The term mutation refers to a permanent change in DNA structure. Genetic mutation is a rare event despite the daily exposure of cells to numerous mutagenic influences. Radiation, chemicals, viruses, and even some products of normal cellular metabolism are all potential mutagens. Most mutations, however, occur spontaneously as a result of copying errors during DNA replication.3 Regardless of the cause, only a few of these changes in DNA result in permanent alterations (mutations). The stability of the genes, and thus the low mutation rate, depends on efficient DNA repair mechanisms.

There are a variety of cellular DNA repair mechanisms. Most require the presence of a normal complementary DNA template to correctly repair the damaged strand of DNA. Single-stranded breaks or loss of bases from only one DNA strand are readily repaired. Double-stranded breaks, involving both strands of complementary DNA, may result in permanent loss of genetic information at the break point when the broken strands are reunited. Different types of DNA damage are detected and repaired by different enzyme systems. The steps in one type of DNA repair are shown in Figure 6-6.

Genetic mutations are generally of two types: a point mutation, which involves a single base pair substitution, or a frameshift mutation, which often changes the genetic code dramatically. A sequence of three DNA bases (codon) is required to code for each amino acid. A point mutation in the gene may cause the affected codon to signify an abnormal amino acid. The inclusion of the abnormal amino acid in the sequence of the protein may or may not be of clinical significance. Sickle cell anemia and α₁-antiprotease deficiency are examples of point mutation disorders in which a single amino acid substitution causes significant dysfunction. A frameshift mutation is due to the addition or deletion of one or more bases, which changes the “reading frame” of the DNA sequence. The DNA sequence is normally “read” in groups of three bases, with no spaces between codons. All of the codon triplets will be changed in the DNA downstream from a frameshift mutation, resulting in a protein with a greatly altered amino acid sequence (Figure 6-7). Numerous genetic disorders are due to mutations in a gene that codes for a particular protein. These are termed single-gene or mendelian disorders. Mutations may also alter chromosome structure through loss, gain, or translocation of chromosome segments. These processes are discussed later in the chapter.

The union of sperm and egg results in a fertilized egg (zygote) with the full complement of 46 chromosomes: 22 pairs of autosomes and 2 sex chromosomes (euploid). Aneuploidy refers to an abnormal number of chromosomes—in humans, either more or less than 46. Aneuploidy is most commonly caused by nondisjunction.3 Nondisjunction means that paired homologous chromosomes fail to separate normally during either the first or the second meiotic division (Figure 6-8). The resulting germ cells then have an abnormal number of chromosomes: one germ cell will have 22 chromosomes and the other will have 24 chromosomes. When the abnormal germ cell combines with a normal germ cell containing 23 chromosomes, the resulting zygote will either be deficient by one chromosome (45) or have an extra chromosome (47). In anaphase lag, one chromosome lags behind and is therefore left out of the newly formed cell nucleus. This results in one daughter cell with the normal number of chromosomes and one with a deficiency of one chromosome, a condition called monosomy. Polysomy refers to the condition of having too many chromosomes.

The causes of aneuploidy are poorly understood; however, advanced maternal age, abnormalities in parental chromosome structure, and abnormalities in crossing over are known to increase the risk of abnormalities in chromosome number in humans.7 Aneuploidy occurs rather frequently during human gametogenesis; however, zygotes with abnormal chromosome numbers are usually nonviable. Approximately one third of human miscarriages involve an aneuploid fetus.⁸ Although monosomy involving the autosomes is not usually compatible with life, autosomal polysomy may result in a viable fetus when a single extra copy of a chromosome carrying relatively few genes is present. Severe disability, however, nearly always results (e.g., trisomy 21—Down syndrome). Disorders involving extra or missing sex chromosomes are more common and less debilitating.

Alterations in chromosome structure are usually due to breakage and loss or rearrangement of pieces of the chromosomes during meiosis or mitosis. During meiosis, the homologous chromosomes normally pair up and exchange genetic alleles in a process called crossing over. Normal crossing over involves precise gene exchange between homologues only, with no net gain or loss of DNA. When the normal process of crossing over goes awry, portions of chromosomes may be lost, attached upside down, or attached to the wrong chromosome. Mitosis also presents opportunities for chromosomal breakage and rearrangement. The severity of the chromosomal rearrangement ranges from insignificant to lethal, depending on the number and importance of the gene loci involved. Gene locations can be described by their position on the long arm (q arm) or the short arm (p arm) of the chromatid. For example, the gene locus 2p13 is located on the short arm of chromosome 2 at region 1, band 3 (Figure 6-9). The common types of chromosomal rearrangements are translocations, inversions, deletions, and duplications (Figure 6-10).

Chromosomal translocations result from the exchange of pieces of DNA between nonhomologous chromosomes. If no genetic material is lost, as in a reciprocal translocation, the individual may have no symptoms or disorder. However, an individual with a reciprocal translocation is at increased risk of producing abnormal gametes. The exchange of a long chromatid arm for a short one results in the formation of one very large chromosome and one very small chromosome (see Figure 6-10). This is called a robertsonian translocation and is responsible for a rare hereditary form of Down syndrome, discussed later in the chapter. Isochromosomes occur when the sister chromatids separate incorrectly at the centromere such that the two identical short arms remain together, as do the two long arms.

Inversion refers to the removal and upside-down reinsertion of a section of chromosome (see Figure 6-10). Like balanced translocations, inversions involve no net loss or gain of genetic material and are often without consequence to the individual. Difficulties result, however, when homologous chromosomes attempt to pair up during meiosis. The chromosome with an inverted section may not pair up properly, resulting in duplications or loss of genes at the time of crossing over. Thus, the offspring of an individual harboring an inversion may be affected.

Loss of chromosomal material is called deletion. Deletions result from a break in the arm of a single chromosome, resulting in a fragment of DNA with no centromere. The piece is then lost at the next cell division. Chromosomal deletions have been associated with some forms of cancer, including retinoblastoma (see Chapter 7). Deletions at both ends of a chromatid may cause the free ends to attach to one another, forming a ring chromosome.

In contrast to a deletion, where genes are lost, duplication results in extra copies of a portion of DNA. The consequences of duplications are generally less severe than those from loss of genetic material.