Mutation can be defined as any type of heritable genetic change. But there are a number of ways in which such changes can occur, ranging from nucleotide changes within a single gene to alterations in chromosome structure or number. Here we will summarize some of the key types of mutation, and gene mutations and chromosomal mutations will be examined in more detail in the following two chapters.
I. Gene mutation: Gene mutations are sometimes called point mutations because they involve the substitution, loss, or gain of one or more nucleotides within a single gene.
A. Base substitution: A mutation caused by the substitution of a single nucleotide for another.
1. Transition mutation: Substitution of one purine for the other purine or substitution of one pyrimidine for the other pyrimidine.
2. Transversion mutation: Substitution of one purine for a pyrimidine, or vice versa.
3. The effect of an altered codon due to base substitution can either be a missense change (altering the amino acid at that point in the protein) or a nonsense change (generating a chain termination triplet that will stop protein synthesis).
B. Frameshift mutation: A mutation caused by the loss or addition of one or more nucleotides to the DNA strand. Frameshift mutations can alter the triplet reading frame so that each codon is affected from the point of the mutation.
1. We can illustrate this by using an analogy. Consider the following series of letters:
S E E T H E R E D C A T A N D T H E F A T D O G. . .
If this sequence is “read” in triplets, as occurs when the nucleotides are translated into an amino acid sequence on the ribosomes, it makes sense (although it is hardly a literary masterpiece). The loss or the gain of one letter (= one nucleotide), however, changes the sense completely. Delete the first C, for example, to illustrate this for yourself. The sentence becomes “SEE THE RED ATA NOT HEF ATD OG. . . ” If this were a protein, the amino acid sequence and protein structure would have been altered significantly.
2. In addition, many frameshift mutations yield chain termination triplets early in the sequence, leading to early termination of protein synthesis.
C. Transposable element insertion: Mobile DNA elements can insert into a chromosome. If this occurs in a coding or regulatory gene region, it will result in a point mutation. Molecular mapping of mutant DNA sequences has shown that a large proportion of mutations are of this type.
D. Changes in DNA due to amplification during replication: Small repeats in the DNA sequence are subject to expansions during replication, perhaps due to slipped miss-pairing. This leads to differences in the number of tandem repeats present in the DNA and can be a major source of genome polymorphism. Variable numbers of trinucleotide repeats are also linked to adverse phenotypes in fragile X syndrome, myotonic dystrophy, Huntington disease, and Kennedy disease.
II. Changes in chromosome structure: Changes in chromosome structure involve breaks in the DNA that are repaired incorrectly. If segments are lost or gained, often large numbers of genes are involved and their developmental consequences are more severe than those of most point mutations. Structural changes are defined here but are illustrated in more detail in Chapter 16.
A. Inversion: A change in gene order within a linkage group.
B. Deletion: A loss of a section from a chromosome.
C. Duplication: The addition of a section to a chromosome so that one chromosome carries two copies of that set of genes.
D. Translocation: The movement of a chromosome segment from one chromosome to a nonhomologous chromosome. This is the only structural change that involves chromosomes from different linkage groups.
III. Changes in chromosome number: Changes in chromosome number can involve anything from the loss or gain of a single chromosome to the addition of whole chromosome sets. The normal genetic makeup of a cell is the euploid (eu- true, ploid- multiple) chromosome number.
A. Aneuploid: The loss or gain of one or more chromosomes, such as 2n + 1, 2n + 2, or 2n − 1.
1. Aneuploids result from a failure of normal chromosome separation in meiosis (nondisjunction).
2. Most aneuploids that involve the loss of a chromosome die early in development. Most aneuploids that have gained a chromosome also die, but some that involve a small chromosome (e.g., Down syndrome in humans) can survive for at least a short time. Since many different genes are involved in such changes, the phenotypes are often characterized by a whole syndrome of effects.
3. Since females have two X chromosomes but males have only one, dosage compensation mechanisms help equalize the genetic effects of sex-linked genes. The second X in females becomes highly coiled, forming a darkly staining spot (the Barr body) in the interphase nucleus. If there are more than two X chromosomes, all those beyond one are inactivated. For this reason, X chromosome aneuploids are generally much less severe than autosomal aneuploids.
B. Polyploid: Having multiple whole sets of chromosomes: 3n (triploid), 4n (tetraploid), and so forth.
1. Polyploids can result from processes like multiple sperm entry or failure of a polar body to separate from the egg. They can also be produced artificially by cell fusion and other techniques.
2. Most polyploidy in animals is lethal. Plants, however, appear to tolerate polyploidy well. In fact, polyploidy is a major mechanism in plant evolution and is widely used in agricultural genetics to produce new varieties.