Frame shift mutation
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A frameshift mutation (also called a framing error or a reading frame shift) 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 replication, DNA or viral repl ...
caused by
indel Indel is a molecular biology term for an Insertion (genetics), insertion or Deletion (genetics), deletion of Nucleobase, bases in the genome of an organism. It is classified among small genetic variations, measuring from 1 to 10 000 base pairs in ...
s ( insertions or deletions) of a number of
nucleotide Nucleotides are Organic compound, 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 ...
s in a DNA sequence that is not divisible by three. Due to the triplet nature of
gene expression Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. T ...
by
codon The genetic code is the set of rules used by living cell (biology), cells to Translation (biology), translate information encoded within genetic material (DNA or RNA sequences of nucleotide triplets, or codons) into proteins. Translation is accom ...
s, the insertion or deletion can change the
reading frame In molecular biology, a reading frame is a way of dividing the nucleic acid sequence, sequence of nucleotides in a nucleic acid (DNA or RNA) molecule into a set of consecutive, non-overlapping triplets. Where these triplets equate to amino acids or ...
(the grouping of the codons), resulting in a completely different
translation Translation is the communication of the Meaning (linguistic), meaning of a #Source and target languages, source-language text by means of an Dynamic and formal equivalence, equivalent #Source and target languages, target-language text. The ...
from the original. The earlier in the sequence the deletion or insertion occurs, the more altered the protein. A frameshift mutation is not the same as a
single-nucleotide polymorphism In genetics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently larg ...
in which a nucleotide is replaced, rather than inserted or deleted. A
frameshift Ribosomal frameshifting, also known as translational frameshifting or translational recoding, is a biological phenomenon that occurs during translation Translation is the communication of the Meaning (linguistic), meaning of a #Source and ...
mutation will in general cause the reading of the codons after the mutation to code for different amino acids. The frameshift mutation will also alter the first stop codon ("UAA", "UGA" or "UAG") encountered in the sequence. The polypeptide being created could be abnormally short or abnormally long, and will most likely not be functional. Frameshift mutations are apparent in severe genetic diseases such as
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 (monogenic) or multiple genes (polygenic) or by a chromosom ...
; they increase susceptibility to certain cancers and classes of
familial hypercholesterolaemia Familial hypercholesterolemia (FH) is a genetic disorder characterized by hypercholesterolemia, high cholesterol levels, specifically very high levels of low-density lipoprotein (LDL cholesterol), in the blood and early cardiovascular disease. Th ...
; in 1997, a frameshift mutation was linked to resistance to infection by the HIV retrovirus. Frameshift mutations have been proposed as a source of biological novelty, as with the alleged creation of
nylonase ''Paenarthrobacter ureafaciens'' KI72, popularly known as nylon-eating bacteria, is a strain of '' Paenarthrobacter ureafaciens'' that can digest certain by-product A by-product or byproduct is a secondary product derived from a production pro ...
, however, this interpretation is controversial. A study by Negoro ''et al'' (2006) found that a frameshift mutation was unlikely to have been the cause and that rather a two amino acid substitution in the
active site In biology Biology is the scientific study of life. It is a natural science with a broad scope but has several unifying themes that tie it together as a single, coherent field. For instance, all organisms are made up of Cell (biology), ce ...
of an ancestral
esterase An esterase is a hydrolase Hydrolase is a class of enzyme that commonly perform as biochemical catalysts that use water to break a chemical bond, which typically results in dividing a larger molecule into smaller molecules. Some common examples ...
resulted in nylonase.


Background

The information contained in DNA determines protein function in the cells of all organisms. Transcription and translation allow this information to be communicated into making proteins. However, an error in reading this communication can cause protein function to be incorrect and eventually cause disease even as the cell incorporates a variety of corrective measures.


Central dogma

In 1956
Francis Crick Francis Harry Compton Crick (8 June 1916 – 28 July 2004) was an English molecular biology, molecular biologist, biophysics, biophysicist, and neuroscientist. He, James Watson, Rosalind Franklin, and Maurice Wilkins played crucial roles in de ...
described the flow of genetic information from DNA to a specific amino acid arrangement for making a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metabo ...
as the central dogma. For a cell to properly function, proteins are required to be produced accurately for structural and for
catalytic Catalysis () is the process of increasing the rate of a chemical reaction A chemical reaction is a process that leads to the IUPAC nomenclature for organic transformations, chemical transformation of one set of chemical substances to an ...
activities. An incorrectly made protein can have detrimental effects on
cell Cell most often refers to: * Cell (biology) The cell is the basic structural and functional unit of life forms. Every cell consists of a cytoplasm enclosed within a Cell membrane, membrane, and contains many biomolecules such as proteins, D ...
viability and in most cases cause the higher
organism In biology, an organism () is any life, living system that functions as an individual entity. All organisms are composed of cells (cell theory). Organisms are classified by taxonomy (biology), taxonomy into groups such as Multicellular o ...
to become unhealthy by abnormal cellular functions. To ensure that 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 gene ...
successfully passes the information on,
proofreading Proofreading is the Reading (activity), reading of a galley proof or an electronic copy of a publication to find and correct reproduction errors of Writing, text or Graphic arts, art. Proofreading is the final step in the editorial cycle before ...
mechanisms such as
exonuclease Exonucleases are enzymes that work by cleaving nucleotides one at a time from the end (exo) of a polynucleotide chain. A hydrolyzing reaction that breaks phosphodiester bonds at either the 3′ or the 5′ end occurs. Its close relative is ...
s and
mismatch repair DNA mismatch repair (MMR) is a system for recognizing and repairing erroneous insertion, deletion, and mis-incorporation of bases that can arise during DNA replication and recombination, as well as repairing some forms of DNA damage. Mismat ...
systems are incorporated in
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 life, living organisms acting as the most essential part for heredity, biologi ...
.


Transcription and translation

After DNA replication, the reading of a selected section of genetic information is accomplished by
transcription Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including: Genetics * Transcription (biology), the copying of DNA into RNA, the fir ...
. Nucleotides containing the genetic information are now on a single strand messenger template called
mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...
. The mRNA is incorporated with a subunit of the
ribosome Ribosomes ( ) are molecular machine, macromolecular machines, found within all cell (biology), cells, that perform Translation (biology), biological protein synthesis (mRNA translation). Ribosomes link amino acids together in the order specifie ...
and interacts with an
rRNA Ribosomal ribonucleic acid (rRNA) is a type of non-coding RNA which is the primary component of ribosomes, essential to all cells. rRNA is a ribozyme which carries out protein synthesis in ribosomes. Ribosomal RNA is transcribed from ribosomal ...
. The genetic information carried in the codons of the mRNA are now read (decoded) by anticodons of the tRNA. As each codon (triplet) is read,
amino acids 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 ami ...
are being joined together until a
stop codon In molecular biology (specifically protein biosynthesis), a stop codon (or termination codon) is a Genetic code, codon (nucleotide triplet within messenger RNA) that signals the termination of the translation (biology), translation process of the ...
(UAG, UGA or UAA) is reached. At this point the
polypeptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called Protein, proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapepti ...
(protein) has been synthesised and is released. For every 1000 amino acid incorporated into the protein, no more than one is incorrect. This fidelity of codon recognition, maintaining the importance of the proper reading frame, is accomplished by proper base pairing at the ribosome A site, GTP hydrolysis activity of
EF-Tu EF-Tu (elongation factor thermo unstable) is a prokaryotic elongation factor responsible for catalyzing the binding of an aminoacyl-tRNA (aa-tRNA) to the ribosome Ribosomes ( ) are molecular machine, macromolecular machines, found within a ...
a form of kinetic stability, and a proofreading mechanism as EF-Tu is released. Frameshifting may also occur during
prophase Prophase () is the first stage of cell division in both mitosis and meiosis. Beginning after interphase, DNA has already been replicated when the Cell (biology), cell enters prophase. The main occurrences in prophase are the condensation of the ...
translation, producing different proteins from overlapping open reading frames, such as the gag-pol-env retroviral proteins. This is fairly common in
viruses A virus is a wikt:submicroscopic, submicroscopic infectious agent that replicates only inside the living Cell (biology), cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and ...
and also occurs in
bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometre The micrometre (Amer ...
and
yeast Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom (biology), kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are est ...
(Farabaugh, 1996).
Reverse transcriptase A reverse transcriptase (RT) is an enzyme used to generate complementary DNA (cDNA) from an RNA template, a process termed reverse transcription. Reverse transcriptases are used by viruses such as HIV and hepatitis B virus, hepatitis B to replic ...
, as opposed to
RNA Polymerase II RNA polymerase II (RNAP II and Pol II) is a Protein complex, multiprotein complex that Transcription (biology), transcribes DNA into precursors of messenger RNA (mRNA) and most small nuclear RNA (snRNA) and microRNA. It is one of the three RNA pol ...
, is thought to be a stronger cause of the occurrence of frameshift mutations. In experiments only 3–13% of all frameshift mutations occurred because of RNA Polymerase II. In
prokaryotes A prokaryote () is a Unicellular organism, single-celled organism that lacks a cell nucleus, nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Greek language, Greek wikt:πρό#Ancient Greek, πρό (, 'before') a ...
the error rate inducing frameshift mutations is only somewhere in the range of .0001 and .00001. There are several biological processes that help to prevent frameshift mutations. Reverse mutations occur which change the mutated sequence back to the original
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 ...
sequence. Another possibility for mutation correction is the use of a
suppressor mutation A suppressor mutation is a second mutation that alleviates or reverts the phenotypic effects of an already existing mutation in a process defined synthetic rescue. Genetic suppression therefore restores the phenotype seen prior to the original b ...
. This offsets the effect of the original mutation by creating a secondary mutation, shifting the sequence to allow for the correct amino acids to be read.
Guide RNA A guide RNA (gRNA) is a piece of RNA that functions as a guide for RNA- or DNA-targeting Enzyme, enzymes, with which it forms Protein–ligand complex, complexes. Very often these enzymes will delete, insert or otherwise alter the targeted RNA o ...
can also be used to insert or delete Uridine into the mRNA after transcription, this allows for the correct reading frame.


Codon-triplet importance

A
codon The genetic code is the set of rules used by living cell (biology), cells to Translation (biology), translate information encoded within genetic material (DNA or RNA sequences of nucleotide triplets, or codons) into proteins. Translation is accom ...
is a set of three
nucleotides Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomer In chemistry, a monomer ( ; ''wikt:mono-, mono-'', "one" + ''wikt:-mer, -mer'', "part") is a molecule that can chemical reaction, react tog ...
, a triplet that code for a certain
amino acid Amino acids are organic compound In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon chemical bond, bonds. Due to carbon's ability to Catenation, catenate (form chains with ot ...
. The first codon establishes the reading frame, whereby a new codon begins. A protein's amino acid backbone
sequence In mathematics, a sequence is an enumerated collection of mathematical object, objects in which repetitions are allowed and order theory, order matters. Like a Set (mathematics), set, it contains Element (mathematics), members (also called ''eleme ...
is defined by contiguous triplets. Codons are key to translation of genetic information for the synthesis of proteins. The reading frame is set when translating the mRNA begins and is maintained as it reads one triplet to the next. The reading of the genetic code is subject to three rules the monitor codons in mRNA. First, codons are read in a 5' to 3' direction. Second, codons are nonoverlapping and the message has no gaps. The last rule, as stated above, that the message is translated in a fixed reading frame.


Mechanism

Frameshift mutations can occur randomly or be caused by an external stimulus. The detection of frameshift mutations can occur via several different methods. Frameshifts are just one type of mutation that can lead to incomplete or incorrect proteins, but they account for a significant percentage of errors in DNA.


Genetic or environmental

This is a genetic mutation at the level of nucleotide bases. Why and how frameshift mutations occur are continually being sought after. An environmental study, specifically the production of UV-induced frameshift mutations by DNA polymerases deficient in 3′ → 5′ exonuclease activity was done. The normal sequence 5′ GTC GTT TTA CAA 3′ was changed to GTC GTT T TTA CAA (MIDT) of GTC GTT C TTA CAA (MIDC) to study frameshifts. E. coli pol I Kf and T7 DNA polymerase mutant
enzymes Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
devoid of 3′ → 5′ exonuclease activity produce UV-induced revertants at higher frequency than did their
exonuclease Exonucleases are enzymes that work by cleaving nucleotides one at a time from the end (exo) of a polynucleotide chain. A hydrolyzing reaction that breaks phosphodiester bonds at either the 3′ or the 5′ end occurs. Its close relative is ...
proficient counterparts. The data indicates that loss of proofreading activity increases the frequency of UV-induced frameshifts.


Detection


Fluorescence

The effects of neighboring bases and secondary structure to detect the frequency of frameshift mutations has been investigated in depth using
fluorescence Fluorescence is the emission of light by a substance that has absorbed light or other electromagnetic radiation. It is a form of luminescence. In most cases, the emitted light has a longer wavelength, and therefore a lower photon energy ...
. Fluorescently tagged DNA, by means of base analogues, permits one to study the local changes of a DNA sequence. Studies on the effects of the length of the primer strand reveal that an equilibrium mixture of four hybridization conformations was observed when template bases looped-out as a bulge, i.e. a structure flanked on both sides by duplex DNA. In contrast, a double-loop structure with an unusual unstacked DNA conformation at its downstream edge was observed when the extruded bases were positioned at the primer–template junction, showing that misalignments can be modified by neighboring DNA secondary structure.


Sequencing

Sanger sequencing Sanger sequencing is a method of DNA sequencing DNA sequencing is the process of determining the nucleic acid sequence – the order of nucleotides in DNA. It includes any method or technology that is used to determine the order of the four bas ...
and
pyrosequencing Pyrosequencing is a method of DNA sequencing (determining the order of nucleotides in DNA) based on the "sequencing by synthesis" principle, in which the sequencing is performed by detecting the nucleotide incorporated by a DNA polymerase. Pyrosequ ...
are two methods that have been used to detect frameshift mutations, however, it is likely that data generated will not be of the highest quality. Even still, 1.96 million
indel Indel is a molecular biology term for an Insertion (genetics), insertion or Deletion (genetics), deletion of Nucleobase, bases in the genome of an organism. It is classified among small genetic variations, measuring from 1 to 10 000 base pairs in ...
s have been identified through Sanger sequencing that do not overlap with other databases. When a frameshift mutation is observed it is compared against the Human Genome Mutation Database (HGMD) to determine if the mutation has a damaging effect. This is done by looking at four features. First, the ratio between the affected and conserved DNA, second the location of the mutation relative to the transcript, third the ratio of conserved and affected amino acids and finally the distance of the indel to the end of the
exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...
. Massively Parallel Sequencing is a newer method that can be used to detect mutations. Using this method, up to 17 gigabases can be sequenced at once, as opposed to limited ranges for
Sanger sequencing Sanger sequencing is a method of DNA sequencing DNA sequencing is the process of determining the nucleic acid sequence – the order of nucleotides in DNA. It includes any method or technology that is used to determine the order of the four bas ...
of only about 1 kilobase. Several technologies are available to perform this test and it is being looked at to be used in clinical applications. When testing for different carcinomas, current methods only allow for looking at one gene at a time. Massively Parallel Sequencing can test for a variety of cancer causing mutations at once as opposed to several specific tests. An experiment to determine the accuracy of this newer sequencing method tested for 21 genes and had no false positive calls for frameshift mutations.


Diagnosis

A US
patent A patent is a type of intellectual property that gives its owner the legal right to exclude others from making, using, or selling an invention for a limited period of time in exchange for publishing an sufficiency of disclosure, enabling disclo ...
(5,958,684) in 1999 by Leeuwen, details the methods and reagents for diagnosis of diseases caused by or associated with a gene having a somatic mutation giving rise to a frameshift mutation. The methods include providing a tissue or fluid sample and conducting gene analysis for frameshift mutation or a protein from this type of mutation. The nucleotide sequence of the suspected gene is provided from published gene sequences or from
cloning Cloning is the process of producing individual organisms with identical or virtually identical DNA, either by natural or artificial means. In nature, some organisms produce clones through asexual reproduction. In the field of biotechnology, cl ...
and sequencing of the suspect gene. The amino acid sequence encoded by the gene is then predicted.


Frequency

Despite the rules that govern the genetic code and the various mechanisms present in a cell to ensure the correct transfer of genetic information during the process of DNA replication as well as during translation, mutations do occur; frameshift mutation is not the only type. There are at least two other types of recognized point mutations, specifically
missense mutation In genetics Genetics is the study of genes, genetic variation, and heredity in organisms.Hartl D, Jones E (2005) It is an important branch in biology because heredity is vital to organisms' evolution. Gregor Mendel, a Moravian Augustinians, A ...
and
nonsense mutation In genetics, a nonsense mutation is a point mutation in a DNA sequence, sequence of DNA that results in a premature stop codon, or a ''nonsense codon'' in the Transcription (genetics), transcribed mRNA, and in leading to a truncated, incomplete, an ...
. A frameshift mutation can drastically change the coding capacity (genetic information) of the message. Small insertions or deletions (those less than 20 base pairs) make up 24% of mutations that manifest in currently recognized genetic disease. Frameshift mutations are found to be more common in repeat regions of DNA. A reason for this is because of slipping of the polymerase enzyme in repeat regions, allowing for mutations to enter the
sequence In mathematics, a sequence is an enumerated collection of mathematical object, objects in which repetitions are allowed and order theory, order matters. Like a Set (mathematics), set, it contains Element (mathematics), members (also called ''eleme ...
.
Experiment An experiment is a procedure carried out to support or refute a hypothesis, or determine the efficacy or likelihood of something previously untried. Experiments provide insight into cause-and-effect by demonstrating what outcome occurs wh ...
s can be run to determine the frequency of the frameshift mutation by adding or removing a pre-set number of nucleotides. Experiments have been run by adding four basepairs, called the +4 experiments, but a team from
Emory University Emory University is a private university, private research university in Atlanta, Georgia (U.S. state), Georgia. Founded in 1836 as "Emory College" by the Methodist Episcopal Church and named in honor of Methodist bishop John Emory, Emory is the ...
looked at the difference in frequency of the mutation by both adding and deleting a base pair. It was shown that there was no difference in the frequency between the addition and deletion of a base pair. There is however, a difference in the end result of the protein.
Huntington's disease Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly Genetic disorder#Autosomal dominant, inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A gener ...
is one of the nine codon reiteration disorders caused by polyglutamine expansion mutations that include spino-cerebellar ataxia (SCA) 1, 2, 6, 7 and 3, spinobulbar muscular atrophy and dentatorubal-pallidoluysianatrophy. There may be a link between diseases caused by polyglutamine and polyalanine expansion mutations, as frame shifting of the original SCA3 gene product encoding CAG/polyglutamines to GCA/polyalanines. Ribosomal slippage during translation of the SCA3 protein has been proposed as the mechanism resulting in shifting from the polyglutamine to the polyalanine-encoding frame. A dinucleotide deletion or single nucleotide insertion within the polyglutamine tract of huntingtin exon 1 would shift the CAG, polyglutamineen coding frame by +1 (+1 frame shift) to the GCA, polyalanine-encoding frame and introduce a novel epitope to the C terminus of Htt exon 1 (APAAAPAATRPGCG).


Diseases

Several diseases have frameshift mutations as at least part of the cause. Knowing prevalent mutations can also aid in the diagnosis of the disease. Currently there are attempts to use frameshift mutations beneficially in the treatment of diseases, changing the reading frame of the amino acids.


Cancer

Frameshift mutations are known to be a factor in
colorectal The large intestine, also known as the large bowel, is the last part of the gastrointestinal tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the ...
cancer as well as other
cancers Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Poss ...
with
microsatellite instability Microsatellite instability (MSI) is the condition of genetic hypermutability (predisposition to mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Vi ...
. As stated previously, frameshift mutations are more likely to occur in a region of repeat sequence. When DNA mismatch repair does not fix the addition or deletion of bases, these mutations are more likely to be pathogenic. This may be in part because the tumor is not told to stop growing. Experiments in yeast and bacteria help to show characteristics of microsatellites that may contribute to defective DNA mismatch repair. These include the length of the
microsatellite A microsatellite is a tract of repetitive DNA in which certain Sequence motif, DNA motifs (ranging in length from one to six or more base pairs) are repeated, typically 5–50 times. Microsatellites occur at thousands of locations within an organ ...
, the makeup of the genetic material and how pure the repeats are. Based on experimental results longer microsatellites have a higher rate of frameshift mutations. The flanking DNA can also contribute to frameshift mutations. In prostate cancer a frameshift mutation changes the
open reading frame In molecular biology, open reading frames (ORFs) are defined as spans of DNA sequence between the start and stop codons. Usually, this is considered within a studied region of a prokaryotic DNA sequence, where only one of the six possible read ...
(ORF) and prevents
apoptosis Apoptosis (from grc, wikt:ἀπόπτωσις, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemistry, Biochemical events lead to characteristic cell changes (Morp ...
from occurring. This leads to an unregulated growth of the
tumor A neoplasm () is a type of abnormal and excessive growth of tissue (biology), tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tiss ...
. While there are environmental factors that contribute to the progression of
prostate cancer Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that surr ...
, there is also a genetic component. During testing of coding regions to identify mutations, 116 genetic variants were discovered, including 61 frameshift mutations. There are over 500 mutations on chromosome 17 that seem to play a role in the development of breast and ovarian cancer in the BRCA1 gene, many of which are frameshift.


Crohn's disease

Crohn's disease Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea (which may be bloody if inflammation is severe), fever, abdominal distension, ...
has an association with the NOD2 gene. The mutation is an insertion of a
Cytosine Cytosine () (nucleoside#List of nucleosides and corresponding nucleobases, symbol C or Cyt) is one of the four Nucleobase, nucleobases found in DNA and RNA, along with adenine, guanine, and thymine (uracil in RNA). It is a pyrimidine derivative, ...
at position 3020. This leads to a premature stop codon, shortening the protein that is supposed to be transcribed. When the protein is able to form normally, it responds to bacterial liposaccharides, where the 3020insC mutation prevents the protein from being responsive.


Cystic fibrosis

Cystic fibrosis Cystic fibrosis (CF) is a rare genetic disorder that affects mostly the lungs, but also the pancreas, liver, kidneys, and intestine. Long-term issues include Shortness of breath, difficulty breathing and coughing up sputum, mucus as a result of ...
(CF) is a disease based on mutations in the CF
transmembrane A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as membrane transport protein, gateways to permit the transport of specific substances across t ...
conductance regulator (CFTR) gene. There are over 1500 mutations identified, but not all cause the disease. Most cases of cystic fibrosis are a result of the ∆F508 mutation, which deletes the entire amino acid. Two frameshift mutations are of interest in diagnosing CF, CF1213delT and CF1154-insTC. Both of these mutations commonly occur in tandem with at least one other mutation. They both lead to a small decrease in the function of the
lungs The lungs are the primary organs of the respiratory system The respiratory system (also respiratory apparatus, ventilatory system) is a biological system consisting of specific organs and structures used for gas exchange in animals and p ...
and occur in about 1% of patients tested. These mutations were identified through Sanger sequencing.


HIV

CCR5 C-C chemokine receptor type 5, also known as CCR5 or CD195, is a protein on the surface of white blood cells that is involved in the immune system as it acts as a receptor (biology), receptor for chemokines. In humans, the ''CCR5'' gene that e ...
is one of the cell entry co-factors associated with HIV, most frequently involved with nonsyncytium-inducing strains, is most apparent in HIV patients as opposed to AIDS patients. A 32 base pair deletion in CCR5 has been identified as a mutation that negates the likelihood of an HIV infection. This region on the open reading frame ORF contains a frameshift mutation leading to a premature stop codon. This leads to the loss of the HIV-coreceptor function in vitro. CCR5-1 is considered the wild type and CCR5-2 is considered to be the mutant allele. Those with a heterozygous mutation for the CCR5 were less susceptible to the development of HIV. In a study, despite high exposure to the HIV virus, there was no one homozygous for the CCR5 mutation that tested positive for HIV.


Tay–Sachs disease

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 (monogenic) or multiple genes (polygenic) or by a chromosom ...
is a fatal disease affecting the central nervous system. It is most frequently found in infants and small children. Disease progression begins in the
womb The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the hollow organ, organ in the female reproductive system, reproductive system of most female mammals, including humans that accommodates the embryonic development, embryonic an ...
but symptoms do not appear until approximately 6 months of age. There is no cure for the disease. Mutations in the β-hexosaminidase A (Hex A) gene are known to affect the onset of Tay-Sachs, with 78 mutations of different types being described, 67 of which are known to cause disease. Most of the mutations observed (65/78) are single base substitutions or SNPs, 11 deletions, 1 large and 10 small, and 2 insertions. 8 of the observed mutations are frameshift, 6 deletions and 2 insertions. A 4 base pair insertion in exon 11 is observed in 80% of Tay-Sachs disease presence in the
Ashkenazi Ashkenazi Jews ( ; he, יְהוּדֵי אַשְׁכְּנַז, translit=Yehudei Ashkenaz, ; yi, אַשכּנזישע ייִדן, Ashkenazishe Yidn), also known as Ashkenazic Jews or ''Ashkenazim'',, Ashkenazi Hebrew pronunciation: , singu ...
Jewish population. The frameshift mutations lead to an early stop codon which is known to play a role in the disease in infants. Delayed onset disease appears to be caused by 4 different mutations, one being a 3 base pair deletion.


Smith–Magenis syndrome

Smith–Magenis syndrome (SMS) is a complex
syndrome A syndrome is a set of medical signs and symptoms which are correlated with each other and often associated with a particular disease A disease is a particular abnormal condition that negatively affects the structure or function (biolog ...
involving intellectual disabilities, sleep disturbance, behavioural problems, and a variety of craniofacial, skeletal, and visceral anomalies. The majority of SMS cases harbor an ~3.5 Mb common deletion that encompasses the retinoic acid induced-1 (RAI1) gene. Other cases illustrate variability in the SMS
phenotype In genetics, the phenotype () is the set of observable characteristics or phenotypic trait, traits of an organism. The term covers the organism's morphology (biology), morphology or physical form and structure, its Developmental biology, dev ...
not previously shown for RAI1 mutation, including hearing loss, absence of self-abusive behaviours, and mild global delays. Sequencing of RAI1 revealed mutation of a heptamericC-tract (CCCCCCC) in exon 3 resulting in frameshift mutations. Of the seven reported frameshift mutations occurring in poly C-tracts in RAI1, four cases (~57%) occur at this heptameric C-tract. The results indicate that this heptameric C-tract is a preferential
recombination hotspot Recombination hotspots are regions in a genome that exhibit elevated rates of Homologous recombination, recombination relative to a neutral expectation. The recombination rate within hotspots can be hundreds of times that of the surrounding region. ...
insertion/deletions (SNindels) and therefore a primary target for analysis in patients suspected for mutations in RAI1.


Hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy Hypertrophic cardiomyopathy (HCM, or HOCM when #Variants, obstructive) is a condition in which the heart becomes hypertrophy, thickened without an obvious cause. The parts of the heart most commonly affected are the interventricular septum and t ...
is the most common cause of sudden death in young people, including trained athletes, and is caused by mutations in genes encoding proteins of the cardiac sarcomere. Mutations in the Troponin C gene (TNNC1) are a rare genetic cause of hypertrophic cardiomyopathy. A recent study has indicated that a frameshift mutation (c.363dupG or p.Gln122AlafsX30) in Troponin C was the cause of hypertrophic cardiomyopathy (and sudden cardiac death) in a 19-year-old male.


Cures

Finding a cure for the diseases caused by frameshift mutations is rare. Research into this is ongoing. One example is a primary
immunodeficiency Immunodeficiency, also known as immunocompromisation, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that a ...
(PID), an inherited condition which can lead to an increase in infections. There are 120 genes and 150 mutations that play a role in primary immunodeficiencies. The standard treatment is currently gene therapy, but this is a highly risky treatment and can often lead to other diseases, such as leukemia. Gene therapy procedures include modifying the zinc fringer nuclease fusion protein, cleaving both ends of the mutation, which in turn removes it from the sequence. Antisense-oligonucleotide mediated exon skipping is another possibility for Duchenne
muscular dystrophy Muscular dystrophies (MD) are a genetically and clinically heterogeneous group of rare neuromuscular diseases that cause progressive weakness and breakdown of skeletal muscles over time. The disorders differ as to which muscles are primarily affe ...
. This process allows for passing over the mutation so that the rest of the sequence remains in frame and the function of the protein stays intact. This, however, does not cure the disease, just treats symptoms, and is only practical in structural proteins or other repetitive genes. A third form of repair is revertant mosaicism, which is naturally occurring by creating a reverse mutation or a mutation at a second site that corrects the reading frame. This reversion may happen by intragenic recombination,
mitotic In cell biology Cell biology (also cellular biology or cytology) is a branch of biology that studies the Anatomy, structure, Physiology, function, and behavior of cell (biology), cells. All living organisms are made of cells. A cell is t ...
gene conversion, second site DNA slipping or site-specific reversion. This is possible in several diseases, such as X-linked severe combined immunodeficiency (SCID), Wiskott–Aldrich syndrome, and Bloom syndrome. There are no drugs or other pharmacogenomic methods that help with PIDs. A European patent (EP1369126A1) in 2003 by Bork records a method used for prevention of cancers and for the curative treatment of cancers and precancers such as DNA-mismatch repair deficient (MMR) sporadic tumours and HNPCC associated tumours. The idea is to use immunotherapy with combinatorial mixtures of tumour-specific frameshift mutation-derived peptides to elicit a cytotoxic T-cell response specifically directed against tumour cells.European Paten

(December 10, 2003) "Use of coding microsatellite region frameshift mutation-derived peptides for treating cancer" by Bork ''et al''


See also

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Translational frameshift Ribosomal frameshifting, also known as translational frameshifting or translational recoding, is a biological phenomenon that occurs during translation Translation is the communication of the Meaning (linguistic), meaning of a #Source and ...
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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 replication, DNA or viral repl ...
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Transcription (genetics) Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins are said to produce messenger RNA (mRNA). Other segments of DNA are copied into RNA molecules called ...
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Translation (biology) In molecular biology and genetics, translation is the process in which ribosomes in the cytoplasm or endoplasmic reticulum synthesize proteins after the process of transcription (biology), transcription of DNA to RNA in the cell's nucleus ( ...
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codon The genetic code is the set of rules used by living cell (biology), cells to Translation (biology), translate information encoded within genetic material (DNA or RNA sequences of nucleotide triplets, or codons) into proteins. Translation is accom ...
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protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metabo ...
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reading frame In molecular biology, a reading frame is a way of dividing the nucleic acid sequence, sequence of nucleotides in a nucleic acid (DNA or RNA) molecule into a set of consecutive, non-overlapping triplets. Where these triplets equate to amino acids or ...
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point mutation A point mutation is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a DNA or RNA sequence of an organism's genome. Point mutations have a variety of effects on the downstream protein product—consequences ...
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Crohn's disease Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea (which may be bloody if inflammation is severe), fever, abdominal distension, ...
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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 (monogenic) or multiple genes (polygenic) or by a chromosom ...


References


Further reading

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External links

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NCBI dbSNP database
— "a central repository for both single base nucleotide substitutions and short deletion and insertion polymorphisms"

- aligns a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metabo ...
against a DNA sequence allowing
frameshift Ribosomal frameshifting, also known as translational frameshifting or translational recoding, is a biological phenomenon that occurs during translation Translation is the communication of the Meaning (linguistic), meaning of a #Source and ...
s and
intron An intron is any Nucleic acid sequence, 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 ...
s
FastY
- compare a DNA sequence to a protein sequence database, allowing gaps and
frameshift Ribosomal frameshifting, also known as translational frameshifting or translational recoding, is a biological phenomenon that occurs during translation Translation is the communication of the Meaning (linguistic), meaning of a #Source and ...
s
Path
- tool that compares two
frameshift Ribosomal frameshifting, also known as translational frameshifting or translational recoding, is a biological phenomenon that occurs during translation Translation is the communication of the Meaning (linguistic), meaning of a #Source and ...
proteins (back-
translation Translation is the communication of the Meaning (linguistic), meaning of a #Source and target languages, source-language text by means of an Dynamic and formal equivalence, equivalent #Source and target languages, target-language text. The ...
principle)
HGMD
- Human Genome Mutation Database {{Mutation Mutation