Point mutation
A point mutation is a genetic
Causes
Point mutations usually take place during 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 or pyrimidine may change the amino acid that the nucleotides code for.
Point mutations may arise from spontaneous
There are multiple ways for point mutations to occur. First,
Categorization
Transition/transversion categorization
In 1959 Ernst Freese coined the terms "transitions" or "transversions" to categorize different types of point mutations.[2][3] Transitions are replacement of a purine base with another purine or replacement of a 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 transversions (Beta). Transition mutations are about ten times more common than transversions.
Functional categorization
Silent mutations code for the same amino acid (a "synonymous substitution"). A silent mutation does not affect the functioning of the 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.[4]
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).[4]
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
By altering just one amino acid, the entire peptide 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 mutations can lead to beneficial as well as harmful traits or diseases. This leads to adaptations 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 is greatly dependent on point mutations in cells. 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.
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 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, 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 is an example of how they can be detrimental.[6]
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.[7]
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.[8]
Specific diseases caused by point mutations
Cancer
Point mutations in multiple tumor suppressor proteins cause
Neurofibromatosis
Sickle-cell anemia
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.[14]
AUG | GUG | CAC | CUG | ACU | CCU | GAG | GAG | AAG | UCU | GCC | GUU | ACU |
START | Val | His | Leu | Thr | Pro | Glu |
Glu |
Lys | Ser | Ala | Val | Thr |
AUG | GUG | CAC | CUG | ACU | CCU | GUG | GAG | AAG | UCU | GCC | GUU | ACU |
START | Val | His | Leu | Thr | Pro | Val | Glu |
Lys | Ser | Ala | Val | Thr |
Tay–Sachs disease
The cause of Tay–Sachs disease 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.[19]
Repeat-induced point mutation
In
RIP occurs during the sexual stage in
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.[27]
Rep and Kistler have speculated that the presence of highly repetitive regions containing transposons, may promote mutation of resident effector genes.[28] So the presence of effector genes within such regions is suggested to promote their adaptation and diversification when exposed to strong selection pressure.[29]
As RIP mutation is traditionally observed to be restricted to repetitive regions and not single copy regions, Fudal et al.[30] 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.[31] 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.[32] Deletion of the rid homolog in Aspergillus nidulans, dmtA, results in loss of fertility[33] while deletion of the rid homolog in Ascobolus immersens, masc1, results in fertility defects and loss of methylation induced premeiotically (MIP).[34]
Consequences
RIP is believed to have evolved as a defense mechanism against
Use in molecular biology
Because RIP is so efficient at detecting and mutating repeats, fungal biologists often use it as a tool for
History
The cellular reproduction process of meiosis was discovered by Oscar Hertwig in 1876. Mitosis was discovered several years later in 1882 by 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.[36]
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.[37]
See also
- Missense mRNA
- PAM matrix
References
- ^ "Point Mutation". Biology Dictionary. 22 November 2016. Retrieved 17 May 2019.
- PMID 16590424.
- .
- ^ a b c d "Genetics Primer". Archived from the original on 11 April 2005.
- S2CID 3071547.
- S2CID 4337913.
- PMID 28188534.
- ^ "A Shortcut to Personalized Medicine". Genetic Engineering & Biotechnology News. 18 June 2008.
- PMID 21859464.
- PMID 23056252.
- S2CID 2136834.
- S2CID 22140210.
- PMID 12011146.
- ^ Genes and Disease. National Center for Biotechnology Information (US). 29 September 1998 – via PubMed.
- PMID 9435331.
- ^ "HBB — Hemoglobin, Beta". Genetics Home Reference. National Library of Medicine.
- ^ a b "Anemia, Sickle Cell". Genes and Disease. Bethesda MD: National Center for Biotechnology Information. 1998. NBK22183.
- ^ a b Clancy S (2008). "Genetic Mutation". Nature Education. 1 (1): 187.
- ^ eMedTV. "Causes of Tay-Sachs". Archived from the original on 6 August 2020. Retrieved 28 December 2011.
- PMID 20854921.
- ^ S2CID 23036409.
- S2CID 25096512.
- PMID 12207702.
- PMID 12742061.
- S2CID 11080216.
- PMID 19714214.
- PMID 21079787.
- PMID 20471307.
- PMID 17610516.
- PMID 19589069.
- PMID 7896093.
- PMID 12072568.
- PMID 18575630.
- S2CID 14143830.
- PMID 2150906.
- ISBN 978-0-521-53100-9.
- S2CID 205011982.
- ISBN 978-0-300-08540-2.
External links
- Point+Mutation at the U.S. National Library of Medicine Medical Subject Headings (MeSH)