![Sanger Sequencing heterozygous point mutation](https://upload.wikimedia.org/wikipedia/commons/1/18/Sanger_Sequencing_heterozygous_point_mutation.png)
A point mutation is a genetic
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
where a single nucleotide base is changed, inserted or deleted from a
DNA or
RNA
Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
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
A synonymous substitution (often called a ''silent'' substitution though they are not always silent) is the evolutionary substitution of one base for another in an exon of a gene coding for a protein, such that the produced amino acid sequence ...
) to deleterious effects (e.g.
frameshift mutations), with regard to protein production, composition, and function.
Causes
Point mutations usually take place during
DNA replication
In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all living organisms acting as the most essential part for biological inheritanc ...
. 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 compound, heterocyclic aromatic organic compound that consists of two rings (pyrimidine and imidazole) fused together. It is water-soluble. Purine also gives its name to the wider class of molecules, purines, which includ ...
or
pyrimidine
Pyrimidine (; ) is an aromatic, heterocyclic, organic compound similar to pyridine (). One of the three diazines (six-membered heterocyclics with two nitrogen atoms in the ring), it has nitrogen atoms at positions 1 and 3 in the ring. The other ...
may change the amino acid that the
nucleotide
Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules wi ...
s code for.
Point mutations may arise from spontaneous
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
s that occur during
DNA replication
In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all living organisms acting as the most essential part for biological inheritanc ...
. The rate of mutation may be increased by
mutagen
In genetics, a mutagen is a physical or chemical agent that permanently changes nucleic acid, genetic material, usually DNA, in an organism and thus increases the frequency of mutations above the natural background level. As many mutations can ca ...
s. Mutagens can be physical, such as radiation from
UV rays
Ultraviolet (UV) is a form of electromagnetic radiation with wavelength from 10 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 i ...
,
X-ray
An X-ray, or, much less commonly, X-radiation, is a penetrating form of high-energy electromagnetic radiation. Most X-rays have a wavelength ranging from 10 picometers to 10 nanometers, corresponding to frequencies in the range 30&nb ...
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
![TsTvMutation](https://upload.wikimedia.org/wikipedia/commons/b/b4/TsTvMutation.jpg)
In 1959
Ernst Freese
Dr. Ernst Freese (September 27, 1925 - March 30, 1990) was a molecular biologist who worked on the mechanism of mutations in DNA. From 1962 until his death he was Chief of the National Institute of Neurological Disorders and Stroke (NINDS) Labora ...
coined the terms "transitions" or "transversions" to categorize different types of point mutations. Transitions are replacement of a
purine
Purine is a heterocyclic compound, heterocyclic aromatic organic compound that consists of two rings (pyrimidine and imidazole) fused together. It is water-soluble. Purine also gives its name to the wider class of molecules, purines, which includ ...
base with another
purine
Purine is a heterocyclic compound, heterocyclic aromatic organic compound that consists of two rings (pyrimidine and imidazole) fused together. It is water-soluble. Purine also gives its name to the wider class of molecules, purines, which includ ...
or replacement of a
pyrimidine
Pyrimidine (; ) is an aromatic, heterocyclic, organic compound similar to pyridine (). One of the three diazines (six-membered heterocyclics with two nitrogen atoms in the ring), it has nitrogen atoms at positions 1 and 3 in the ring. The other ...
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
Transversion, in molecular biology, refers to a point mutation in DNA in which a single (two ring) purine ( A or G) is changed for a (one ring) pyrimidine ( T or C), or vice versa. A transversion can be spontaneous, or it can be caused by ioni ...
s (Beta). Transition mutations are about ten times more common than transversions.
Functional categorization
Nonsense mutations
In genetics, 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 in leading to a truncated, incomplete, and usually nonfunctional protein produc ...
include stop-gain and start-loss. Stop-gain is a mutation that results in a premature
termination codon
In molecular biology (specifically protein biosynthesis), a stop codon (or termination codon) is a codon (nucleotide triplet within messenger RNA) that signals the termination of the translation process of the current protein. Most codons in mess ...
(''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 mu ...
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
The wild type (WT) is the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard "normal" allele at a locus, in contrast to that produced by a non-standard, "m ...
. 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 disorders typically inherited from a person's parents. The most common type is known as sickle cell anaemia. It results in an abnormality in the oxygen-carrying protein haemoglobin found in red blo ...
is caused by a single point mutation (a missense mutation) in the beta-
hemoglobin
Hemoglobin (haemoglobin BrE) (from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globus'' 'ball, sphere' + ''-in'') (), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein present in red blood cells (erythrocyte ...
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
that converts a GAG
codon
The genetic code is the set of rules used by living cells to translate information encoded within genetic material ( DNA or RNA sequences of nucleotide triplets, or codons) into proteins. Translation is accomplished by the ribosome, which links ...
into GUG, which encodes the
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
valine
Valine (symbol Val or V) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH3+ form under biological conditions), an α- carboxylic acid group (which is in the deprotonat ...
rather than
glutamic acid
Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can synt ...
. 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 mutations in DNA that do not have an observable effect on the organism's phenotype. They are a specific type of neutral mutation. The phrase ''silent mutation'' is often used interchangeably with the phrase '' synonymous mutat ...
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 substitution of one base for another in an exon of a gene coding for a protein, such that the produced amino acid sequence ...
"). A silent mutation does not affect the functioning of the
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
. 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 caused by indels ( insertions or deletions) of a number of nucleotides in a DNA sequence that is not divisible by three. Due to the triplet nature ...
).
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 is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e. a region inside a gene."The notion of the cistron .e., gene. ...
, then this may interfere with correct splicing of the transcribed
pre-mRNA
A primary transcript is the single-stranded ribonucleic acid (RNA) product synthesized by transcription of DNA, and processed to yield various mature RNA products such as mRNAs, tRNAs, and rRNAs. The primary transcripts designated to be mRNAs a ...
.
By altering just one amino acid, the entire
peptide
Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides.
A ...
may change, thereby changing the entire protein. The new protein is called a
protein variant
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
. 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 cells (cells that, when fully developed, become sperm and ova). Mutations in these cells are the only mutations that can be passed on to offspring, when either a mu ...
s can lead to beneficial as well as harmful traits or diseases. This leads to
adaptation
In biology, adaptation has three related meanings. Firstly, it is the dynamic evolutionary process of natural selection that fits organisms to their environment, enhancing their evolutionary fitness. Secondly, it is a state reached by the po ...
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 characteristics of biological populations over successive generations. These characteristics are the expressions of genes, which are passed on from parent to offspring during reproduction. Variation ...
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:
Locations
* Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery w ...
. 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. It is a key mechanism of evolution, the change in the heritable traits characteristic of a population over generations. Charle ...
.
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 that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...
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 and protein found in eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important roles in r ...
, 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 tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
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 tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
. For instance, point mutations in Adenomatous Polyposis Coli promote tumorigenesis.
A novel assay,
Fast parallel proteolysis (FASTpp), 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. The three types are neurofibromatosis type I (NF1), neurofibromatosis type II
Neurofibromatosis type II (also known as MISME syndrome – multi ...
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 of Ras-bound GTP. ''N ...
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. It results in an abnormality in the oxygen-carrying protein haemoglobin found in red bl ...
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 (haemoglobin BrE) (from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globus'' 'ball, sphere' + ''-in'') (), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein present in red blood cells (erythrocyte ...
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. It results in an abnormality in the oxygen-carrying protein haemoglobin found in red blo ...
polypeptide chain.
Tay–Sachs disease
The cause of Tay–Sachs disease
Tay–Sachs disease is a genetic disorder that results in the destruction of nerve cells in the brain and spinal cord. The most common form is infantile Tay–Sachs disease, which becomes apparent around three to six months of age, with the baby ...
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.
Repeat-induced point mutation
In molecular biology
Molecular biology is the branch of biology that seeks to understand the molecular basis of biological activity in and between cells, including biomolecular synthesis, modification, mechanisms, and interactions. The study of chemical and physi ...
, repeat-induced point mutation or RIP is a process by which DNA accumulates G: C to A: T 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. The genus name, meaning "nerve spore" in Greek, refers to the characteristic striations on the spores. The first published account of this fungus was from an infestation ...
'', ''Podospora anserina
''Podospora anserina'' is a filamentous ascomycete fungus from the order Sordariales. It is considered a model organism for the study of molecular biology of senescence (aging), prions, sexual reproduction, and meiotic drive. It has an obligat ...
'', ''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, neck blast, wheat blast, and Imochi (Japanese:稲熱) is a ...
'', ''Leptosphaeria maculans
''Leptosphaeria maculans'' (anamorph ''Phoma lingam'') is a fungal pathogen of the phylum Ascomycota that is the causal agent of blackleg disease on ''Brassica'' crops. Its genome has been sequenced, and ''L. maculans'' is a well-studied model ph ...
'', '' Gibberella zeae'' and ''Nectria haematococca
''Fusarium solani'' is a species complex of at least 26 closely related filamentous fungi in the division Ascomycota, family Nectriaceae. It is the anamorph of '' Nectria haematococca''. It is a common soil fungus and colonist of plant mater ...
''. In ''Neurospora crassa
''Neurospora crassa'' is a type of red bread mold of the phylum Ascomycota. The genus name, meaning "nerve spore" in Greek, refers to the characteristic striations on the spores. The first published account of this fungus was from an infestation ...
'', 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 ...
''de novo''.
RIP occurs during the sexual stage in haploid nuclei after fertilization but prior to meiotic
Meiosis (; , since it is a reductional division) is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, such as sperm or egg cells. It involves two rounds of division that ultimately res ...
DNA replication
In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all living organisms acting as the most essential part for biological inheritanc ...
. In ''Neurospora crassa
''Neurospora crassa'' is a type of red bread mold of the phylum Ascomycota. The genus name, meaning "nerve spore" in Greek, refers to the characteristic striations on the spores. The first published account of this fungus was from an infestation ...
'', repeat sequences
Repeated sequences (also known as repetitive elements, repeating units or repeats) are short or long patterns of nucleic acids (DNA or RNA) that occur in multiple copies throughout the genome. In many organisms, a significant fraction of the genom ...
of at least 400 base pair
A base pair (bp) is a fundamental unit of double-stranded nucleic acids consisting of two nucleobases bound to each other by hydrogen bonds. They form the building blocks of the DNA double helix and contribute to the folded structure of both DNA ...
s in length are vulnerable to RIP. Repeats with as low as 80% nucleotide
Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules wi ...
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 mutation
Transition, in genetics and molecular biology, refers to a point mutation that changes a purine nucleotide to another purine ( A ↔ G), or a pyrimidine nucleotide to another pyrimidine ( C ↔ T). Approximately two out of three single nucle ...
s.
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 G: C to A: T 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 in the phylum Ascomycota. It has been an important research organism for studying eukaryo ...
'', ''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 nucleic acid sequence in DNA that can change its position within a genome, sometimes creating or reversing mutations and altering the cell's genetic identity and genome size. Transpo ...
, 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, adapted structurally to this way of lif ...
by invading and multiplying within the genome.
RIP creates multiple missense
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 mu ...
and nonsense mutation
In genetics, 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 in leading to a truncated, incomplete, and usually nonfunctional protein produc ...
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 or protein, resulting from expression of a gene. A measurement of the amount of gene product is sometimes used to infer how active a gene is. Abnormal amounts of gene product can be correlated ...
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 ...
, 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 la ...
. A second copy of a single-copy gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
is first transformed into the genome
In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ge ...
. 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
* Friendship ...
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
In genetics, 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 in leading to a truncated, incomplete, and usually nonfunctional protein produc ...
, 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 mu ...
can be obtained.
History
The cellular reproduction process of meiosis
Meiosis (; , since it is a reductional division) is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, such as sperm or egg cells. It involves two rounds of division that ultimately resu ...
was discovered by Oscar Hertwig
Oscar Hertwig (21 April 1849 in Friedberg – 25 October 1922 in Berlin) was a German embryologist and zoologist known for his research in developmental biology and evolution. Hertwig is credited as the first man to observe sexual reproduction ...
in 1876. Mitosis
In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis gives rise to genetically identical cells in which the total number of chromosomes is mainta ...
was discovered several years later in 1882 by Walther Flemming
Walther Flemming (21 April 1843 – 4 August 1905) was a German biologist and a founder of cytogenetics.
He was born in Sachsenberg (now part of Schwerin) as the fifth child and only son of the psychiatrist Carl Friedrich Flemming (1799–1880) ...
.
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 and molecular biologist currently at Harvard University, known for his demonstration, with Franklin Stahl, of semi-conservative DNA replication. After completing his Ph.D. under Linus ...
and Franklin Stahl
Franklin (Frank) William Stahl (born October 8, 1929) is an American molecular biologist and geneticist. With Matthew Meselson, Stahl conducted the famous Meselson-Stahl experiment showing that DNA is replicated by a semiconservative mechanism, ...
are credited with the discovery of DNA replication
In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all living organisms acting as the most essential part for biological inheritanc ...
. Watson and Crick
Crick may refer to:
Places
* Crick, Monmouthshire, Wales
* Crick, Northamptonshire, England
* Crick Road, Oxford, England
People with the name
* Crick (surname)
Other uses
* Crick, the cricket from ''Beat Bugs''
* Francis Crick Institute
...
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
Missense mRNA is a messenger RNA bearing one or more mutated codons that yield polypeptides with an amino acid sequence different from the wild-type or naturally occurring polypeptide. Missense mRNA molecules are created when template DNA str ...
References
External links
*
{{Use dmy dates, date=December 2020
Modification of genetic information
Mutation
Molecular biology