At that particular spot, C would pair with G, forming a double helix with the same sequence as its original i. This type of mutation is known as a base, or base-pair, substitution. Base substitutions involving replacement of one purine for another or one pyrimidine for another e.
Likewise, when strand-slippage replication errors are not corrected, they become insertion and deletion mutations. Much of the early research on strand-slippage mutations was conducted by George Streisinger in the s. Streisinger, a professor at the University of Oregon and a fish hobbyist, is known by some as the "founding father of zebrafish research.
Streisinger used this virus to show that most nucleotide insertion and deletion mutations occur in areas of DNA that contain many repeated sequences also called tandem repeats , and he formulated the strand-slippage hypothesis to explain why this was the case Streisinger et al. In Figure 3, notice the series of repeat T's on the template strand where the slippage has occurred.
When slippage takes place, the presence of nearby duplicate bases stabilizes the slippage so that replication can proceed. During the next round of replication, when the two strands separate, the insertion or deletion on either the template or primer strand, respectively, will be perpetuated as a permanent mutation. Scientists have collected enough evidence to confirm Streisinger's strand-slippage hypothesis, and this type of mutagenesis remains an active field of scientific research. Figure 3: Strand slippage during DNA replication.
When strand slippage occurs during DNA replication, a DNA strand may loop out, resulting in the addition or deletion of a nucleotide on the newly-synthesized strand. Although most mutations are believed to be caused by replication errors, they can also be caused by various environmentally induced and spontaneous changes to DNA that occur prior to replication but are perpetuated in the same way as unfixed replication errors.
As with replication errors, most environmentally induced DNA damage is repaired, resulting in fewer than 1 out of every 1, chemically induced lesions actually becoming permanent mutations. The same is true of so-called spontaneous mutations.
Rather, they are usually caused by normal chemical reactions that go on in cells, such as hydrolysis. These types of errors include depurination , which occurs when the bond connecting a purine to its deoxyribose sugar is broken by a molecule of water, resulting in a purine-free nucleotide that can't act as a template during DNA replication, and deamination , which results in the loss of an amino group from a nucleotide, again by reaction with water.
Again, most of these spontaneous errors are corrected by DNA repair processes. But if this does not occur, a nucleotide that is added to the newly synthesized strand can become a permanent mutation.
Mutation rates vary substantially among taxa, and even among different parts of the genome in a single organism. Scientists have reported mutation rates as low as 1 mistake per million 10 -8 to 1 billion 10 -9 nucleotides, mostly in bacteria , and as high as 1 mistake per 10 -2 to 1, 10 -3 nucleotides, the latter in a group of error-prone polymerase genes in humans Johnson et al.
Even mutation rates as low as 10 can accumulate quickly over time, particularly in rapidly reproducing organisms like bacteria. This is one reason why antibiotic resistance is such an important public health problem; after all, mutations that accumulate in a population of bacteria provide ample genetic variation with which to adapt or respond to the natural selection pressures imposed by antibacterial drugs Smolinski et al. Take E. The genome of this common intestinal bacterium has about 4.
Assuming a mutation rate of 10 -9 i. That may not seem like much. At that point, approximately 10, of these bacteria will have accumulated at least one mutation. As the number of bacteria carrying different mutations increases, so too does the likelihood that at least one of them will develop a drug-resistant phenotype.
Likewise, in eukaryotes, cells accumulate mutations as they divide. In humans, if enough somatic mutations i. Or, less frequently, some cancer mutations are inherited from one or both parents; these are often referred to as germ-line mutations. One of the first cancer-associated somatic mutations was discovered in , when researchers found that a mutated HRAS gene was associated with bladder cancer Reddy et al.
HRAS encodes for a protein that helps regulate cell division. Since then, scientists have identified several hundred additional "cancer genes. Of course, not all mutations are "bad. However, too much of a good thing can be dangerous. If DNA repair were perfect and no mutations ever accumulated, there would be no genetic variation—and this variation serves as the raw material for evolution. Successful organisms have thus evolved the means to repair their DNA efficiently but not too efficiently, leaving just enough genetic variability for evolution to continue.
Crick, F. Codon-anticodon pairing: The wobble hypothesis. Journal of Molecular Biology 19 , — link to article. Johnson, R. Journal of Biological Chemistry , — Reddy, E. A point mutation is responsible for the acquisition of transforming properties by the T24 human bladder carcinoma oncogene. Nature , — link to article. Smolinski, M. Streisinger, G. Frameshift mutations and the genetic code. Watson, J. Molecular structure of nucleic acids. Wijnen, J. Nature Genetics 20 , — link to article.
Restriction Enzymes. Genetic Mutation. Functions and Utility of Alu Jumping Genes. Transposons: The Jumping Genes. Table 2 summarizes the types of mutations and provides examples of various diseases associated with each. Mutations can result from a number of events, including unequal crossing-over during meiosis Figure 3. In addition, some areas of the genome simply seem to be more prone to mutation than others.
These "hot spots" are often a result of the DNA sequence itself being more accessible to mutagens. Hot spots include areas of the genome with highly repetitive sequences, such as trinucleotide repeats, in which a sequence of three nucleotides is repeated many times.
During DNA replication, these repeat regions are often altered because the polymerase can "slip" as it disassociates and reassociates with the DNA strand Viguera et al. To better understand a polymerase slip, imagine you are reading a page of text that is a repeat of a simple sequence.
Say that the whole page is just copies of the word "And" "And And And Now, imagine that while reading the page, you briefly glance away and then look back at the text.
It's quite likely that you will have lost your place. As a result, you may read the wrong number of copies from the page. Similarly, DNA polymerase sometimes slips and makes mistakes when reading repeats.
Figure 3: Unequal crossing-over during meiosis. When homologous chromosomes misalign during meiosis, unequal crossing-over occurs. The result is the deletion of a DNA sequence in one chromosome, and the insertion of a DNA sequence in the other chromosome.
Genetics: A Conceptual Approach, 2nd ed. All rights reserved. In other cases, mutations alter the way a gene is read through either the insertion or the deletion of a single base. In these so-called frameshift mutations, entire proteins are altered as a result of the deletion or insertion. This occurs because nucleotides are read by ribosomes in groups of three, called codons.
Thus, if the number of bases removed or inserted from a gene is not a multiple of three, the reading frame for the rest of the protein is thrown off.
To better understand this concept, consider the following sentence composed entirely of three-letter words, which provides an analogy for a series of three-letter codons:.
Now, say that a mutation eliminates the first G. As a result, the rest of the sentence is read incorrectly:. The same will happen in a protein. For example, a protein might have the following coding sequence:. A codon translation table Figure 4 can be used to determine that this mRNA sequence would encode the following stretch of protein:. Now, suppose that a mutation removes the fourth nucleotide.
The resulting code, separated into triplet codons, would read as follows:. Each of the STOP codons tells the ribosome to terminate protein synthesis at that point. Thus, the mutant protein is entirely different due to the deletion, and it's shorter due to the premature stop codon. Figure 4: The amino acids specified by each mRNA codon.
Multiple codons can code for the same amino acid. The codons are written 5' to 3', as they appear in the mRNA. As previously mentioned, DNA in any cell can be altered by way of a number of factors, including environmental influences, certain chemicals, spontaneous mutations, and errors that occur during the process of replication. Each of these mechanisms is discussed in greater detail in the following sections.
UV light can also cause covalent bonds to form between adjacent pyrimidine bases on a DNA strand, which results in the formation of pyrimidine dimers.
Repair machinery exists to cope with these mutations, but it is somewhat prone to error, which means that some dimers go unrepaired. Furthermore, some people have an inherited genetic disorder called xeroderma pigmentosum XP , which involves mutations in the genes that code for the proteins involved in repairing UV-light damage. In people with XP, exposure to UV light triggers a high frequency of mutations in skin cells, which in turn results in a high occurrence of skin cancer.
As a result, such individuals are unable to go outdoors during daylight hours. In addition to ultraviolet light, organisms are exposed to more energetic ionizing radiation in the form of cosmic rays, gamma rays, and X-rays. Ionizing radiation induces double-stranded breaks in DNA, and the resulting repair can likewise introduce mutations if carried out imperfectly. Unlike UV light, however, these forms of radiation penetrate tissue well, so they can cause mutations anywhere in the body.
Deamination , or the removal of an amine group from a base, may also occur. Deamination of cytosine converts it to uracil , which will pair with adenine instead of guanine at the next replication, resulting in a base substitution.
Repair enzymes can recognize uracil as not belonging in DNA, and they will normally repair such a lesion. However, if the cytosine residue in question is methylated a common modification involved in gene regulation , deamination will instead result in conversion to thymine. Because thymine is a normal component of DNA, this change will go unrecognized by repair enzymes Figure 6.
Figure 6: Deamination is a spontaneous mutation that occurs when an amine group is removed from a nitrogenous base. The nitrogenous base cytosine is converted to uracil after the loss of an amine group. Because uracil forms base-pairs with adenine, while cytosine forms base-pairs with guanine, the conversion of cytosine to uracil causes base substitutions in DNA.
Genetics: A Conceptual Approach , 2nd ed. Errors that occur during DNA replication play an important role in some mutations, especially trinucleotide repeat TNR expansions.
It is thought that the ability of repeat sequences to form secondary structures, such as intrastrand hairpins, during replication might contribute to slippage of DNA polymerase, causing this enzyme to slide back and repeat replication of the previous segment Figure 7.
Supporting this hypothesis, lagging-strand synthesis has been shown to be particularly sensitive to repeat expansion. As previously mentioned, repeats also occur in nonmitotic tissue, and CAG repeats have further been shown to accumulate in mice defective for individual DNA repair pathways, suggesting that multiple repair mechanisms must be operative in repeat expansion in nonproliferating cells Pearson et al.
In agreement with this hypothesis, studies have revealed increased repeat instability following induction of double-stranded breaks and UV-induced lesions, which are corrected by nucleotide excision repair. To date, all diseases associated with TNRs involve repeat instability upon transmission from parent to offspring, often in a sex-specific manner.
For example, the CAG repeats that characterize Huntington's disease typically exhibit greater expansion when inherited paternally. This expansion has been shown to occur prior to meiosis, when germ cells are proliferating. Thus, mutations are not always a result of mutagens encountered in the environment. There is a natural—albeit low—error rate that occurs during DNA replication. In most cases, the extensive network of DNA repair machinery that exists in the cell halts cell division before an incorrectly placed nucleotide is set in place and a mismatch is made in the complementary strand.
However, if the repair machinery does not catch the mistake before the complementary strand is formed, the mutation is established in the cell. This mutation can then be inherited in daughter cells or in embryos if the mutation has occurred in the germ line. Together, these different classes of mutations and their causes serve to place organisms at risk for disease and to provide the raw material for evolution.
Thus, mutations are often detrimental to individuals, but they serve to diversify the overall population. Denissenko, M. Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in P Science , — Greenblatt, M. Mutations in the P53 tumor suppressor gene: Clues to cancer etiology and molecular pathogenesis. Cancer Research 54 , — International Human Genome Sequencing Consortium. Initial sequencing and analysis of the human genome.
Nature , — link to article. Subsititution refers to the replacement of one amino acid with another amino acid in a protein or the replacement of one nucleotide with another in DNA or RNA. Substitutions generally give rise to--or they always give rise to--either a polymorphism, that is, a difference between one person, one individual, in a population or another, or a special kind of polymorphism that we call a mutation.
In either case, all individuals in the population originally had the same sequence of a gene. There were substitution events that resulted in a change in DNA sequence, which resulted in a change in RNA sequence, which then could result in a change in amino acid sequence.
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