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 In contrast with somatic mutations, germ-line mutations are passed on to an organism's progeny. As a result, future generations of organisms will carry the mutation in all of their cells both somatic and germ-line. What kinds of mutations exist?
Base substitution. Base substitutions are the simplest type of gene-level mutation, and they involve the swapping of one nucleotide for another during DNA replication. For example, during replication, a thymine nucleotide might be inserted in place of a guanine nucleotide. With base substitution mutations, only a single nucleotide within a gene sequence is changed, so only one codon is affected Figure 1. Figure 1: Only a single codon in the gene sequence is changed in base substitution mutation.
The nitrogenous bases are paired so that blue and orange nucleotides are complementary and red and green nucleotides are complementary.
However, the 5 th nucleotide from the right on both the bottom and top strand form a mismatched pair: an orange nucleotide pairs with a red nucleotide. This mismatched pair is highlighted in cyan. The sugar molecules of each individual nucleotide in the chain are connected to adjacent sugar molecules, which are represented by gray horizontal cylinders. The nitrogenous bases hang down from the sugar molecules and look like vertical bars that are twice as long and half as wide as the gray cylinders; the bases are either blue, red, green, or orange.
A second chain of 12 nucleotides forms the second DNA strand below the upper template strand; this strand is labeled the replicating strand in the lower right. Here, the nitrogenous bases point upward from the sugar-phosphate chain, nearly meeting the ends of the nitrogenous bases from the upper strand. Because there are only 12 nucleotides in the lower strand and 16 nucleotides in the upper strand, four nucleotides on the left side of the upper strand are not bound to a complementary nucleotide on the lower strand.
A 13 th nucleotide is shown joining the left end of the lower replicating strand. Although a base substitution alters only a single codon in a gene, it can still have a significant impact on protein production. In fact, depending on the nature of the codon change, base substitutions can lead to three different subcategories of mutations. The first of these subcategories consists of missense mutations , in which the altered codon leads to insertion of an incorrect amino acid into a protein molecule during translation; the second consists of nonsense mutations , in which the altered codon prematurely terminates synthesis of a protein molecule; and the third consists of silent mutations , in which the altered codon codes for the same amino acid as the unaltered codon.
Insertions and deletions. A second chain of 13 nucleotides forms the second DNA strand below the upper template strand; this strand is labeled the replicating strand in the lower right. The sixth nucleotide from right to left has slipped out of place, causing a bulge in the DNA strand. The presence of this bulge causes a misalignment of nucleotide pairs; therefore, an extra nucleotide has been added to complete the remaining DNA strand with correct base pairs.
This extra nucleotide in position 8 from the right has a cyan aura around it. A 14 th nucleotide is shown joining the left end of the lower replicating strand. Figure 3: In a deletion mutation, a wrinkle forms on the DNA template strand, which causes a nucleotide to be omitted from the replicated strand. A second chain of eight nucleotides forms the second DNA strand below the first strand. The nucleotide that should have paired with nucleotide 7 on the upper strand has been left out of the replicating bottom strand, causing a bulge in the upper strand.
As a result, upper nucleotides 6, 7, and 8 do not align with a complementary nucleotide on the lower strand. The nucleotides in the bottom strand that would have aligned with upper nucleotides 6 and 8 have a cyan aura around them. Because there are only eight nucleotides in the lower strand and 13 nucleotides in the upper strand, several nucleotides on the left side of the upper strand are not bound to a complementary nucleotide on the lower strand.
One additional free-floating nucleotide is about to be added to the growing bottom strand. Frameshift mutations. Figure 4: If the number of bases removed or inserted from a segment of DNA is not a multiple of three a , a different sequence with a different set of reading frames is transcribed to mRNA b.
The nitrogenous bases hang down from the sugar molecules and look like vertical bars that are twice as long and half as wide as the gray cylinders; the bases are blue, red, green, or orange. A second chain of 12 nucleotides forms the lower DNA strand, labeled the replicating strand in the lower right.
The first, fifth, tenth, and fifteenth nucleotides from left to right are absent in the replicating strand. The effect of the missing nucleotides is illustrated in panel B.
The intended sequence of the replicating strand is shown color-coded below the template strand sequence. UC Berkeley. There are many different ways that DNA can be changed, resulting in different types of mutation. Here is a quick summary of a few of these:. A substitution is a mutation that exchanges one base for another i. Such a substitution could:.
Thus the amino acid sequence encoded by the gene is not changed and the mutation is said to be silent. Missence : When base substitution results in the generation of a codon that specifies a different amino acid and hence leads to a different polypeptide sequence.
Depending on the type of amino acid substitution the missense mutation is either conservative or nonconservative. Nonsense : When a base substitution results in a stop codon ultimately truncating translation and most likely leading to a nonfunctional protein. A deletion, resulting in a frameshift, results when one or more base pairs are lost from the DNA see Figure above. If one or two bases are deleted the translational frame is altered resulting in a garbled message and nonfunctional product.
A deletion of three or more bases leave the reading frame intact. A deletion of one or more codons results in a protein missing one or more amino acids. This may be deleterious or not. The insertion of additional base pairs may lead to frameshifts depending on whether or not multiples of three base pairs are inserted. Combinations of insertions and deletions leading to a variety of outcomes are also possible. On very, very rare occasions DNA polymerase will incorporate a noncomplementary base into the daughter strand.
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