Our analysis further suggests that genetic elements supporting productive frameshifting could rapidly evolve de novo, even in essential genes.
Keywords: antibiotic resistance; evolution; frameshift suppression; gene regulation; rpoB. Abstract A fundamental feature of life is that ribosomes read the genetic code in messenger RNA mRNA as triplets of nucleotides in a single reading frame. If a mutation disrupts this reading frame, then the entire DNA sequence following the mutation will be read incorrectly. A frameshift mutation is a particular type of mutation that involves either insertion or deletion of extra bases of DNA.
Now, what's important here is the number three. The number of bases that are either added or subtracted can't be divisible by three. And that's important because the cell reads a gene in groups of three bases.
The DNA in any cell can be altered through environmental exposure to certain chemicals, ultraviolet radiation , other genetic insults, or even errors that occur during the process of replication. If a mutation occurs in a germ-line cell one that will give rise to gametes , i. This means that every cell in the developing embryo will carry the mutation.
As opposed to germ-line mutations, somatic mutations occur in cells found elsewhere in an organism's body. Such mutations are passed to daughter cells during the process of mitosis Figure 2 , but they are not passed to offspring conceived via sexual reproduction. Figure 2: Mutations can occur in germ-line cells or somatic cells. Somatic mutations occur in non-reproductive cells; they are passed to daughter cells during mitosis but not to offspring during sexual reproduction.
Genetics: A Conceptual Approach, 2nd ed All rights reserved. Figure Detail. As mentioned, sickle-cell anemia is the result of a change in a single nucleotide, and it represents just one class of mutations called point mutations. Changes in the DNA sequence can also occur at the level of the chromosome , in which large segments of chromosomes are altered. In this case, fragments of chromosomes can be deleted, duplicated , inverted, translocated to different chromosomes, or otherwise rearranged, resulting in changes such as modification of gene dosage, the complete absence of genes , or the alteration of gene sequence.
The type of variation that occurs when entire areas of chromosomes are duplicated or lost, called copy number variation CNV , has especially important implications for human disease and evolution. 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.
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