HOME

TheInfoList




A point mutation or substitution is a genetic
mutation In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mechan ...
where a single nucleotide base is changed, inserted or deleted from a
DNA Deoxyribonucleic acid (; DNA) is a molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon rings. A molecule is an electrically neutral gro ...

DNA
or
RNA Ribonucleic acid (RNA) is a polymer A polymer (; Greek ''wikt:poly-, poly-'', "many" + ''wikt:-mer, -mer'', "part") is a Chemical substance, substance or material consisting of very large molecules, or macromolecules, composed of many Re ...

RNA
sequence of an organism's genome. Point mutations have a variety of effects on the downstream protein product—consequences that are moderately predictable based upon the specifics of the mutation. These consequences can range from no effect (e.g. synonymous mutations) to deleterious effects (e.g.
frameshift mutations A frameshift mutation (also called a framing error or a reading frame shift) is a genetic mutation caused by indels (gene insertion, insertions or genetic deletion, deletions) of a number of nucleotides in a DNA sequence that is not divisible by t ...

frameshift mutations
), with regard to protein production, composition, and function.


Causes

Point mutations usually take place during
DNA replication In molecular biology Molecular biology is the branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, mo ...

DNA replication
. DNA replication occurs when one double-stranded DNA molecule creates two single strands of DNA, each of which is a template for the creation of the complementary strand. A single point mutation can change the whole DNA sequence. Changing one
purine Purine is a heterocyclic 125px, Pyridine, a heterocyclic compound A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different chemical element, elements as members of its ring(s). Heterocyclic chemi ...

purine
or
pyrimidine Pyrimidine is an aromatic In chemistry Chemistry is the scientific Science () is a systematic enterprise that builds and organizes knowledge Knowledge is a familiarity or awareness, of someone or something, such as facts ...

pyrimidine
may change the amino acid that the
nucleotide Nucleotides are organic molecules , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen chemical bond, bonds. Due to carbon's ability to Catenation, ...

nucleotide
s code for. Point mutations may arise from spontaneous
mutation In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mechan ...
s that occur during
DNA replication In molecular biology Molecular biology is the branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, mo ...

DNA replication
. The rate of mutation may be increased by
mutagen In genetics, a mutagen is a physical or chemical agent that permanently changes genetic material, usually DNA Deoxyribonucleic acid (; DNA) is a molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy image of penta ...
s. Mutagens can be physical, such as radiation from
UV rays Ultraviolet (UV) is a form of electromagnetic radiation with wavelength from 10 nanometer, nm (with a corresponding frequency around 30 PHz) to 400 nm (750 THz), shorter than that of visible light, but longer than X-rays. UV radiation is p ...
,
X-ray An X-ray, or, much less commonly, X-radiation, is a penetrating form of high-energy electromagnetic radiation In physics Physics is the natural science that studies matter, its Elementary particle, fundamental constituents, its Moti ...

X-ray
s 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. There are multiple ways for point mutations to occur. First, ultraviolet (UV) light and higher-frequency light are capable of ionizing electrons, which in turn can affect DNA. Reactive oxygen molecules with free radicals, which are a byproduct of cellular metabolism, can also be very harmful to DNA. These reactants can lead to both single-stranded DNA breaks and double-stranded DNA breaks. Third, bonds in DNA eventually degrade, which creates another problem to keep the integrity of DNA to a high standard. There can also be replication errors that lead to substitution, insertion, or deletion mutations.


Categorization


Transition/transversion categorization

In 1959
Ernst Freese Dr. Ernst Freese (September 27, 1925 - March 30, 1990) was a molecular biologist who worked on the mechanism of mutations Image:Darwin Hybrid Tulip Mutation 2014-05-01.jpg, A tulip flower exhibiting a partially yellow petal due to a mutation in ...

Ernst Freese
coined the terms "transitions" or "transversions" to categorize different types of point mutations. Transitions are replacement of a
purine Purine is a heterocyclic 125px, Pyridine, a heterocyclic compound A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different chemical element, elements as members of its ring(s). Heterocyclic chemi ...

purine
base with another
purine Purine is a heterocyclic 125px, Pyridine, a heterocyclic compound A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different chemical element, elements as members of its ring(s). Heterocyclic chemi ...

purine
or replacement of a
pyrimidine Pyrimidine is an aromatic In chemistry Chemistry is the scientific Science () is a systematic enterprise that builds and organizes knowledge Knowledge is a familiarity or awareness, of someone or something, such as facts ...

pyrimidine
with another pyrimidine. Transversions are replacement of a purine with a pyrimidine or vice versa. There is a systematic difference in mutation rates for transitions (Alpha) and
transversion 300px, Illustration of a transversion: each of the 8 nucleotide changes between a purine and a pyrimidine (in red). The 4 other changes are transitions (in blue). Transversion, in molecular biology, refers to a point mutation 350px, Schematic ...
s (Beta). Transition mutations are about ten times more common than transversions.


Functional categorization

Nonsense mutations Nonsense is a Linguistics, communication, via speech, writing, or any other symbolic system, that lacks any coherent meaning. Sometimes in ordinary usage, nonsense is synonymous with absurdity or the ridiculous. Many poets, novelists and songwrit ...
include stop-gain and start-loss. Stop-gain is a mutation that results in a premature
termination codon In molecular biology (specifically protein biosynthesis Protein biosynthesis (or protein synthesis) is a core biological process, occurring inside cells, balancing the loss of cellular protein Proteins are large biomolecules or macromolec ...
(''a stop was gained''), which signals the end of translation. This interruption causes the protein to be abnormally shortened. The number of amino acids lost mediates the impact on the protein's functionality and whether it will function whatsoever. Stop-loss is a mutation in the original termination codon (''a stop was lost''), resulting in abnormal extension of a protein's carboxyl terminus. Start-gain creates an AUG start codon upstream of the original start site. If the new AUG is near the original start site, in-frame within the processed transcript and downstream to a ribosomal binding site, it can be used to initiate translation. The likely effect is additional amino acids added to the amino terminus of the original protein. Frame-shift mutations are also possible in start-gain mutations, but typically do not affect translation of the original protein. Start-loss is a point mutation in a transcript's AUG start codon, resulting in the reduction or elimination of protein production.
Missense mutations In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Substitution of protein from DNA mutations Missense mut ...
code for a different amino acid. A missense mutation changes a codon so that a different protein is created, a non-synonymous change. Conservative mutations result in an amino acid change. However, the properties of the amino acid remain the same (e.g., hydrophobic, hydrophilic, etc.). At times, a change to one amino acid in the protein is not detrimental to the organism as a whole. Most proteins can withstand one or two point mutations before their function changes. Non-conservative mutations result in an amino acid change that has different properties than the
wild type Unlike culinary bananas, wild-type bananas have numerous large, hard seeds. The wild type (WT) is the phenotype right , Here the relation between genotype and phenotype is illustrated, using a Punnett square, for the character of petal col ...
. The protein may lose its function, which can result in a disease in the organism. For example,
sickle-cell disease Sickle cell disease (SCD) is a group of blood disorder Hematologic diseases are disorders which primarily affect the blood & blood-forming organs. Hematologic diseases include rare genetic disorders, anemia, HIV, sickle cell disease & complica ...
is caused by a single point mutation (a missense mutation) in the beta-
hemoglobin Hemoglobin or haemoglobin (spelling differences Despite the various English dialects Dialect The term dialect (from Latin , , from the Ancient Greek word , , "discourse", from , , "through" and , , "I speak") is used in two distinct wa ...

hemoglobin
gene In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mecha ...

gene
that converts a GAG
codon The genetic code is the set of rules used by living cells Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Closed spaces * Monastic cell, a small room, hut, or cave in which a monk or reli ...

codon
into GUG, which encodes the
amino acid Amino acids are organic compound In , organic compounds are generally any s that contain - . Due to carbon's ability to (form chains with other carbon s), millions of organic compounds are known. The study of the properties, reactions, a ...

amino acid
valine Valine (symbol Val or V) is an α-amino acid Amino acids are organic compound , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen chemical bond, bo ...

valine
rather than
glutamic acid Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid Amino acids are organic compound , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compound ...
. The protein may also exhibit a "gain of function" or become activated, such is the case with the mutation changing a valine to glutamic acid in the BRAF gene; this leads to an activation of the RAF protein which causes unlimited proliferative signalling in cancer cells. These are both examples of a non-conservative (missense) mutation.
Silent mutation Silent mutations are mutation Image:Darwin Hybrid Tulip Mutation 2014-05-01.jpg, A tulip flower exhibiting a partially yellow petal due to a mutation in its genes In biology, a mutation is an alteration in the base sequence, nucleotide sequence ...
s code for the same amino acid (a "
synonymous substitution A synonymous substitution (often called a ''silent'' substitution though they are not always silent) is the evolutionary Evolution is change in the Heredity, heritable Phenotypic trait, characteristics of biological populations over successi ...
"). A silent mutation does not affect the functioning of the
protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowdery Kendrew in 1958, for which they received a No ...

protein
. A single nucleotide can change, but the new codon specifies the same amino acid, resulting in an unmutated protein. This type of change is called synonymous change since the old and new codon code for the same amino acid. This is possible because 64 codons specify only 20 amino acids. Different codons can lead to differential protein expression levels, however.


Single base pair insertions and deletions

Sometimes the term ''point mutation'' is used to describe insertions or deletions of a single base pair (which has more of an adverse effect on the synthesized protein due to the nucleotides' still being read in triplets, but in different frames: a mutation called a
frameshift mutation A frameshift mutation (also called a framing error or a reading frame shift) is a genetic mutation Image:Darwin Hybrid Tulip Mutation 2014-05-01.jpg, A tulip flower exhibiting a partially yellow petal due to a mutation in its genes In biology ...

frameshift mutation
).


General consequences

Point mutations that occur in non-coding sequences are most often without consequences, although there are exceptions. If the mutated base pair is in the promoter sequence of a gene, then the expression of the gene may change. Also, if the mutation occurs in the splicing site of an
intron An intron (for ''intragenic region'') is any Nucleic acid sequence, nucleotide sequence within a gene that is removed by RNA splicing during Post-transcriptional modification, maturation of the final RNA product. In other words, introns are non-c ...

intron
, then this may interfere with correct splicing of the transcribed
pre-mRNA A primary transcript is the single-stranded ribonucleic acid (RNA Ribonucleic acid (RNA) is a polymer A polymer (; Greek ''wikt:poly-, poly-'', "many" + ''wikt:-mer, -mer'', "part") is a Chemical substance, substance or material cons ...

pre-mRNA
. By altering just one amino acid, the entire
peptide Peptides (from Greek language Greek ( el, label=Modern Greek Modern Greek (, , or , ''Kiní Neoellinikí Glóssa''), generally referred to by speakers simply as Greek (, ), refers collectively to the dialects of the Greek language spoken ...
may change, thereby changing the entire protein. The new protein is called a protein variant. If the original protein functions in cellular reproduction then this single point mutation can change the entire process of cellular reproduction for this organism. Point
germline mutation A germline mutation, or germinal mutation, is any detectable variation within germ cell A germ cell is any biological cell The cell (from Latin ''cella'', meaning "small room") is the basic structural, functional, and biological unit of al ...
s can lead to beneficial as well as harmful traits or diseases. This leads to
adaptation In , adaptation has three related meanings. Firstly, it is the dynamic evolutionary process that fits s to their environment, enhancing their . Secondly, it is a state reached by the population during that process. Thirdly, it is a or adapti ...

adaptation
s based on the environment where the organism lives. An advantageous mutation can create an advantage for that organism and lead to the trait's being passed down from generation to generation, improving and benefiting the entire population. The scientific theory of
evolution Evolution is change in the heritable Heredity, also called inheritance or biological inheritance, is the passing on of Phenotypic trait, traits from parents to their offspring; either through asexual reproduction or sexual reproduction, ...

evolution
is greatly dependent on point mutations in
cells Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Closed spaces * Monastic cell, a small room, hut, or cave in which a monk or religious recluse lives * Prison cell, a room used to hold peopl ...
. The theory explains the diversity and history of living organisms on Earth. In relation to point mutations, it states that beneficial mutations allow the organism to thrive and reproduce, thereby passing its positively affected mutated genes on to the next generation. On the other hand, harmful mutations cause the organism to die or be less likely to reproduce in a phenomenon known as
natural selection Natural selection is the differential survival and reproduction of individuals due to differences in phenotype right , Here the relation between genotype and phenotype is illustrated, using a Punnett square, for the character of peta ...
. There are different short-term and long-term effects that can arise from mutations. Smaller ones would be a halting of the cell cycle at numerous points. This means that a codon coding for the amino acid
glycine Glycine (symbol Gly or G; ) is an amino acid Amino acids are organic compound , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen chemical bond ...

glycine
may be changed to a stop codon, causing the proteins that should have been produced to be deformed and unable to complete their intended tasks. Because the mutations can affect the DNA and thus the
chromatin Chromatin is a complex of DNA Deoxyribonucleic acid (; DNA) is a molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon rings. A molecu ...
, it can prohibit mitosis from occurring due to the lack of a complete chromosome. Problems can also arise during the processes of transcription and replication of DNA. These all prohibit the cell from reproduction and thus lead to the death of the cell. Long-term effects can be a permanent changing of a chromosome, which can lead to a mutation. These mutations can be either beneficial or detrimental.
Cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumor A benign tumor is a mass of cells Cell most often refers to: * Cell (biolo ...

Cancer
is an example of how they can be detrimental. Other effects of point mutations, or single nucleotide polymorphisms in DNA, depend on the location of the mutation within the gene. For example, if the mutation occurs in the region of the gene responsible for coding, the amino acid sequence of the encoded protein may be altered, causing a change in the function, protein localization, stability of the protein or protein complex. Many methods have been proposed to predict the effects of missense mutations on proteins. Machine learning algorithms train their models to distinguish known disease-associated from neutral mutations whereas other methods do not explicitly train their models but almost all methods exploit the evolutionary conservation assuming that changes at conserved positions tend to be more deleterious. While majority of methods provide a binary classification of effects of mutations into damaging and benign, a new level of annotation is needed to offer an explanation of why and how these mutations damage proteins. Moreover, if the mutation occurs in the region of the gene where transcriptional machinery binds to the protein, the mutation can affect the binding of the transcription factors because the short nucleotide sequences recognized by the transcription factors will be altered. Mutations in this region can affect rate of efficiency of gene transcription, which in turn can alter levels of mRNA and, thus, protein levels in general. Point mutations can have several effects on the behavior and reproduction of a protein depending on where the mutation occurs in the amino acid sequence of the protein. If the mutation occurs in the region of the gene that is responsible for coding for the protein, the amino acid may be altered. This slight change in the sequence of amino acids can cause a change in the function, activation of the protein meaning how it binds with a given enzyme, where the protein will be located within the cell, or the amount of free energy stored within the protein. If the mutation occurs in the region of the gene where transcriptional machinery binds to the protein, the mutation can affect the way in which transcription factors bind to the protein. The mechanisms of transcription bind to a protein through recognition of short nucleotide sequences. A mutation in this region may alter these sequences and, thus, change the way the transcription factors bind to the protein. Mutations in this region can affect the efficiency of gene transcription, which controls both the levels of mRNA and overall protein levels.


Specific diseases caused by point mutations


Cancer

Point mutations in multiple tumor suppressor proteins cause
cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumor A benign tumor is a mass of cells Cell most often refers to: * Cell (biolo ...

cancer
. For instance, point mutations in Adenomatous Polyposis Coli promote tumorigenesis. A novel assay,
Fast parallel proteolysis (FASTpp) Fast parallel proteolysis (FASTpp) is a method to determine the thermostability Thermostability is the quality of a substance to resist irreversible change in its chemical A chemical substance is a form of matter having constant chemical composi ...
, might help swift screening of specific stability defects in individual cancer patients.


Neurofibromatosis

Neurofibromatosis Neurofibromatosis (NF) is a group of three conditions in which tumors grow in the nervous system In Biology, biology, the nervous system is a Complex system, highly complex part of an animal that coordinates its Behavior, actions and Sense, ...

Neurofibromatosis
is caused by point mutations in the
Neurofibromin 1 Neurofibromin 1 (''NF1'') is a gene in humans that is located on chromosome 17. ''NF1'' codes for neurofibromin, a GTPase-activating protein that negatively regulates RAS/MAPK pathway activity by accelerating the hydrolysis Hydrolysis (; ) is ...
or Neurofibromin 2 gene.


Sickle-cell anemia

Sickle-cell anemia Sickle cell disease (SCD) is a group of blood disorders typically inherited from a person's parents. The most common type is known as sickle cell anaemia (SCA). It results in an abnormality in the oxygen-carrying protein haemoglobin found in r ...
is caused by a point mutation in the β-globin chain of hemoglobin, causing the hydrophilic amino acid glutamic acid to be replaced with the hydrophobic amino acid valine at the sixth position. The β-globin gene is found on the short arm of chromosome 11. The association of two wild-type α-globin subunits with two mutant β-globin subunits forms hemoglobin S (HbS). Under low-oxygen conditions (being at high altitude, for example), the absence of a polar amino acid at position six of the β-globin chain promotes the non-covalent polymerisation (aggregation) of hemoglobin, which distorts red blood cells into a sickle shape and decreases their elasticity.
Hemoglobin Hemoglobin or haemoglobin (spelling differences Despite the various English dialects Dialect The term dialect (from Latin , , from the Ancient Greek word , , "discourse", from , , "through" and , , "I speak") is used in two distinct wa ...

Hemoglobin
is a protein found in red blood cells, and is responsible for the transportation of oxygen through the body. There are two subunits that make up the hemoglobin protein: beta-globins and alpha-globins. Beta-hemoglobin is created from the genetic information on the HBB, or "hemoglobin, beta" gene found on chromosome 11p15.5. A single point mutation in this polypeptide chain, which is 147 amino acids long, results in the disease known as Sickle Cell Anemia. Sickle-cell anemia is an autosomal recessive disorder that affects 1 in 500 African Americans, and is one of the most common blood disorders in the United States. The single replacement of the sixth amino acid in the beta-globin, glutamic acid, with valine results in deformed red blood cells. These sickle-shaped cells cannot carry nearly as much oxygen as normal red blood cells and they get caught more easily in the capillaries, cutting off blood supply to vital organs. The single nucleotide change in the beta-globin means that even the smallest of exertions on the part of the carrier results in severe pain and even heart attack. Below is a chart depicting the first thirteen amino acids in the normal and abnormal
sickle cell Sickle cell disease (SCD) is a group of blood disorders typically inherited from a person's parents. The most common type is known as sickle cell anaemia (SCA). It results in an abnormality in the oxygen-carrying protein haemoglobin found in r ...

sickle cell
polypeptide chain.


Tay–Sachs disease

The cause of
Tay–Sachs disease Tay–Sachs disease is a genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene In biology, a gene (from ''genos'' "...Wilhelm Johannse ...
is a genetic defect that is passed from parent to child. This genetic defect is located in the HEXA gene, which is found on chromosome 15. The HEXA gene makes part of an enzyme called beta-hexosaminidase A, which plays a critical role in the nervous system. This enzyme helps break down a fatty substance called GM2 ganglioside in nerve cells. Mutations in the HEXA gene disrupt the activity of beta-hexosaminidase A, preventing the breakdown of the fatty substances. As a result, the fatty substances accumulate to deadly levels in the brain and spinal cord. The buildup of GM2 ganglioside causes progressive damage to the nerve cells. This is the cause of the signs and symptoms of Tay-Sachs disease.


Color blindness

People who are
colorblind Color blindness (color vision deficiency) is the decreased ability to see color or differences in color Color ( American English), or colour ( Commonwealth English), is the characteristic of visual perception described through color ...

colorblind
have mutations in their genes that cause a loss of either red or green cones, and they therefore have a hard time distinguishing between colors. There are three kinds of cones in the human eye: red, green, and blue. Now researchers have discovered that some people with the gene mutation that causes colorblindness lose an entire set of "color" cones with no change to the clearness of their vision overall.


Repeat-induced point mutation

In
molecular biology Molecular biology is the branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, P ...
, repeat-induced point mutation or RIP is a process by which
DNA Deoxyribonucleic acid (; DNA) is a molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon rings. A molecule is an electrically neutral gro ...

DNA
accumulates : to : transition mutations. Genomic evidence indicates that RIP occurs or has occurred in a variety of fungi while experimental evidence indicates that RIP is active in ''
Neurospora crassa ''Neurospora crassa'' is a type of red bread mold of the phylum Ascomycota Ascomycota is a phylum of the kingdom Fungi that, together with the Basidiomycota, forms the subkingdom Dikarya. Its members are commonly known as the sac fungi or ascomy ...
'', ''
Podospora anserina ''Podospora anserina'' is a model filamentous Ascomycota, ascomycete fungus. It is pseudohomothallic and non-pathogenic to humans. This species is coprophilous, colonising the dung of herbivorous animals. Taxonomy ''Podospora anserina'' was or ...

Podospora anserina
'', ''
Magnaporthe grisea ''Magnaporthe grisea'', also known as rice blast fungus, rice rotten neck, rice seedling blight, blast of rice, oval leaf spot of graminea, pitting disease, ryegrass blast, Johnson spot, and neck blast is a plant-pathogenic fungus A fungus ...

Magnaporthe grisea
'', '' Leptosphaeria maculans'', ''
Gibberella zeae ''Gibberella zeae'', also known by the name of its anamorph ''Fusarium graminearum'', is a fungus, fungal plant pathogen which causes fusarium head blight, a devastating disease on wheat and barley. The pathogen is responsible for billions of doll ...
'' and '' Nectria haematococca''. In ''
Neurospora crassa ''Neurospora crassa'' is a type of red bread mold of the phylum Ascomycota Ascomycota is a phylum of the kingdom Fungi that, together with the Basidiomycota, forms the subkingdom Dikarya. Its members are commonly known as the sac fungi or ascomy ...
'', sequences mutated by RIP are often
methylated In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These t ...

methylated
''de novo''. RIP occurs during the sexual stage in haploid nuclei after fertilization but prior to
meiotic Meiosis (; , because it is a reductional division) is a special type of cell division of germ cells in Sexual reproduction, sexually-reproducing organisms used to produce the gametes, such as sperm or egg cells. It involves two rounds of divi ...

meiotic
DNA replication In molecular biology Molecular biology is the branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, mo ...

DNA replication
. In ''
Neurospora crassa ''Neurospora crassa'' is a type of red bread mold of the phylum Ascomycota Ascomycota is a phylum of the kingdom Fungi that, together with the Basidiomycota, forms the subkingdom Dikarya. Its members are commonly known as the sac fungi or ascomy ...
'',
repeat sequences Repeated sequences (also known as repetitive elements, repeating units or repeats) are patterns of nucleic acids (DNA or RNA) that occur in multiple copies throughout the genome. Repetitive DNA was first detected because of its rapid reassociation, ...
of at least 400
base pair A base pair (bp) is a fundamental unit of double-stranded nucleic acids Nucleic acids are biopolymer Biopolymers are natural polymers produced by the cells of Organism, living organisms. Biopolymers consist of monomeric units that are Covalent_ ...
s in length are vulnerable to RIP. Repeats with as low as 80%
nucleotide Nucleotides are organic molecules , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen chemical bond, bonds. Due to carbon's ability to Catenation, ...

nucleotide
identity may also be subject to RIP. Though the exact mechanism of repeat recognition and mutagenesis are poorly understood, RIP results in repeated sequences undergoing multiple transition mutations. The RIP mutations do not seem to be limited to repeated sequences. Indeed, for example, in the phytopathogenic fungus ''L. maculans'', RIP mutations are found in single copy regions, adjacent to the repeated elements. These regions are either non-coding regions or genes encoding small secreted proteins including avirulence genes. The degree of RIP within these single copy regions was proportional to their proximity to repetitive elements. Rep and Kistler have speculated that the presence of highly repetitive regions containing transposons, may promote mutation of resident effector genes. So the presence of effector genes within such regions is suggested to promote their adaptation and diversification when exposed to strong selection pressure. As RIP mutation is traditionally observed to be restricted to repetitive regions and not single copy regions, Fudal ''et al.'' suggested that leakage of RIP mutation might occur within a relatively short distance of a RIP-affected repeat. Indeed, this has been reported in ''N. crassa'' whereby leakage of RIP was detected in single copy sequences at least 930 bp from the boundary of neighbouring duplicated sequences. To elucidate the mechanism of detection of repeated sequences leading to RIP may allow to understand how the flanking sequences may also be affected.


Mechanism

RIP causes : to : transition mutations within repeats, however, the mechanism that detects the repeated sequences is unknown. RID is the only known protein essential for RIP. It is a DNA methyltransferease-like protein, that when mutated or knocked out results in loss of RIP. Deletion of the ''rid'' homolog in ''
Aspergillus nidulans ''Aspergillus nidulans'' (also called ''Emericella nidulans'' when referring to its sexual form, or teleomorph) is one of many species of filamentous fungi A fungus (plural The plural (sometimes list of glossing abbreviations, abbreviate ...

Aspergillus nidulans
'', ''dmtA'', results in loss of fertility while deletion of the ''rid'' homolog in '' Ascobolus immersens'', ''masc1'', results in fertility defects and loss of methylation induced premeiotically (MIP).


Consequences

RIP is believed to have evolved as a defense mechanism against
transposable elements A transposable element (TE, transposon, or jumping gene) is a DNA sequence that can change its position within a genome, sometimes creating or reversing mutations and altering the cell's genetic identity and genome size. Transposition often resul ...
, which resemble
parasites Parasitism is a Symbiosis, close relationship between species, where one organism, the parasite, lives on or inside another organism, the Host (biology), host, causing it some harm, and is adaptation (biology), adapted structurally to this w ...

parasites
by invading and multiplying within the genome. RIP creates multiple
missense In genetics Genetics is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions ...
and
nonsense mutation Nonsense is a communication Communication (from Latin ''communicare'', meaning "to share") is the act of developing Semantics, meaning among Subject (philosophy), entities or Organization, groups through the use of sufficiently mutually under ...
s in the coding sequence. This hypermutation of G-C to A-T in repetitive sequences eliminates functional
gene product A gene product is the biochemical material, either RNA Ribonucleic acid (RNA) is a polymer A polymer (; Greek '' poly-'', "many" + '' -mer'', "part") is a substance or material consisting of very large molecule File:Pentacene on Ni( ...
s of the sequence (if there were any to begin with). In addition, many of the C-bearing nucleotides become
methylated In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These t ...

methylated
, thus decreasing transcription.


Use in molecular biology

Because RIP is so efficient at detecting and mutating repeats, fungal biologists often use it as a tool for
mutagenesis Mutagenesis is a process by which the genetic information of an organism is changed by the production of a mutation. It may occur spontaneously in nature, or as a result of exposure to mutagens. It can also be achieved experimentally using laborat ...

mutagenesis
. A second copy of a single-copy
gene In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mecha ...

gene
is first transformed into the
genome In the fields of molecular biology Molecular biology is the branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, M ...

genome
. The fungus must then
mate Mate may refer to: Science * Mate, one of a pair of animals involved in: ** Mate choice, intersexual selection ** Mating * Multi-antimicrobial extrusion protein, or MATE, an efflux transporter family of proteins Person or title * Mate (colloqu ...

mate
and go through its sexual cycle to activate the RIP machinery. Many different mutations within the duplicated gene are obtained from even a single fertilization event so that inactivated alleles, usually due to
nonsense mutations Nonsense is a Linguistics, communication, via speech, writing, or any other symbolic system, that lacks any coherent meaning. Sometimes in ordinary usage, nonsense is synonymous with absurdity or the ridiculous. Many poets, novelists and songwrit ...
, as well as alleles containing
missense mutations In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Substitution of protein from DNA mutations Missense mut ...
can be obtained.


History

The cellular reproduction process of
meiosis Meiosis (; , because it is a reductional division) is a special type of of in organisms used to produce the , such as or . It involves two rounds of division that ultimately result in four cells with only one copy of each (). Additionall ...

meiosis
was discovered by
Oscar Hertwig Illustration from O. Hertwig's book ''Lehrbuch der Entwicklungsgeschichte des Menschen und der Wirbeltiere'' (Textbook of developmental history of humans and vertebrates), 1906. Oscar Hertwig (21 April 1849 in Friedberg – 25 October 1922 in B ...
in 1876.
Mitosis In cell biology Cell biology (also cellular biology or cytology) is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical proce ...

Mitosis
was discovered several years later in 1882 by
Walther Flemming Walther Flemming (21 April 1843 – 4 August 1905) was a German biologist Francesco Redi, the founder of biology, is recognized to be one of the greatest biologists of all time A biologist is a professional who has specialized knowledg ...

Walther Flemming
. Hertwig studied sea urchins, and noticed that each egg contained one nucleus prior to fertilization and two nuclei after. This discovery proved that one spermatozoon could fertilize an egg, and therefore proved the process of meiosis. Hermann Fol continued Hertwig's research by testing the effects of injecting several spermatozoa into an egg, and found that the process did not work with more than one spermatozoon. Flemming began his research of cell division starting in 1868. The study of cells was an increasingly popular topic in this time period. By 1873, Schneider had already begun to describe the steps of cell division. Flemming furthered this description in 1874 and 1875 as he explained the steps in more detail. He also argued with Schneider's findings that the nucleus separated into rod-like structures by suggesting that the nucleus actually separated into threads that in turn separated. Flemming concluded that cells replicate through cell division, to be more specific mitosis.
Matthew Meselson Matthew Stanley Meselson (born May 24, 1930) is a geneticist A geneticist is a biologist who studies genetics, the science of genes, heredity, and variation of organism In biology, an organism (from Ancient Greek, Greek: ὀργανι ...
and
Franklin Stahl Franklin (Frank) William Stahl (born October 8, 1929) is an American American(s) may refer to: * American, something of, from, or related to the United States of America, commonly known as the United States The United States of America ( ...
are credited with the discovery of
DNA replication In molecular biology Molecular biology is the branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, mo ...

DNA replication
. Watson and acknowledged that the structure of DNA did indicate that there is some form of replicating process. However, there was not a lot of research done on this aspect of DNA until after Watson and Crick. People considered all possible methods of determining the replication process of DNA, but none were successful until Meselson and Stahl. Meselson and Stahl introduced a heavy isotope into some DNA and traced its distribution. Through this experiment, Meselson and Stahl were able to prove that DNA reproduces semi-conservatively.


See also

* Missense mRNA


References


External links

* {{Use dmy dates, date=December 2020 Modification of genetic information Mutation Molecular biology