Levodopa was first synthesized and isolated in the early 1910s. The antiparkinsonian effects of levodopa were discovered in the 1950s and 1960s. Following this, it was introduced for the treatment of Parkinson's disease in 1970.
In humans, conversion of levodopa to dopamine does not only occur within the central nervous system. Cells in the peripheral nervous system
perform the same task. Thus administering levodopa alone will lead to
increased dopamine signaling in the periphery as well. Excessive
peripheral dopamine signaling is undesirable as it causes many of the
adverse side effects
seen with sole levodopa administration. To bypass these effects, it is
standard clinical practice to coadminister (with levodopa) a peripheral DOPA decarboxylase inhibitor (DDCI) such as carbidopa (medicines containing carbidopa, either alone or in combination with levodopa, are branded as Lodosyn (Aton Pharma) Sinemet (Merck Sharp & Dohme Limited), Pharmacopa (Jazz Pharmaceuticals), Atamet (UCB), Syndopa and Stalevo (Orion Corporation) or with a benserazide
(combination medicines are branded Madopar or Prolopa), to prevent the
peripheral synthesis of dopamine from levodopa). However, when consumed
as a botanical extract, for example from M pruriens supplements, a peripheral DOPA decarboxylase inhibitor is not present.
Inbrija (previously known as CVT-301) is an inhaled powder
formulation of levodopa indicated for the intermittent treatment of "off
episodes" in patients with Parkinson's disease currently taking carbidopa/levodopa. It was approved by the United States Food and Drug Administration on 21 December 2018, and is marketed by Acorda Therapeutics.
Coadministration of pyridoxine without a DDCI accelerates the peripheral decarboxylation
of levodopa to such an extent that it negates the effects of levodopa
administration, a phenomenon that historically caused great confusion.
In addition, levodopa, co-administered with a peripheral DDCI, is efficacious for the short-term treatment of restless leg syndrome.
The two types of response seen with administration of levodopa are:
The short-duration response is related to the half-life of the drug.
The longer-duration response depends on the accumulation of effects over at least two weeks, during which ΔFosB accumulates in nigrostriatal neurons.
In the treatment of Parkinson's disease, this response is evident only
in early therapy, as the inability of the brain to store dopamine is not
yet a concern.
Nausea, which is often reduced by taking the drug with food, although protein reduces drug absorption. Levodopa is an amino acid, so protein competitively inhibits levodopa absorption.
Gastrointestinal bleeding
Disturbed respiration, which is not always harmful, and can actually benefit patients with upper airway obstruction
Possible dopamine dysregulation: The long-term use of levodopa in Parkinson's disease has been linked to the so-called dopamine dysregulation syndrome.
Clinicians try to avoid these side effects and adverse reactions
by limiting levodopa doses as much as possible until absolutely
necessary.
Metabolites of dopamine, such as DOPAL, are known to be dopaminergic neurotoxins. The long term use of levodopa increases oxidative stress through monoamine oxidase
led enzymatic degradation of synthesized dopamine causing neuronal
damage and cytotoxicity. The oxidative stress is caused by the formation
of reactive oxygen species (H2O2) during the monoamine oxidase led metabolism of dopamine. It is further perpetuated by the richness of Fe2+ ions in striatum via the Fenton reaction and intracellular autooxidation. The increased oxidation can potentially cause mutations in DNA due to the formation of 8-oxoguanine, which is capable of pairing with adenosine during mitosis. See also the catecholaldehyde hypothesis.
Levodopa was first synthesized in 1911 by Torquato Torquati from the Vicia faba bean. It was first isolated in 1913 by Marcus Guggenheim from the V.faba bean. Guggenheim tried levodopa at a dose of 2.5mg and thought that it was inactive aside from nausea and vomiting.
In work that earned him a Nobel Prize in 2000, Swedish scientist Arvid Carlsson first showed in the 1950s that administering levodopa to animals with drug-induced (reserpine) Parkinsonian symptoms caused a reduction in the intensity of the animals' symptoms. In 1960 or 1961 Oleh Hornykiewicz, after discovering greatly reduced levels of dopamine in autopsied brains of patients with Parkinson's disease,
published together with the neurologist Walther Birkmayer dramatic
therapeutic antiparkinson effects of intravenously administered levodopa
in patients. This treatment was later extended to manganese poisoning and later Parkinsonism by George Cotzias and his coworkers, who used greatly increased oral doses, for which they won the 1969 Lasker Prize.
The first study reporting improvements in patients with Parkinson's
disease resulting from treatment with levodopa was published in 1968.
Levodopa was first marketed in 1970 by Roche under the brand name Larodopa.
Levodopa is the generic name of the drug and its INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, USPTooltip United States Pharmacopeia, BANTooltip British Approved Name, DCFTooltip Dénomination Commune Française, DCITTooltip Denominazione Comune Italiana, and JANTooltip Japanese Accepted Name.
Levodopa prodrugs, with the potential for better pharmacokinetics, reduced fluctuations in levodopa levels, and reduced "on–off" phenomenon, are being researched and developed.
Depression
Levodopa has been reported to be inconsistently effective as an antidepressant in the treatment of depressive disorders. However, it was found to enhance psychomotor activation in people with depression.
In 2015, a retrospective analysis comparing the incidence of age-related macular degeneration (AMD) between patients taking versus not taking levodopa found that the drug delayed onset of AMD by around 8years. The authors state that significant effects were obtained for both dry and wet AMD.
A red tulip exhibiting a partially yellow petal due to a somatic mutation in a cell that formed that petal
Mutations may or may not produce detectable changes in the observable characteristics (phenotype) of an organism. Mutations play a part in both normal and abnormal biological processes including: evolution, cancer, and the development of the immune system, including junctional diversity. Mutation is the ultimate source of all genetic variation, providing the raw material on which evolutionary forces such as natural selection can act.
Mutation can result in many different types of change in sequences. Mutations in genes can have no effect, alter the product of a gene, or prevent the gene from functioning properly or completely. Mutations can also occur in non-genic regions. A 2007 study on genetic variations between different species of Drosophila suggested that, if a mutation changes a protein produced by a gene, the result is likely to be harmful, with an estimated 70% of amino acidpolymorphisms that have damaging effects, and the remainder being either neutral or marginally beneficial.
Mutation and DNA damage
are the two major types of errors that occur in DNA, but they are
fundamentally different. DNA damage is a physical alteration in the DNA
structure, such as a single or double strand break, a modified
guanosine residue in DNA such as 8-hydroxydeoxyguanosine, or a polycyclic aromatic hydrocarbon
adduct. DNA damages can be recognized by enzymes, and therefore can be
correctly repaired using the complementary undamaged strand in DNA as a
template or an undamaged sequence in a homologous chromosome if it is
available. If DNA damage remains in a cell, transcription of a gene may be prevented and thus translation into a protein may also be blocked. DNA replication
may also be blocked and/or the cell may die. In contrast to a DNA
damage, a mutation is an alteration of the base sequence of the DNA.
Ordinarily, a mutation cannot be recognized by enzymes once the base
change is present in both DNA strands, and thus a mutation is not
ordinarily repaired. At the cellular level, mutations can alter protein
function and regulation. Unlike DNA damages, mutations are replicated
when the cell replicates. At the level of cell populations, cells with
mutations will increase or decrease in frequency according to the
effects of the mutations on the ability of the cell to survive and
reproduce. Although distinctly different from each other, DNA damages
and mutations are related because DNA damages often cause errors of DNA
synthesis during replication or repair and these errors are a major
source of mutation.
Overview
Mutations can involve the duplication of large sections of DNA, usually through genetic recombination.
These duplications are a major source of raw material for evolving new
genes, with tens to hundreds of genes duplicated in animal genomes every
million years. Most genes belong to larger gene families of shared ancestry, detectable by their sequence homology.
Novel genes are produced by several methods, commonly through the
duplication and mutation of an ancestral gene, or by recombining parts
of different genes to form new combinations with new functions.
Here, protein domains
act as modules, each with a particular and independent function, that
can be mixed together to produce genes encoding new proteins with novel
properties. For example, the human eye uses four genes to make structures that sense light: three for cone cell or colour vision and one for rod cell or night vision; all four arose from a single ancestral gene. Another advantage of duplicating a gene (or even an entire genome) is that this increases engineering redundancy; this allows one gene in the pair to acquire a new function while the other copy performs the original function. Other types of mutation occasionally create new genes from previously noncoding DNA.
Changes in chromosome
number may involve even larger mutations, where segments of the DNA
within chromosomes break and then rearrange. For example, in the Homininae, two chromosomes fused to produce human chromosome 2; this fusion did not occur in the lineage of the other apes, and they retain these separate chromosomes.
In evolution, the most important role of such chromosomal
rearrangements may be to accelerate the divergence of a population into new species by making populations less likely to interbreed, thereby preserving genetic differences between these populations.
Sequences of DNA that can move about the genome, such as transposons,
make up a major fraction of the genetic material of plants and animals,
and may have been important in the evolution of genomes. For example, more than a million copies of the Alu sequence are present in the human genome, and these sequences have now been recruited to perform functions such as regulating gene expression.
Another effect of these mobile DNA sequences is that when they move
within a genome, they can mutate or delete existing genes and thereby
produce genetic diversity.
Nonlethal mutations accumulate within the gene pool and increase the amount of genetic variation. The abundance of some genetic changes within the gene pool can be reduced by natural selection, while other "more favorable" mutations may accumulate and result in adaptive changes.
For example, a butterfly may produce offspring with new mutations. The majority of these mutations will have no effect; but one might change the colour
of one of the butterfly's offspring, making it harder (or easier) for
predators to see. If this color change is advantageous, the chances of
this butterfly's surviving and producing its own offspring are a little
better, and over time the number of butterflies with this mutation may
form a larger percentage of the population.
Neutral mutations are defined as mutations whose effects do not influence the fitness of an individual. These can increase in frequency over time due to genetic drift. It is believed that the overwhelming majority of mutations have no significant effect on an organism's fitness.
Also, DNA repair mechanisms are able to mend most changes before they
become permanent mutations, and many organisms have mechanisms, such as apoptotic pathways, for eliminating otherwise-permanently mutated somatic cells.
Beneficial mutations can improve reproductive success.
Four classes of mutations are (1) spontaneous mutations (molecular decay), (2) mutations due to error-prone replication bypass of naturally occurring DNA damage (also called error-prone translesion synthesis), (3) errors introduced during DNA repair, and (4) induced mutations caused by mutagens.
Scientists may sometimes deliberately introduce mutations into cells or
research organisms for the sake of scientific experimentation.
One 2017 study claimed that 66% of cancer-causing mutations are
random, 29% are due to the environment (the studied population spanned
69 countries), and 5% are inherited.
Humans on average pass 60 new mutations to their children but
fathers pass more mutations depending on their age with every year
adding two new mutations to a child.
Spontaneous mutation
Spontaneous mutations
occur with non-zero probability even given a healthy, uncontaminated
cell. Naturally occurring oxidative DNA damage is estimated to occur
10,000 times per cell per day in humans and 100,000 times per cell per
day in rats. Spontaneous mutations can be characterized by the specific change:
Tautomerism – A base is changed by the repositioning of a hydrogen atom, altering the hydrogen bonding pattern of that base, resulting in incorrect base pairing during replication. Theoretical results suggest that proton tunnelling is an important factor in the spontaneous creation of GC tautomers.
Deamination – Hydrolysis changes a normal base to an atypical base containing a keto group in place of the original amine group. Examples include C → U and A → HX (hypoxanthine), which can be corrected by DNA repair mechanisms; and 5MeC (5-methylcytosine) → T, which is less likely to be detected as a mutation because thymine is a normal DNA base.
Slipped strand mispairing
– Denaturation of the new strand from the template during replication,
followed by renaturation in a different spot ("slipping"). This can lead
to insertions or deletions.
Error-prone replication bypass
There is increasing evidence that the majority of spontaneously arising mutations are due to error-prone replication (translesion synthesis) past DNA damage in the template strand. In mice, the majority of mutations are caused by translesion synthesis.[39] Likewise, in yeast, Kunz et al.[40] found that more than 60% of the spontaneous single base pair substitutions and deletions were caused by translesion synthesis.
Although naturally occurring double-strand breaks occur at a
relatively low frequency in DNA, their repair often causes mutation. Non-homologous end joining (NHEJ) is a major pathway for repairing double-strand breaks. NHEJ involves removal of a few nucleotides
to allow somewhat inaccurate alignment of the two ends for rejoining
followed by addition of nucleotides to fill in gaps. As a consequence,
NHEJ often introduces mutations.
Alkylating agents (e.g., N-ethyl-N-nitrosourea
(ENU). These agents can mutate both replicating and non-replicating
DNA. In contrast, a base analogue can mutate the DNA only when the
analogue is incorporated in replicating the DNA. Each of these classes
of chemical mutagens has certain effects that then lead to transitions, transversions, or deletions.
Nitrous acid converts amine groups on A and C to diazo groups, altering their hydrogen bonding patterns, which leads to incorrect base pairing during replication.
Radiation
Ultraviolet light (UV) (including non-ionizing radiation). Two nucleotide bases in DNA—cytosine and thymine—are most vulnerable to radiation that can change their properties. UV light can induce adjacent pyrimidine bases in a DNA strand to become covalently joined as a pyrimidine dimer. UV radiation, in particular longer-wave UVA, can also cause oxidative damage to DNA.
Ionizing radiation. Exposure to ionizing radiation, such as gamma radiation, can result in mutation, possibly resulting in cancer or death.
Whereas in former times mutations were assumed to occur by chance, or
induced by mutagens, molecular mechanisms of mutation have been
discovered in bacteria and across the tree of life. As S. Rosenberg
states, "These mechanisms reveal a picture of highly regulated
mutagenesis, up-regulated temporally by stress responses and activated
when cells/organisms are maladapted to their environments—when
stressed—potentially accelerating adaptation."
Since they are self-induced mutagenic mechanisms that increase the
adaptation rate of organisms, they have some times been named as
adaptive mutagenesis mechanisms, and include the SOS response in
bacteria, ectopic intrachromosomal recombination and other chromosomal events such as duplications.
Classification of types
By effect on structure
Five types of chromosomal mutationsTypes of small-scale mutations
The sequence of a gene can be altered in a number of ways.
Gene mutations have varying effects on health depending on where they
occur and whether they alter the function of essential proteins.
Mutations in the structure of genes can be classified into several
types.
Large-scale mutations in chromosomal structure include:
Amplifications (or gene duplications)
or repetition of a chromosomal segment or presence of extra piece of a
chromosome broken piece of a chromosome may become attached to a
homologous or non-homologous chromosome so that some of the genes are
present in more than two doses leading to multiple copies of all
chromosomal regions, increasing the dosage of the genes located within
them.
Polyploidy, duplication of entire sets of chromosomes, potentially resulting in a separate breeding population and speciation.
Deletions of large chromosomal regions, leading to loss of the genes within those regions.
Mutations whose effect is to juxtapose previously separate pieces of
DNA, potentially bringing together separate genes to form functionally
distinct fusion genes (e.g., bcr-abl).
Large scale changes to the structure of chromosomes called chromosomal rearrangement that can lead to a decrease of fitness but also to speciation in isolated, inbred populations. These include:
Interstitial deletions: an intra-chromosomal deletion that removes a
segment of DNA from a single chromosome, thereby apposing previously
distant genes. For example, cells isolated from a human astrocytoma, a type of brain tumour, were found to have a chromosomal deletion removing sequences between the Fused in Glioblastoma
(FIG) gene and the receptor tyrosine kinase (ROS), producing a fusion
protein (FIG-ROS). The abnormal FIG-ROS fusion protein has
constitutively active kinase activity that causes oncogenic transformation (a transformation from normal cells to cancer cells).
Loss of heterozygosity: loss of one allele, either by a deletion or a genetic recombination event, in an organism that previously had two different alleles.
Small-scale mutations
Small-scale mutations affect a gene in one or a few nucleotides. (If only a single nucleotide is affected, they are called point mutations.) Small-scale mutations include:
Insertions add one or more extra nucleotides into the DNA. They are usually caused by transposable elements, or errors during replication of repeating elements. Insertions in the coding region of a gene may alter splicing of the mRNA (splice site mutation), or cause a shift in the reading frame (frameshift), both of which can significantly alter the gene product. Insertions can be reversed by excision of the transposable element.
Deletions
remove one or more nucleotides from the DNA. Like insertions, these
mutations can alter the reading frame of the gene. In general, they are
irreversible: Though exactly the same sequence might, in theory, be
restored by an insertion, transposable elements able to revert a very
short deletion (say 1–2 bases) in any location either are highly unlikely to exist or do not exist at all.
Substitution mutations, often caused by chemicals or malfunction of DNA replication, exchange a single nucleotide for another. These changes are classified as transitions or transversions. Most common is the transition that exchanges a purine for a purine (A ↔ G) or a pyrimidine
for a pyrimidine, (C ↔ T). A transition can be caused by nitrous acid,
base mispairing, or mutagenic base analogues such as BrdU. Less common
is a transversion, which exchanges a purine for a pyrimidine or a
pyrimidine for a purine (C/T ↔ A/G). An example of a transversion is the
conversion of adenine
(A) into a cytosine (C). Point mutations are modifications of single
base pairs of DNA or other small base pairs within a gene. A point
mutation can be reversed by another point mutation, in which the
nucleotide is changed back to its original state (true reversion) or by
second-site reversion (a complementary mutation elsewhere that results
in regained gene functionality). As discussed below, point mutations that occur within the protein coding region of a gene may be classified as synonymous or nonsynonymous substitutions, the latter of which in turn can be divided into missense or nonsense mutations.
By impact on protein sequence
The structure of a eukaryotic protein-coding gene. A mutation in the protein coding region
(red) can result in a change in the amino acid sequence. Mutations in
other areas of the gene can have diverse effects. Changes within regulatory sequences (yellow and blue) can effect transcriptional and translational regulation of gene expression.Point mutations classified by impact on proteinSelection of disease-causing mutations, in a standard table of the genetic code of amino acids
The effect of a mutation on protein sequence depends in part on where in the genome it occurs, especially whether it is in a coding or non-coding region. Mutations in the non-coding regulatory sequences
of a gene, such as promoters, enhancers, and silencers, can alter
levels of gene expression, but are less likely to alter the protein
sequence. Mutations within introns and in regions with no known biological function (e.g. pseudogenes, retrotransposons) are generally neutral, having no effect on phenotype – though intron mutations could alter the protein product if they affect mRNA splicing.
Mutations that occur in coding regions of the genome are more
likely to alter the protein product, and can be categorized by their
effect on amino acid sequence:
A frameshift mutation
is caused by insertion or deletion of a number of nucleotides that is
not evenly divisible by three from a DNA sequence. Due to the triplet
nature of gene expression by codons, the insertion or deletion can
disrupt the reading frame, or the grouping of the codons, resulting in a
completely different translation from the original.
The earlier in the sequence the deletion or insertion occurs, the more
altered the protein produced is. (For example, the code CCU GAC UAC CUA
codes for the amino acids proline, aspartic acid, tyrosine, and leucine.
If the U in CCU was deleted, the resulting sequence would be CCG ACU
ACC UAx, which would instead code for proline, threonine, threonine, and
part of another amino acid or perhaps a stop codon
(where the x stands for the following nucleotide).) By contrast, any
insertion or deletion that is evenly divisible by three is termed an in-frame mutation.
A point substitution mutation results in a change in a single nucleotide and can be either synonymous or nonsynonymous.
A synonymous substitution
replaces a codon with another codon that codes for the same amino acid,
so that the produced amino acid sequence is not modified. Synonymous
mutations occur due to the degenerate nature of the genetic code. If this mutation does not result in any phenotypic effects, then it is called silent,
but not all synonymous substitutions are silent. (There can also be
silent mutations in nucleotides outside of the coding regions, such as
the introns, because the exact nucleotide sequence is not as crucial as
it is in the coding regions, but these are not considered synonymous
substitutions.)
A nonsynonymous substitution
replaces a codon with another codon that codes for a different amino
acid, so that the produced amino acid sequence is modified.
Nonsynonymous substitutions can be classified as nonsense or missense
mutations:
A missense mutation
changes a nucleotide to cause substitution of a different amino acid.
This in turn can render the resulting protein nonfunctional. Such
mutations are responsible for diseases such as Epidermolysis bullosa, sickle-cell disease, and SOD1-mediated ALS.
On the other hand, if a missense mutation occurs in an amino acid codon
that results in the use of a different, but chemically similar, amino
acid, then sometimes little or no change is rendered in the protein. For
example, a change from AAA to AGA will encode arginine, a chemically similar molecule to the intended lysine. In this latter case the mutation will have little or no effect on phenotype and therefore be neutral.
A nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon, or a nonsense codon
in the transcribed mRNA, and possibly a truncated, and often
nonfunctional protein product. This sort of mutation has been linked to
different diseases, such as congenital adrenal hyperplasia. (See Stop codon.)
By effect on function
A
mutation becomes an effect on function mutation when the exactitude of
functions between a mutated protein and its direct interactor undergoes
change. The interactors can be other proteins, molecules, nucleic acids,
etc. There are many mutations that fall under the category of by effect
on function, but depending on the specificity of the change the
mutations listed below will occur.
Loss-of-function mutations, also called inactivating mutations,
result in the gene product having less or no function (being partially
or wholly inactivated). When the allele has a complete loss of function (null allele), it is often called an amorph or amorphic mutation in Muller's morphs schema. Phenotypes associated with such mutations are most often recessive. Exceptions are when the organism is haploid, or when the reduced dosage of a normal gene product is not enough for a normal phenotype (this is called haploinsufficiency). A disease that is caused by a loss-of-function mutation is Gitelman syndrome and cystic fibrosis.
Gain-of-function mutations also called activating mutations, change
the gene product such that its effect gets stronger (enhanced
activation) or even is superseded by a different and abnormal function.
When the new allele is created, a heterozygote
containing the newly created allele as well as the original will
express the new allele; genetically this defines the mutations as dominant
phenotypes. Several of Muller's morphs correspond to the gain of
function, including hypermorph (increased gene expression) and neomorph
(novel function).
Dominant negative mutations (also called anti-morphic mutations)
have an altered gene product that acts antagonistically to the wild-type
allele. These mutations usually result in an altered molecular function
(often inactive) and are characterized by a dominant or semi-dominant phenotype. In humans, dominant negative mutations have been implicated in cancer (e.g., mutations in genes p53, ATM, CEBPA, and PPARgamma). Marfan syndrome is caused by mutations in the FBN1 gene, located on chromosome 15, which encodes fibrillin-1, a glycoprotein component of the extracellular matrix. Marfan syndrome is also an example of dominant negative mutation and haploinsufficiency.
Lethal mutations result in rapid organismal death when occurring
during development and cause significant reductions of life expectancy
for developed organisms. An example of a disease that is caused by a
dominant lethal mutation is Huntington's disease.
Null mutations, also known as Amorphic mutations, are a form of
loss-of-function mutations that completely prohibit the gene's function.
The mutation leads to a complete loss of operation at the phenotypic
level, also causing no gene product to be formed. Atopic eczema and dermatitis syndrome are common diseases caused by a null mutation of the gene that activates filaggrin.
Suppressor mutations are a type of mutation that causes the double
mutation to appear normally. In suppressor mutations the phenotypic
activity of a different mutation is completely suppressed, thus causing
the double mutation to look normal. There are two types of suppressor
mutations, there are intragenic
and extragenic suppressor mutations. Intragenic mutations occur in the
gene where the first mutation occurs, while extragenic mutations occur
in the gene that interacts with the product of the first mutation. A
common disease that results from this type of mutation is Alzheimer's disease.
Neomorphic mutations are a part of the gain-of-function mutations
and are characterized by the control of new protein product synthesis.
The newly synthesized gene normally contains a novel gene expression or
molecular function. The result of the neomorphic mutation is the gene
where the mutation occurs has a complete change in function.
A back mutation or reversion is a point mutation that restores the original sequence and hence the original phenotype.
By effect on fitness (harmful, beneficial, neutral mutations)
In genetics, it is sometimes useful to classify mutations as either harmful or beneficial (or neutral):
A harmful, or deleterious, mutation decreases the fitness of the organism. Many, but not all mutations in essential genes are harmful (if a mutation does not change the amino acid sequence in an essential protein, it is harmless in most cases).
A beneficial, or advantageous mutation increases the fitness of the organism. Examples are mutations that lead to antibiotic resistance in bacteria (which are beneficial for bacteria but usually not for humans).
A neutral mutation has no harmful or beneficial effect on the
organism. Such mutations occur at a steady rate, forming the basis for
the molecular clock. In the neutral theory of molecular evolution,
neutral mutations provide genetic drift as the basis for most variation
at the molecular level. In animals or plants, most mutations are
neutral, given that the vast majority of their genomes is either
non-coding or consists of repetitive sequences that have no obvious
function ("junk DNA").
Large-scale quantitative mutagenesis screens, in which
thousands of millions of mutations are tested, invariably find that a
larger fraction of mutations has harmful effects but always returns a
number of beneficial mutations as well. For instance, in a screen of all
gene deletions in E. coli,
80% of mutations were negative, but 20% were positive, even though many
had a very small effect on growth (depending on condition). Gene deletions involve removal of whole genes, so that point mutations almost always have a much smaller effect. In a similar screen in Streptococcus pneumoniae, but this time with transposon
insertions, 76% of insertion mutants were classified as neutral, 16%
had a significantly reduced fitness, but 6% were advantageous.
This classification is obviously relative and somewhat
artificial: a harmful mutation can quickly turn into a beneficial
mutations when conditions change. Also, there is a gradient from
harmful/beneficial to neutral, as many mutations may have small and
mostly neglectable effects but under certain conditions will become
relevant. Also, many traits are determined by hundreds of genes (or
loci), so that each locus has only a minor effect. For instance, human
height is determined by hundreds of genetic variants ("mutations") but
each of them has a very minor effect on height, apart from the impact of nutrition. Height (or size) itself may be more or less beneficial as the huge range of sizes in animal or plant groups shows.
Distribution of fitness effects (DFE)
Attempts have been made to infer the distribution of fitness effects (DFE) using mutagenesis
experiments and theoretical models applied to molecular sequence data.
DFE, as used to determine the relative abundance of different types of
mutations (i.e., strongly deleterious, nearly neutral or advantageous),
is relevant to many evolutionary questions, such as the maintenance of genetic variation, the rate of genomic decay, the maintenance of outcrossingsexual reproduction as opposed to inbreeding and the evolution of sex and genetic recombination.
DFE can also be tracked by tracking the skewness of the distribution of
mutations with putatively severe effects as compared to the
distribution of mutations with putatively mild or absent effect. In summary, the DFE plays an important role in predicting evolutionary dynamics. A variety of approaches have been used to study the DFE, including theoretical, experimental and analytical methods.
Mutagenesis experiment: The direct method to investigate the DFE
is to induce mutations and then measure the mutational fitness effects,
which has already been done in viruses, bacteria, yeast, and Drosophila. For example, most studies of the DFE in viruses used site-directed mutagenesis to create point mutations and measure relative fitness of each mutant. In Escherichia coli, one study used transposon mutagenesis to directly measure the fitness of a random insertion of a derivative of Tn10. In yeast, a combined mutagenesis and deep sequencing approach has been developed to generate high-quality systematic mutant libraries and measure fitness in high throughput. However, given that many mutations have effects too small to be detected and that mutagenesis experiments can detect only mutations of moderately large effect; DNA sequence analysis can provide valuable information about these mutations.
The distribution of fitness effects (DFE) of mutations in vesicular stomatitis virus. In this experiment, random mutations were introduced into the virus by site-directed mutagenesis, and the fitness
of each mutant was compared with the ancestral type. A fitness of zero,
less than one, one, more than one, respectively, indicates that
mutations are lethal, deleterious, neutral, and advantageous.
This
figure shows a simplified version of loss-of-function,
switch-of-function, gain-of-function, and conservation-of-function
mutations.Molecular sequence analysis: With rapid development of DNA sequencing
technology, an enormous amount of DNA sequence data is available and
even more is forthcoming in the future. Various methods have been
developed to infer the DFE from DNA sequence data.By examining DNA sequence differences within and between species, we
are able to infer various characteristics of the DFE for neutral,
deleterious and advantageous mutations.
To be specific, the DNA sequence analysis approach allows us to
estimate the effects of mutations with very small effects, which are
hardly detectable through mutagenesis experiments.
One of the earliest theoretical studies of the distribution of fitness effects was done by Motoo Kimura, an influential theoretical population geneticist. His neutral theory of molecular evolution proposes that most novel mutations will be highly deleterious, with a small fraction being neutral. A later proposal by Hiroshi Akashi proposed a bimodal model for the DFE, with modes centered around highly deleterious and neutral mutations.
Both theories agree that the vast majority of novel mutations are
neutral or deleterious and that advantageous mutations are rare, which
has been supported by experimental results. One example is a study done
on the DFE of random mutations in vesicular stomatitis virus.
Out of all mutations, 39.6% were lethal, 31.2% were non-lethal
deleterious, and 27.1% were neutral. Another example comes from a high
throughput mutagenesis experiment with yeast.
In this experiment it was shown that the overall DFE is bimodal, with a
cluster of neutral mutations, and a broad distribution of deleterious
mutations.
Though relatively few mutations are advantageous, those that are play an important role in evolutionary changes.
Like neutral mutations, weakly selected advantageous mutations can be
lost due to random genetic drift, but strongly selected advantageous
mutations are more likely to be fixed. Knowing the DFE of advantageous
mutations may lead to increased ability to predict the evolutionary
dynamics. Theoretical work on the DFE for advantageous mutations has
been done by John H. Gillespie and H. Allen Orr. They proposed that the distribution for advantageous mutations should be exponential
under a wide range of conditions, which, in general, has been supported
by experimental studies, at least for strongly selected advantageous
mutations.
In general, it is accepted that the majority of mutations are
neutral or deleterious, with advantageous mutations being rare; however,
the proportion of types of mutations varies between species. This
indicates two important points: first, the proportion of effectively
neutral mutations is likely to vary between species, resulting from
dependence on effective population size; second, the average effect of deleterious mutations varies dramatically between species. In addition, the DFE also differs between coding regions and noncoding regions, with the DFE of noncoding DNA containing more weakly selected mutations.
By inheritance
A mutation has caused this moss rose plant to produce flowers of different colours. This is a somatic mutation that may also be passed on in the germline.
In multicellular organisms with dedicated reproductive cells, mutations can be subdivided into germline mutations, which can be passed on to descendants through their reproductive cells, and somatic mutations (also called acquired mutations), which involve cells outside the dedicated reproductive group and which are not usually transmitted to descendants.
Diploid organisms (e.g., humans) contain two copies of each
gene—a paternal and a maternal allele. Based on the occurrence of
mutation on each chromosome, we may classify mutations into three types.
A wild type or homozygous non-mutated organism is one in which neither allele is mutated.
A heterozygous mutation is a mutation of only one allele.
A homozygous mutation is an identical mutation of both the paternal and maternal alleles.
Compound heterozygous mutations or a genetic compound consists of two different mutations in the paternal and maternal alleles.
A germline mutation in the reproductive cells of an individual gives rise to a constitutional mutation in the offspring, that is, a mutation that is present in every cell. A constitutional mutation can also occur very soon after fertilization, or continue from a previous constitutional mutation in a parent. A germline mutation can be passed down through subsequent generations of organisms.
The distinction between germline and somatic mutations is
important in animals that have a dedicated germline to produce
reproductive cells. However, it is of little value in understanding the
effects of mutations in plants, which lack a dedicated germline. The
distinction is also blurred in those animals that reproduce asexually through mechanisms such as budding, because the cells that give rise to the daughter organisms also give rise to that organism's germline.
A new germline mutation not inherited from either parent is called a de novo mutation.
A change in the genetic structure that is not inherited from a parent, and also not passed to offspring, is called a somatic mutation.Somatic mutations are not inherited by an organism's offspring because they do not affect the germline.
However, they are passed down to all the progeny of a mutated cell
within the same organism during mitosis. A major section of an organism
therefore might carry the same mutation. These types of mutations are
usually prompted by environmental causes, such as ultraviolet radiation
or any exposure to certain harmful chemicals, and can cause diseases
including cancer.
With plants, some somatic mutations can be propagated without the need for seed production, for example, by grafting and stem cuttings. These type of mutation have led to new types of fruits, such as the "Delicious" apple and the "Washington" navel orange.
Human and mouse somatic cells have a mutation rate more than ten times higher than the germline mutation rate for both species; mice have a higher rate of both somatic and germline mutations per cell division than humans. The disparity in mutation rate between the germline and somatic tissues likely reflects the greater importance of genome maintenance in the germline than in the soma.
Special classes
Conditional mutation
is a mutation that has wild-type (or less severe) phenotype under
certain "permissive" environmental conditions and a mutant phenotype
under certain "restrictive" conditions. For example, a
temperature-sensitive mutation can cause cell death at high temperature
(restrictive condition), but might have no deleterious consequences at a
lower temperature (permissive condition).
These mutations are non-autonomous, as their manifestation depends upon
presence of certain conditions, as opposed to other mutations which
appear autonomously. The permissive conditions may be temperature, certain chemicals, light or mutations in other parts of the genome. In vivo
mechanisms like transcriptional switches can create conditional
mutations. For instance, association of Steroid Binding Domain can
create a transcriptional switch that can change the expression of a gene
based on the presence of a steroid ligand.
Conditional mutations have applications in research as they allow
control over gene expression. This is especially useful studying
diseases in adults by allowing expression after a certain period of
growth, thus eliminating the deleterious effect of gene expression seen
during stages of development in model organisms.[98] DNA Recombinase systems like Cre-Lox recombination used in association with promoters
that are activated under certain conditions can generate conditional
mutations. Dual Recombinase technology can be used to induce multiple
conditional mutations to study the diseases which manifest as a result
of simultaneous mutations in multiple genes. Certain inteins
have been identified which splice only at certain permissive
temperatures, leading to improper protein synthesis and thus,
loss-of-function mutations at other temperatures.
Conditional mutations may also be used in genetic studies associated
with ageing, as the expression can be changed after a certain time
period in the organism's lifespan.
In
order to categorize a mutation as such, the "normal" sequence must be
obtained from the DNA of a "normal" or "healthy" organism (as opposed to
a "mutant" or "sick" one), it should be identified and reported;
ideally, it should be made publicly available for a straightforward
nucleotide-by-nucleotide comparison, and agreed upon by the scientific
community or by a group of expert geneticists and biologists, who have the responsibility of establishing the standard
or so-called "consensus" sequence. This step requires a tremendous
scientific effort. Once the consensus sequence is known, the mutations
in a genome can be pinpointed, described, and classified. The committee
of the Human Genome Variation Society (HGVS) has developed the standard
human sequence variant nomenclature, which should be used by researchers and DNA diagnostic
centers to generate unambiguous mutation descriptions. In principle,
this nomenclature can also be used to describe mutations in other
organisms. The nomenclature specifies the type of mutation and base or
amino acid changes.
Nucleotide substitution (e.g., 76A>T) – The number is the
position of the nucleotide from the 5' end; the first letter represents
the wild-type nucleotide, and the second letter represents the
nucleotide that replaced the wild type. In the given example, the
adenine at the 76th position was replaced by a thymine.
If it becomes necessary to differentiate between mutations in genomic DNA, mitochondrial DNA, and RNA,
a simple convention is used. For example, if the 100th base of a
nucleotide sequence mutated from G to C, then it would be written as
g.100G>C if the mutation occurred in genomic DNA, m.100G>C if the
mutation occurred in mitochondrial DNA, or r.100g>c if the mutation
occurred in RNA. Note that, for mutations in RNA, the nucleotide code is
written in lower case.
Amino acid substitution (e.g., D111E) – The first letter is the one letter code of the wild-type amino acid, the number is the position of the amino acid from the N-terminus,
and the second letter is the one letter code of the amino acid present
in the mutation. Nonsense mutations are represented with an X for the
second amino acid (e.g. D111X).
Amino acid deletion (e.g., ΔF508) – The Greek letter Δ (delta)
indicates a deletion. The letter refers to the amino acid present in
the wild type and the number is the position from the N terminus of the
amino acid were it to be present as in the wild type.
Mutation rates
vary substantially across species, and the evolutionary forces that
generally determine mutation are the subject of ongoing investigation.
In humans, the mutation rate is about 50–90 de novo
mutations per genome per generation, that is, each human accumulates
about 50–90 novel mutations that were not present in his or her parents.
This number has been established by sequencing thousands of human trios, that is, two parents and at least one child.
The genomes of RNA viruses are based on RNA
rather than DNA. The RNA viral genome can be double-stranded (as in
DNA) or single-stranded. In some of these viruses (such as the
single-stranded human immunodeficiency virus),
replication occurs quickly, and there are no mechanisms to check the
genome for accuracy. This error-prone process often results in
mutations.
The rate of de novo mutations, whether germline or somatic, vary among organisms. Individuals within the same species can even express varying rates of mutation. Overall, rates of de novo mutations are low compared to those of inherited mutations, which categorizes them as rare forms of genetic variation.
Many observations of de novo mutation rates have associated higher
rates of mutation correlated to paternal age. In sexually reproducing
organisms, the comparatively higher frequency of cell divisions in the
parental sperm donor germline drive conclusions that rates of de novo
mutation can be tracked along a common basis. The frequency of error
during the DNA replication process of gametogenesis,
especially amplified in the rapid production of sperm cells, can
promote more opportunities for de novo mutations to replicate
unregulated by DNA repair machinery. This claim combines the observed effects of increased probability for mutation in rapid spermatogenesis with short periods of time between cellular divisions that limit the efficiency of repair machinery.
Rates of de novo mutations that affect an organism during its
development can also increase with certain environmental factors. For
example, certain intensities of exposure to radioactive elements can
inflict damage to an organism's genome, heightening rates of mutation.
In humans, the appearance of skin cancer during one's lifetime is induced by overexposure to UV radiation that causes mutations in the cellular and skin genome.
Randomness of mutations
There
is a widespread assumption that mutations are (entirely) "random" with
respect to their consequences (in terms of probability). This was shown
to be wrong as mutation frequency can vary across regions of the genome,
with such DNA repair-
and mutation-biases being associated with various factors. For
instance, Monroe and colleagues demonstrated that—in the studied plant (Arabidopsis thaliana)—more
important genes mutate less frequently than less important ones. They
demonstrated that mutation is "non-random in a way that benefits the
plant". Additionally, previous experiments typically used to demonstrate mutations being random with respect to fitness (such as the Fluctuation Test and Replica plating)
have been shown to only support the weaker claim that those mutations
are random with respect to external selective constraints, not fitness
as a whole.
Disease causation
Changes
in DNA caused by mutation in a coding region of DNA can cause errors in
protein sequence that may result in partially or completely
non-functional proteins. Each cell, in order to function correctly,
depends on thousands of proteins to function in the right places at the
right times. When a mutation alters a protein that plays a critical role
in the body, a medical condition can result. One study on the
comparison of genes between different species of Drosophila
suggests that if a mutation does change a protein, the mutation will
most likely be harmful, with an estimated 70 per cent of amino acid
polymorphisms having damaging effects, and the remainder being either
neutral or weakly beneficial.
Some mutations alter a gene's DNA base sequence but do not change the
protein made by the gene. Studies have shown that only 7% of point
mutations in noncoding DNA of yeast are deleterious and 12% in coding
DNA are deleterious. The rest of the mutations are either neutral or
slightly beneficial.
If a mutation is present in a germ cell,
it can give rise to offspring that carries the mutation in all of its
cells. This is the case in hereditary diseases. In particular, if there
is a mutation in a DNA repair gene within a germ cell, humans carrying
such germline mutations may have an increased risk of cancer. A list of
34 such germline mutations is given in the article DNA repair-deficiency disorder. An example of one is albinism, a mutation that occurs in the OCA1 or OCA2 gene. Individuals with this disorder are more prone to many types of cancers, other disorders and have impaired vision.
DNA damage can cause an error when the DNA is replicated, and
this error of replication can cause a gene mutation that, in turn, could
cause a genetic disorder. DNA damages are repaired by the DNA repair
system of the cell. Each cell has a number of pathways through which
enzymes recognize and repair damages in DNA. Because DNA can be damaged
in many ways, the process of DNA repair is an important way in which the
body protects itself from disease. Once DNA damage has given rise to a
mutation, the mutation cannot be repaired.
On the other hand, a mutation may occur in a somatic cell of an
organism. Such mutations will be present in all descendants of this cell
within the same organism. The accumulation of certain mutations over
generations of somatic cells is part of cause of malignant transformation, from normal cell to cancer cell.
Cells with heterozygous loss-of-function mutations (one good copy
of gene and one mutated copy) may function normally with the unmutated
copy until the good copy has been spontaneously somatically mutated.
This kind of mutation happens often in living organisms, but it is
difficult to measure the rate. Measuring this rate is important in
predicting the rate at which people may develop cancer.
Point mutations may arise from spontaneous mutations that occur
during DNA replication. The rate of mutation may be increased by
mutagens. Mutagens can be physical, such as radiation from UV rays, X-rays
or extreme heat, or chemical (molecules that misplace base pairs or
disrupt the helical shape of DNA). Mutagens associated with cancers are
often studied to learn about cancer and its prevention.
Beneficial and conditional mutations
Although
mutations that cause changes in protein sequences can be harmful to an
organism, on occasions the effect may be positive in a given
environment. In this case, the mutation may enable the mutant organism
to withstand particular environmental stresses better than wild-type
organisms, or reproduce more quickly. In these cases a mutation will
tend to become more common in a population through natural selection.
That said, the same mutation can be beneficial in one condition and
disadvantageous in another condition. Examples include the following:
HIV resistance: a specific 32 base pair deletion in human CCR5 (CCR5-Δ32) confers HIV resistance to homozygotes and delays AIDS onset in heterozygotes. One possible explanation of the etiology of the relatively high frequency of CCR5-Δ32 in the European population is that it conferred resistance to the bubonic plague in mid-14th century Europe. People with this mutation were more likely to survive infection; thus its frequency in the population increased. This theory could explain why this mutation is not found in Southern Africa, which remained untouched by bubonic plague. A newer theory suggests that the selective pressure on the CCR5 Delta 32 mutation was caused by smallpox instead of the bubonic plague.
Malaria resistance: An example of a harmful mutation is sickle-cell disease, a blood disorder in which the body produces an abnormal type of the oxygen-carrying substance haemoglobin in the red blood cells. One-third of all indigenous inhabitants of Sub-Saharan Africa carry the allele, because, in areas where malaria is common, there is a survival value in carrying only a single sickle-cell allele (sickle cell trait).
Those with only one of the two alleles of the sickle-cell disease are
more resistant to malaria, since the infestation of the malaria Plasmodium is halted by the sickling of the cells that it infests.
Antibiotic resistance: Practically all bacteria develop
antibiotic resistance when exposed to antibiotics. In fact, bacterial
populations already have such mutations that get selected under
antibiotic selection. Obviously, such mutations are only beneficial for the bacteria but not for those infected.
Lactase persistence. A mutation allowed humans to express the enzyme lactase after they are naturally weaned from breast milk, allowing adults to digest lactose, which is likely one of the most beneficial mutations in recent human evolution.
Role in evolution
By
introducing novel genetic qualities to a population of organisms, de
novo mutations play a critical role in the combined forces of
evolutionary change. However, the weight of genetic diversity generated
by mutational change is often considered a generally "weak" evolutionary
force.
Although the random emergence of mutations alone provides the basis for
genetic variation across all organic life, this force must be taken in
consideration alongside all evolutionary forces at play. Spontaneous de
novo mutations as cataclysmic events of speciation depend on factors
introduced by natural selection, genetic flow, and genetic drift.
For example, smaller populations with heavy mutational input (high
rates of mutation) are prone to increases of genetic variation which
lead to speciation in future generations. In contrast, larger
populations tend to see lesser effects of newly introduced mutated
traits. In these conditions, selective forces diminish the frequency of
mutated alleles, which are most often deleterious, over time.
Compensated pathogenic deviations
Compensated
pathogenic deviations refer to amino acid residues in a protein
sequence that are pathogenic in one species but are wild type residues
in the functionally equivalent protein in another species. Although the
amino acid residue is pathogenic in the first species, it is not so in
the second species because its pathogenicity is compensated by one or
more amino acid substitutions in the second species. The compensatory
mutation can occur in the same protein or in another protein with which
it interacts.
It is critical to understand the effects of compensatory
mutations in the context of fixed deleterious mutations due to the
population fitness decreasing because of fixation. Effective population size refers to a population that is reproducing. An increase in this population size has been correlated with a decreased rate of genetic diversity.
The position of a population relative to the critical effect population
size is essential to determine the effect deleterious alleles will have
on fitness.
If the population is below the critical effective size fitness will
decrease drastically, however if the population is above the critical
effect size, fitness can increase regardless of deleterious mutations
due to compensatory alleles.
Compensatory mutations in RNA
As the function of a RNA molecule is dependent on its structure,
the structure of RNA molecules is evolutionarily conserved. Therefore,
any mutation that alters the stable structure of RNA molecules must be
compensated by other compensatory mutations. In the context of RNA, the
sequence of the RNA can be considered as ' genotype' and the structure
of the RNA can be considered as its 'phenotype'. Since RNAs have
relatively simpler composition than proteins, the structure of RNA
molecules can be computationally predicted with high degree of accuracy.
Because of this convenience, compensatory mutations have been studied
in computational simulations using RNA folding algorithms.
Evolutionary mechanism of compensation
Compensatory
mutations can be explained by the genetic phenomenon epistasis whereby
the phenotypic effect of one mutation is dependent upon mutation(s) at
other loci. While epistasis was originally conceived in the context of
interaction between different genes, intragenic epistasis has also been
studied recently.
Existence of compensated pathogenic deviations can be explained by
'sign epistasis', in which the effects of a deleterious mutation can be
compensated by the presence of an epistatic mutation in another loci.
For a given protein, a deleterious mutation (D) and a compensatory
mutation (C) can be considered, where C can be in the same protein as D
or in a different interacting protein depending on the context. The
fitness effect of C itself could be neutral or somewhat deleterious such
that it can still exist in the population, and the effect of D is
deleterious to the extent that it cannot exist in the population.
However, when C and D co-occur together, the combined fitness effect
becomes neutral or positive.
Thus, compensatory mutations can bring novelty to proteins by forging
new pathways of protein evolution : it allows individuals to travel from
one fitness peak to another through the valleys of lower fitness.
DePristo et al. 2005 outlined two models to explain the dynamics of compensatory pathogenic deviations (CPD). In the first hypothesis P is a pathogenic amino acid mutation that and C is a neutral compensatory mutation.
Under these conditions, if the pathogenic mutation arises after a
compensatory mutation, then P can become fixed in the population.
The second model of CPDs states that P and C are both deleterious
mutations resulting in fitness valleys when mutations occur
simultaneously.
Using publicly available, Ferrer-Costa et al. 2007 obtained
compensatory mutations and human pathogenic mutation datasets that were
characterized to determine what causes CPDs.[130]
Results indicate that the structural constraints and the location in
protein structure determine whether compensated mutations will occur.
Experimental evidence of compensatory mutations
Experiment in bacteria
Lunzer et al.
tested the outcome of swapping divergent amino acids between two
orthologous proteins of isopropymalate dehydrogenase (IMDH). They
substituted 168 amino acids in Escherichia coli IMDH that are wild type residues in IMDH Pseudomonas aeruginosa. They found that over one third of these substitutions compromised IMDH enzymatic activity in the Escherichia coli
genetic background. This demonstrated that identical amino acid states
can result in different phenotypic states depending on the genetic
background. Corrigan et al. 2011 demonstrated how Staphylococcus aureus was able to grow normally without the presence of lipoteichoic acid due to compensatory mutations.
Whole genome sequencing results revealed that when Cyclic-di-AMP
phosphodiesterase (GdpP) was disrupted in this bacterium, it compensated
for the disappearance of the cell wall polymer, resulting in normal
cell growth.
Research has shown that bacteria can gain drug resistance through
compensatory mutations that do not impede or having little effect on
fitness. Previous research from Gagneux et al. 2006 has found that laboratory grown Mycobacterium tuberculosis
strains with rifampicin resistance have reduced fitness, however drug
resistant clinical strains of this pathogenic bacteria do not have
reduced fitness.
Comas et al. 2012 used whole genome comparisons between clinical
strains and lab derived mutants to determine the role and contribution
of compensatory mutations in drug resistance to rifampicin. Genome analysis reveal rifampicin resistant strains have a mutation in rpoA and rpoC. A similar study investigated the bacterial fitness associated with compensatory mutations in rifampin resistant Escherichia coli.
Results obtained from this study demonstrate that drug resistance is
linked to bacterial fitness as higher fitness costs are linked to
greater transcription errors.
Experiment in virus
Gong et al.
collected obtained genotype data of influenza nucleoprotein from
different timelines and temporally ordered them according to their time
of origin. Then they isolated 39 amino acid substitutions that occurred
in different timelines and substituted them in a genetic background that
approximated the ancestral genotype. They found that 3 of the 39
substitutions significantly reduced the fitness of the ancestral
background. Compensatory mutations are new mutations that arise and have
a positive or neutral impact on a populations fitness. Previous research has shown that populations have can compensate detrimental mutations. Burch and Chao tested Fisher's geometric model of adaptive evolution by testing whether bacteriophage φ6 evolves by small steps. Their results showed that bacteriophage φ6 fitness declined rapidly and recovered in small steps . Viral nucleoproteins have been shown to avoid cytotoxic T lymphocytes (CTLs) through arginine-to glycine substitutions.
This substitution mutations impacts the fitness of viral
nucleoproteins, however compensatory co-mutations impede fitness
declines and aid the virus to avoid recognition from CTLs.
Mutations can have three different effects; mutations can have
deleterious effects, some increase fitness through compensatory
mutations, and lastly mutations can be counterbalancing resulting in
compensatory neutral mutations.
Application in human evolution and disease
In
the human genome, the frequency and characteristics of de novo
mutations have been studied as important contextual factors to our
evolution. Compared to the human reference genome, a typical human
genome varies at approximately 4.1 to 5.0 million loci, and the majority
of this genetic diversity is shared by nearly 0.5% of the population.
The typical human genome also contains 40,000 to 200,000 rare variants
observed in less than 0.5% of the population that can only have occurred
from at least one de novo germline mutation in the history of human
evolution.
De novo mutations have also been researched as playing a crucial role
in the persistence of genetic disease in humans. With recents
advancements in next-generation sequencing
(NGS), all types of de novo mutations within the genome can be directly
studied, the detection of which provides a magnitude of insight toward
the causes of both rare and common genetic disorders. Currently, the
best estimate of the average human germline SNV mutation rate is 1.18 x
10^-8, with an approximate ~78 novel mutations per generation. The
ability to conduct whole genome sequencing of parents and offspring
allows for the comparison of mutation rates between generations,
narrowing down the origin possibilities of certain genetic disorders.
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