastic enclaves (notably in Ireland, which had become
Christian but was never conquered by Rome). The learning of Classical Antiquity was better preserved in the Eastern Roman Empire. Justinian's Corpus Juris Civilis Roman civil law code was created in the East in his capital of Constantinople, and that city maintained trade and intermittent political control over outposts such as Venice
in the West for centuries. Classical Greek learning was also subsumed,
preserved, and elaborated in the rising Eastern world, which gradually
supplanted Roman-Byzantine control as a dominant cultural-political
force. Thus, much of the learning of classical antiquity was slowly
reintroduced to European civilization in the centuries following the
collapse of the Western Roman Empire.
After the fall of Rome,
much of Greco-Roman art, literature, science and even technology were
all but lost in the western part of the old empire. However, this would
become the center of a new West. Europe fell into political anarchy,
with many warring kingdoms and principalities. Under the Frankish kings,
it eventually, and partially, reunified, and the anarchy evolved into feudalism.
The Medieval West referred specifically to the Catholic "Latin" West, also called "Frankish" during Charlemagne's
reign, in contrast to the Orthodox East, where Greek remained the
language of the Byzantine Empire. The earliest recorded concept of
Europe as a cultural sphere (instead of simply a geographic term) was
formed by Alcuin of York in the late 8th century during the Carolingian Renaissance, limited to the territories that practised Western Christianity
at the time. "European" as a cultural term did not include much of the
territories where the Orthodox Church represented the dominant religion
until the 19th century.
Much of the basis of the post-Roman cultural world had been set
before the fall of the Western Roman Empire, mainly through the
integration and reshaping of Roman ideas through Christian thought. The Eastern Orthodox Church founded many cathedrals, monasteries and seminaries, some of which continue to exist today.
Medieval Christianity is credited with creating the first modern universities. The Catholic Church established a hospital system in medieval Europe that vastly improved upon the Roman valetudinaria and Greek healing temples.
These hospitals were established to cater to "particular social groups
marginalized by poverty, sickness, and age," according to the historian
of hospitals, Guenter Risse. Christianity played a role in ending practices common among pagan societies, such as human sacrifice, slavery, infanticide and polygamy. Francisco de Vitoria, a disciple of Thomas Aquinas
and a Catholic thinker who studied the issue regarding the human rights
of colonized natives, is recognized by the United Nations as a father
of international law, and now also by historians of economics and
democracy as a leading light for the West's democracy and rapid economic
development. Joseph Schumpeter, an economist of the twentieth century, referring to the Scholastics, wrote, "it is they who come nearer than does any other group to having been the 'founders' of scientific economics."
The rediscovery of the Justinian Code
in Western Europe early in the 10th century rekindled a passion for the
discipline of law, which crossed many of the re-forming boundaries
between East and West. In the Catholic or Frankish west, Roman law
became the foundation on which all legal concepts and systems were
based. Its influence is found in all Western legal systems, although in
different manners and to different extents. The study of canon law,
the legal system of the Catholic Church, fused with that of Roman law
to form the basis of the refounding of Western legal scholarship.
From Late Antiquity, through the Middle Ages, and onwards, while Eastern Europe was shaped by the Eastern Orthodox Church, Southern and Central Europe were increasingly stabilized by the Catholic Church which, as Roman imperial governance faded from view, was the only consistent force in Western Europe. In 1054 came the Great Schism that, following the Greek East and Latin West divide, separated Europe into religious and cultural regions present to this day.
Later Middle Ages (Rome and Reformation)
In the 14th century, the Renaissance starting from Italy and then spreading throughout Europe,
there was a massive artistic, architectural, scientific and
philosophical revival, as a result of the Christian revival of Greek
philosophy, and the long Christian medieval tradition that established
the use of reason as one of the most important of human activities. This period is commonly referred to as the Renaissance. In the following century, this process was further enhanced by an exodus of Greek Christian priests and scholars to Italian cities such as Florence and Venice after the end of the Byzantine Empire with the fall of Constantinople.
Until the Age of Enlightenment, Christian culture took over as the predominant force in Western civilization, guiding the course of philosophy, art, and science for many years. Movements in art and philosophy, such as the Humanist movement of the Renaissance and the Scholastic movement of the High Middle Ages, were motivated by a drive to connect Catholicism with Greek and Arab thought imported by Christian pilgrims. However, due to the division in Western Christianity caused by the Protestant Reformation and the Enlightenment, religious influence—especially the temporal power of the Pope—began to wane.
During the Reformation and Enlightenment, the ideas of civil rights, equality before the law, procedural justice,
and democracy as the ideal form of society began to be
institutionalized as principles forming the basis of modern Western
culture, particularly in Protestant regions.
Expansion of the West: the Era of Colonialism (15th–20th centuries)
From
the late 15th century to the 17th century, Western culture began to
spread to other parts of the world through explorers and missionaries
during the Age of Discovery, and by imperialists from the 17th century to the early 20th century. During the Great Divergence, a term coined by Samuel Huntington
the Western world overcame pre-modern growth constraints and emerged
during the 19th century as the most powerful and wealthy world civilization of the time, eclipsing Qing China, Mughal India, Tokugawa Japan, and the Ottoman Empire.
The process was accompanied and reinforced by the Age of Discovery and
continued into the modern period. Scholars have proposed a wide variety
of theories to explain why the Great Divergence happened, including lack
of government intervention, geography, colonialism, and customary
traditions.
The Age of Discovery faded into the Age of Enlightenment
of the 18th century, during which cultural and intellectual forces in
European society emphasized reason, analysis, and individualism rather
than traditional lines of authority. It challenged the authority of
institutions that were deeply rooted in society, such as the Catholic
Church; there was much talk of ways to reform society with toleration,
science and skepticism.
The Industrial Revolution
was the transition to new manufacturing processes in the period from
about 1760 to sometime between 1820 and 1840. This included going from
hand production methods to machines, new chemical manufacturing and iron
production processes, improved efficiency of water power, the increasing use of steam power, and the development of machine tools. These transitions began in Great Britain and spread to Western Europe and North America within a few decades.
A Watt steam engine. The steam engine, made of iron and fueled primarily by coal, propelled the Industrial Revolution in Great Britain and the world.
The Industrial Revolution marks a major turning point in history;
almost every aspect of daily life was influenced in some way. In
particular, average income and population began to exhibit unprecedented
sustained growth. Some economists say that the major impact of the
Industrial Revolution was that the standard of living
for the general population began to increase consistently for the first
time in history, although others have said that it did not begin to
meaningfully improve until the late 19th and 20th centuries. The precise start and end of the Industrial Revolution is still debated
among historians, as is the pace of economic and social changes. GDP per capita was broadly stable before the Industrial Revolution and the emergence of the modern capitalist economy, while the Industrial Revolution began an era of per-capita economic growth in capitalist economies.
Economic historians are in agreement that the onset of the Industrial
Revolution is the most important event in the history of humanity since
the domestication of animals, plants and fire.
The First Industrial Revolution evolved into the Second Industrial Revolution
in the transition years between 1840 and 1870, when technological and
economic progress continued with the increasing adoption of steam
transport (steam-powered railways, boats, and ships), the large-scale
manufacture of machine tools and the increasing use of machinery in
steam-powered factories.
In the 20th century, Christianity declined
in influence in many Western countries, mostly in the European Union
where some member states have experienced falling church attendance and
membership in recent years, and also elsewhere. Secularism
(separating religion from politics and science) increased. Christianity
remains the dominant religion in the Western world, where 70% are
Christians.
The West went through a series of great cultural and social
changes between 1945 and 1980. The emergent mass media (film, radio,
television and recorded music) created a global culture that could
ignore national frontiers. Literacy became almost universal, encouraging
the growth of books, magazines and newspapers. The influence of cinema
and radio remained, while televisions became near essentials in every
home.
By the mid-20th century, Western culture was exported worldwide,
and the development and growth of international transport and
telecommunication (such as transatlantic cable and the radiotelephone)
played a decisive role in modern globalization. The West has
contributed a great many technological, political, philosophical,
artistic and religious aspects to modern international culture: having
been a crucible of Catholicism, Protestantism, democracy, industrialisation; the first major civilisation to seek to abolish slavery during the 19th century, the first to enfranchise women (beginning in Australasia at the end of the 19th century) and the first to put to use such technologies as steam, electric and nuclear power. The West invented cinema, television, the personal computer, the Internet and video games; developed sports such as soccer, cricket, golf, tennis, rugby, basketball, and volleyball; and transported humans to an astronomical object for the first time with the 1969 Apollo 11Moon Landing.
In
music, Catholic monks developed the first forms of modern Western
musical notation to standardize liturgy throughout the worldwide Church,
and an enormous body of religious music has been composed for it
through the ages. This led directly to the emergence and development of
European classical music and its many derivatives. The Baroque
style, which encompassed music, art, and architecture, was particularly
encouraged by the post-Reformation Catholic Church as such forms
offered a means of religious expression that was stirring and emotional,
intended to stimulate religious fervor.
The symphony, concerto, sonata, opera, and oratorio have their origins in Italy. Many musical instruments developed in the West have come to see widespread use all over the world; among them are the guitar, violin, piano, pipe organ, saxophone, trombone, clarinet, accordion, and the theremin. In turn, it has been claimed that some European instruments have roots in earlier Eastern instruments that were adopted from the medieval Islamic world. The solo piano, symphony orchestra, and the string quartet are also significant musical innovations of the West.
Jan van Eyck, among other renaissance painters, made great advances in oil painting, and perspective drawings and paintings had their earliest practitioners in Florence. In art, the Celtic knot
is a very distinctive Western repeated motif. Depictions of the nude
human male and female in photography, painting, and sculpture are
frequently considered to have special artistic merit. Realistic portraiture is especially valued.
Photography and the motion picture as both a technology and basis for entirely new art forms were also developed in the West.
Restoration of a fresco from an Ancient
Roman villa bedroom, circa 50–40 BC, dimensions of the room: 265.4 × 334
× 583.9 cm, in the Metropolitan Museum of Art (New York City)
Mona Lisa, by Leonardo da Vinci, c. 1503 – 1506, perhaps continuing until circa 1517, oil on poplar panel, 77 cm × 53 cm, Louvre (Paris)
Photo of the interior of the apartment of Eugène Atget, taken in 1910 in Paris
Rêverie, by Alphonse Mucha, poster for the publishing house Champenois (1897)
Dance and performing arts
Classical music, opera and ballet: Swan Lake pictured
The ballet is a distinctively Western form of performance dance. The ballroom dance is an important Western variety of dance for the elite. The polka, the square dance, the flamenco, and the Irish step dance are very well known Western forms of folk dance.
The soap opera, a popular culture dramatic form, originated in
the United States first on radio in the 1930s, then a couple of decades
later on television. The music video was also developed in the West in
the middle of the 20th century. Musical theatre was developed in the
West in the 19th and 20th Centuries, from music hall, comic opera, and Vaudeville; with significant contributions from the Jewish diaspora, African-Americans, and other marginalized peoples.
Western literature encompasses the literary traditions of Europe, as well as North America, Oceania and Latin America.
While epic literary works in verse such as the Mahabharata and Homer's Iliad
are ancient and occurred worldwide, the prose novel as a distinct form
of storytelling, with developed, consistent human characters and,
typically, some connected overall plot (although both of these
characteristics have sometimes been modified and played with in later
times), was popularized by the West
in the 17th and 18th centuries. Of course, extended prose fiction had
existed much earlier; both novels of adventure and romance in the Hellenistic world and in Heian Japan. Both Petronius' Satyricon (c. 60 CE) and the Tale of Genji by Murasaki Shikibu
(c. 1000 CE) have been cited as the world's first major novel but they
had a very limited long-term impact on literary writing beyond their own
day until much more recent times.
Tragedy,
from its ritually and mythologically inspired Greek origins to modern
forms where struggle and downfall are often rooted in psychological or
social, rather than mythical, motives, is also widely considered a
specifically European creation and can be seen as a forerunner of some
aspects of both the novel and of classical opera.
Architecture
Important Western architectural motifs include the Doric, Corinthian, and Ionic orders of Greek architecture, and the Romanesque, Gothic, Renaissance, Baroque, and Victorian
styles, which are still widely recognized and used in contemporary
Western architecture. Much of Western architecture emphasizes repetition
of simple motifs, straight lines and expansive, undecorated planes. A
modern ubiquitous architectural form that emphasizes this characteristic
is the skyscraper, their modern equivalent first developed in New York and Chicago. The predecessor of the skyscraper can be found in the medieval towers erected in Bologna.
The Parthenon under restoration in 2008, the most iconic Classical building, built from 447 BC to 432 BC, located in Athens
Western foodways were, until recently, considered to have their roots in the cuisines of Classical Rome and Greece, but the influence of Arab and Near Eastern cuisine on the West has become a topic of research in recent decades. The Crusaders, known mostly for fighting over holy land, settled in the Levant and acclimated to the local culture and cuisine. Fulcher of Chartres
said "For we who were occidentals have now become orientals." These
cultural experiences, carried back to France by notables like Eleanor of Aquitaine
influenced Western European foodways. Many Oriental ingredients were
relatively new to the Western lands. Sugar, almonds, pistachios,
rosewater, and dried citrus fruits were all novelties to the Crusaders
who encountered them in Saracen lands. Pepper, ginger and cinnamon were
the most widely used spices of the European courts and noble households.
By the end of the Middle Ages, cloves, nutmeg, mastic, galingale, and other imported spices had become part of the Western cuisine.
Saracen influence can be seen in medieval cookbooks. Some recipes retain their Arabic names in Italian translations of the Liber de Coquina. Known as bruet Sarassinois in the cuisine of North France, the concept of sweet and sour sauce is attested to in Greek tradition when Anthimus
finishes his stew with vinegar and honey. Saracens combined sweet
ingredients like date-juice and honey with pomegranate, lemons and
citrus juices, or other sour ingredients. The technique of browning
pieces of meat and simmering in liquid with vegetables is used in many
recipes from the Baghdad cookery book. The same technique appears in the late-13th century Viandier. Fried pieces of beef simmered in wine with sugar and cloves was called bruet of Sarcynesse in English.
Scientific and technological inventions and discoveries
Medieval
Christians believed that to seek the geometric, physical and
mathematical principles that govern the world was to seek and worship
God. Detail of a scene in the bowl of the letter 'P' with a woman with a
set-square and dividers; using a compass to measure distances on a
diagram. In her left hand she holds a square, an implement for testing
or drawing right angles. She is watched by a group of students. In the
Middle Ages, it is unusual to see women represented as teachers, in
particular when the students appear to be monks. She is most likely the
personification of Geometry, based on Martianus Capella's famous book De
Nuptiis Philologiae et Mercurii [5th c.], a standard source for
allegorical imagery of the seven liberal arts. Illustration at the
beginning of Euclid's Elementa, in the translation attributed to Adelard
of Bath.A doctor of philosophy of the University of Oxford,
in full academic dress. The typical dress for graduation are gowns and
hoods or hats adapted from the daily dress of university staff in the
Middle Ages, which was in turn based on the attire worn by medieval
clergy.The Greek Antikythera mechanism is generally referred to as the first known analogue computer.Apollo 11 astronaut Buzz Aldrin, Apollo Lunar Module pilot of the first crewed mission to land on the Moon, poses for a photograph beside the deployed United States flag during his Extravehicular Activity (EVA) on the lunar surface.
A notable feature of Western culture is its strong emphasis and focus
on innovation and invention through science and technology, and its
ability to generate new processes, materials and material artifacts with
its roots dating back to the Ancient Greeks. The scientific method
as "a method or procedure that has characterized natural science since
the 17th century, consisting in systematic observation, measurement, and
experiment, and the formulation, testing, and modification of
hypotheses" was fashioned by the 17th-century Italian Galileo Galilei, with roots in the work of medieval scholars such as the 11th-century Iraqi physicistIbn al-Haytham and the 13th-century English friar Roger Bacon.
By the will of the Swedish inventor Alfred Nobel the Nobel Prizes were established in 1895. The prizes in Chemistry, Literature, Peace, Physics, and Physiology or Medicine were first awarded in 1901.
The percentage of ethnically European Nobel prize winners during the
first and second halves of the 20th century were respectively 98 and 94
percent.
The world's most widely adopted system of measurement, the International System of Units, derived from the metric system, was first developed in France and evolved through contributions from various Westerners.
Westerners are also known for their explorations of the globe and outer space. The first expedition to circumnavigate the Earth (1522) was by Westerners, as well as the first journey to the South Pole (1911), and the first Moon landing (1969). The landing of robots on Mars (2004 and 2012) and on an asteroid (2001), the Voyager 2 explorations of the outer planets (Uranus in 1986 and Neptune in 1989), Voyager 1's passage into interstellar space (2013), and New Horizons' flyby of Pluto (2015) were significant recent Western achievements.
The roots of modern-day Western mass media can be traced back to the late 15th century, when printing presses
began to operate throughout wealthy European cities. The emergence of
news media in the 17th century has to be seen in close connection with
the spread of the printing press, from which the publishing press derives its name.
In the 16th century, a decrease in the preeminence of Latin
in its literary use, along with the impact of economic change, the
discoveries arising from trade and travel, navigation to the New World,
science and arts and the development of increasingly rapid
communications through print led to a rising corpus of vernacular media
content in European society.
After the launch of the satellite Sputnik 1 by the Soviet Union in 1957, satellite transmission technology was dramatically realised, with the United States launching Telstar
in 1962 linking live media broadcasts from the UK to the US. The first
digital broadcast satellite (DBS) system began transmitting in US in
1975.
Beginning in the 1990s, the Internet has contributed to a
tremendous increase in the accessibility of Western media content.
Departing from media offered in bundled content packages (magazines,
CDs, television and radio slots), the Internet has primarily offered unbundled content items (articles, audio and video files).
The native religions of Europe were polytheistic but not homogenous – however, they were similar insofar as they were predominantly Indo-European in origin. Roman religion was similar to but not the same as Hellenic religion – likewise for indigenous Germanic polytheism, Celtic polytheism and Slavic polytheism.
Before this time many Europeans from the north, especially
Scandinavians, remained polytheistic, though southern Europe was
predominantly Christian from the 5th century onwards.
Western culture at a fundamental level is influenced by the Judeo-Christian and Greco-Roman traditions.
These cultures had a number of similarities, such as a common emphasis
on the individual, but they also embody fundamentally conflicting
worldviews. For example, in Judaism and Christianity, God is the
ultimate authority, while Greco-Roman tradition considers the ultimate
authority to be reason. Christian attempts to reconcile these frameworks were responsible for the preservation of Greek philosophy. Historically, Europe has been the center and cradle of Christian civilization.
According to a survey by Pew Research Center from 2011, Christianity remains the dominant religion in the Western world where 70–84% are Christians, According to this survey, 76% of Europeans described themselves as Christians,and about 86% of the Americas' population identified themselves as Christians, (90% in Latin America and 77% in North America). 73% in Oceania self-identify as Christian, and 76% in South Africa are Christian.
Eurobarometer polls about religiosity in the European Union in 2012 found that Christianity was the largest religion in the European Union, accounting for 72% of the population. Catholics are the largest Christian group, accounting for 48%, while Protestants make up 12%, Eastern Orthodox make up 8% and other Christians make up 4% of the population respectively. In addition, Non-believers/Agnostics account for 16%, atheists account for 7%, and Muslims account for 2% of the population respectively. According to Scholars, in 2017, Europe's population was 77.8% Christian (up from 74.9% 1970), these changes were largely largely ascribed to the collapse of Communism and switching to Christianity in the former Soviet Union and Eastern Bloc countries.
At the same time, there has been an increase in the share of agnostic or atheist residents in Europe that accounted for 18% of the European population in 2012. In particular, over half of the population of the Czech Republic (79%) was agnostic, atheist or irreligious, compared to the United Kingdom (52%), Germany (25–33%), France (30–35%) and the Netherlands (39–44%).
As in other areas, the Jewish diaspora and Judaism exist in the Western world.
There are also small but increasing numbers of people across the
Western world who seek to revive the indigenous religions of their
European ancestors; such groups include Germanic, Roman, Hellenic, Celtic, Slavic, and polytheistic reconstructionist movements. Likewise, Wicca, New Age spirituality and other neo-pagan belief systems enjoy notable minority support in Western states.
Since classical antiquity, sport has been an important facet of Western cultural expression.
A wide range of sports was already established by the time of Ancient Greece
and the military culture and the development of sports in Greece
influenced one another considerably. Sports became such a prominent part
of their culture that the Greeks created the Olympic Games, which in ancient times were held every four years in a small village in the Peloponnesus called Olympia. Baron Pierre de Coubertin, a Frenchman, instigated the modern revival of the Olympic movement. The first modern Olympic games were held at Athens in 1896.
The Romans built immense structures such as the amphitheatres to house their festivals of sport. The Romans exhibited a passion for blood sports, such as the infamous Gladiatorial battles that pitted contestants against one another in a fight to the death. The Olympic Games revived many of the sports of classical antiquity—such as Greco-Roman wrestling, discus and javelin.
The sport of bullfighting
is a traditional spectacle of Spain, Portugal, southern France, and
some Latin American countries. It traces its roots to prehistoric bull worship and sacrifice
and is often linked to Rome, where many human-versus-animal events were
held. Bullfighting spread from Spain to its American colonies, and in
the 19th century to France, where it developed into a distinctive form
in its own right.
Jousting
and hunting were popular sports in the European Middle Ages, and the
aristocratic classes developed passions for leisure activities. A great
number of popular global sports were first developed or codified in
Europe. The modern game of golf originated in Scotland, where the first written record of golf is James II's banning of the game in 1457, as an unwelcome distraction to learning archery.
The Industrial Revolution
that began in Great Britain in the 18th century brought increased
leisure time, leading to more opportunities for citizens to participate
in athletic activities and also follow spectator sports. These trends
continued with the advent of mass media and global communication. The
bat and ball sport of cricket was first played in England during the 16th century and was exported around the globe via the British Empire.
A number of popular modern sports were devised or codified in the
United Kingdom during the 19th century and obtained global prominence;
these include ping pong, modern tennis, association football, netball and rugby.
Football (or soccer) remains hugely popular in Europe, but has grown from its origins to be known as the world game. Similarly, sports such as cricket, rugby, and netball were exported around the world, particularly among countries in the Commonwealth of Nations, thus India and Australia are among the strongest cricketing states, while victory in the Rugby World Cup has been shared among New Zealand, Australia, England, and South Africa.
Australian Rules Football, an Australian variation of football with similarities to Gaelic football and rugby, evolved in the British colony of Victoria
in the mid-19th century. The United States also developed unique
variations of English sports. English migrants took antecedents of baseball to America during the colonial period. The history of American football
can be traced to early versions of rugby football and association
football. Many games are known as "football" were being played at
colleges and universities in the United States in the first half of the
19th century. American football resulted from several major divergences
from rugby, most notably the rule changes instituted by Walter Camp, the "Father of American football". Basketball was invented in 1891 by James Naismith, a Canadian physical education instructor working in Springfield, Massachusetts, in the United States. Volleyball was created in Holyoke, Massachusetts, a city directly north of Springfield, in 1895.
Themes and traditions
A Madonna and Child painting by an anonymous Italian from the first half of the 19th century, oil on canvas
Western culture has developed many themes and traditions, the most significant of which are:[citation needed]
Greco-Roman classic letters, arts, architecture, philosophical
and cultural tradition, which include the influence of preeminent
authors and philosophers such as Socrates, Plato, Aristotle, Homer, Virgil, and Cicero, as well as a long mythologic tradition.
Secular humanism, rationalism and Enlightenment thought. This set the basis for a new critical attitude and open questioning of religion, favouring freethinking and questioning of the church as an authority, which resulted in open-minded and reformist ideals inside, such as liberation theology, which partly adopted these currents, and secular and political tendencies such as separation of church and state (sometimes termed laicism), agnosticism and atheism.
Generalized usage of some form of the Latin alphabet, used by the majority of Europe, Greek alphabet, used in Greece or Cyrillic script, used by southern and eastern Slavic states of Eastern Orthodox tradition, historically influenced by the Byzantine Empire or the Bulgarian Empire, and later within the Russian czarist or the Soviet area of influence. Other variants of the Latin or Greek alphabets are found in the Gothic and Coptic alphabets, which historically superseded older scripts, such as runes, and the Egyptian Demotic and Hieroglyphic systems.
A large influence, in modern times, of many of the ideals and values developed and inherited from Romanticism.
An emphasis on, and use of, science as a means of understanding the natural world and humanity's place in it.
More pronounced use and application of innovation and scientific
developments, as well as a more rational approach to scientific progress
(what has been known as the scientific method).
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