DNA Mutation


Mutation means any change in the base sequence of DNA. The most common change is a substitution, addition, rearrangement, or deletion of one or more bases. A mutation need not give rise to a mutant phenotype. 
A mutagen is a physical agent or chemical reagent that causes mutations. For example, nitrous acid reacts with some DNA bases, changing their chemistry and hydrogen bonding properties, and is a mutagen. 
Mutagenesis is the process of producing a mutation. If it occurs in nature without the action of a known mutagen, it is called spontaneous mutagenesis and the resulting mutations are spontaneous mutations. If a mutagen is used, the process is called induced mutagenesis.
Types of Mutations:
  • Mutations can be categorized in several ways. One system is based on the nature of the change, specifically on the number of bases changed. Thus, we distinguish a point mutation, in which a single base pair is changed from a multiple mutation, in which two or more base pairs differ from the wild-type sequence. 
  • A point mutation may be a base substitution, abase insertion, or a base deletion, but the term most frequently refers to a base substitution. A second system is based on the consequence of the change in terms of the amino acid sequence that is affected. For example, if there is an amino acid substitution, the mutation is a missense mutation. 
  • If the substitution produces a protein that is active at one temperature (typically 30°C and inactive at a higher temperature (usually 40-42°C the mutation is called a temperature-sensitive (Ts) mutation. Sometimes no amino acid corresponds to a new base sequence; in that case, termination of synthesis of the protein occurs at that point, and the mutation is called a chain termination mutation or nonsense mutation. These mutations generate one of the three nonsense codons: UAA, UAG, or UGA. 
  • Replication errors can be introduced by base analogues that can be added to a replicating DNA molecule. Such a base analogue must be able to pair with the base on the complementary strand being copied, or the 3' à 5' editing function would remove it. However, if it can tautomerize, or if it has two modes of hydrogen bonding, it will be mutagenic. 
  • The substituted base 5-bromouracil (BU) is an analogue of thymine in as much as the bromine atom has about the same van der Waals radius as the methyl group of thymine. BU forms a nucleoside triphosphate, and DNA polymerases will add BU to a DNA strand opposite an adenine. However, BU tautomerizes at high frequency to a form that can pair with guanine. Thus, if BU replaces a thymine, in subsequent rounds of replication it occasionally generates a guanine in the complementary strand, which in turn specifies cytosine, resulting in formation of a GC pair. 
  • A chemical mutagen is a substance that can alter a base that has already been incorporated into DNA and thereby change its hydrogen bonding specificity. Nitrous acid, a powerful mutagen, converts amino groups to keto groups by oxidative deamination. Thus, cytosine, adenine, and guanine are converted to uracil (U), hypoxanthine (H), and xanthine (X), respectively, which can form the base pairs UA, HC, and XC, respectively. 
  • As a consequence, in a later round of replication, GC-to-AT and AT-to-GC mutations can occur. The chemical mutagen hydroxylamine reacts specifically with cytosine and converts it to a modified base that pairs only with adenine; thus, a GC pair ultimately becomes an AT pair. An interesting class of mutagen is intercalating agents, e.g., the acridines. These planar molecules insert between base pairs. 
  • When replication occurs in the region of an intercalated molecule, one or both daughter strands are synthesized that either lack one or more nucleotides or have additional ones. These changes alter the reading frame of the base sequence of a gone and hence are called frameshift mutations.

Triplet Repeats and Fragile Sites:
  • Inherited and acquired (sporadic) mutations account for an enormous diversity of human diseases and disorders. At least 300 genetic disorders include mental retardation as one of the symptoms, implying that many genes can affect brain development and mental functions. 
  • In the 1970s, a defect at the tip of the long arm of X chromosomes, called a fragile site, was discovered in a large number of patients with mental retardation. It is now known that a specific mutation is responsible for the fragile site on the X chromosome and the associated inherited disorder fragile X syndrome. 
  • This particular mutation accounts for about 20% of all mental retardation; about 1 in 1500 boys and 1 in 2500 girls are born with fragile X syndrome. Although fragile X syndrome is classified a Mendelian dominant sex-linked disorder, it does not behave as a classically dominant gene inherited disease. 
  • Only about 80% of males and 35% of females who carry the mutation and a fragile site suffer from mental retardation. For many years it remained a mystery how both men and women could carry a fragile X chromosome and be unaffected.
  • In the 1990s, the molecular explanation for fragile X syndrome was revealed. The gene responsible for fragile X syndrome (FMR1) was found to contain a repeat of the trinucleotide CGG. In unaffected individuals, the number of CGG repeats ranges from about 5 to 54 copies. 
  • In mentally retarded individuals, the number of CGG repeats is dramatically increased to hundreds or thousands of copies. When the CGG repeat exceeds 230, the DNA becomes abnormally methylated in that region and the gene becomes nonfunctional. 
  • Presumably the amplification of the CGG repeat occurs during DNA replication in germ cells prior to meiosis perhaps due to "stuttering" of the DNA polymerase as it reads the repeating trinucleotides. Why amplification of the CGG repeats occurs in some X chromosomes but not others and in some individuals and not others is unresolved. 
  • Triplet repeats account for a growing list of muscular neurologic diseases including Huntington's disease, myotonic dystrophy, Friedreich's ataxia, and others. Triplet repeats represent an entirely new class of mutations. 
  • They are not caused by any external mutagenic agent but are generated during normal DNA replication. Fragile sites are chromosomal regions that are prone to breakage during chromosome movement or recombination; fragile sites can be visualized by a variety of cytological techniques and dyes that bind to metaphase chromosomes. 
  • Fragile sites are relatively common in chromosomes and there is a growing suspicion that they may play a greater role in disease, especially cancer, than previously thought. The chromosomes in many tumor cells exhibit fragile sites that are not present in normal cells. 
  • What is not yet clear is whether a fragile site initiates the conversion of a normal cell to a cancer cell or is merely the consequence of the altered growth properties of the tumor cell. One possibility is that fragile sites are more susceptible to carcinogenic chemicals and that mutations in fragile sites contribute to the transformation of a normal cell to a tumor cell.


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