Mutations: Heritable Changes in Genes

Accurate DNA replication, transcription, and translation all depend on the reliable pairing of complementary bases. Errors occur, though infrequently, in all three processes — least often in DNA replication. But, the consequences of DNA errors are the most severe because only they are heritable.

Mutationsare heritable changes in genetic information. In unicellular organisms, any mutations that occur are passed on to the daughter cells when the cell divides. In multicellular organisms, there are two general types of mutations in terms of inheritance:

- Somatic mutationsare those that occur in somatic (body) cells. These mutations are passed on to the daughter cells after mitosis, and to the offspring of those cells in turn but are not passed on to sexually produced offspring. A mutation in a single skin cell, for example, could result in a patch of skin cells, all with the same mutation, but would not be passed on to a person’s children.

- Germ line mutationsare those that occur in the cells of the germ line—the specialized cells that give rise to gametes. A gamete with the mutation passes it on to a new organism at fertilization. Very small changes in the genetic material can lead to easily observable changes in the phenotype. Some effects of mutations in humans are readily detectable—dwarfism, for instance or the presence of more than five fingers on each hand. A mutant genotype in a microorganism may be obvious if, for example, it results in a change in nutritional requirements, as we described for Neurospora earlier (see Figure ). Other mutations may not be easily observable. In humans, for example, a particular mutation drastically lowers the level of an enzyme called glucose 6-phosphate dehydrogenase that is present in many tissues, including red blood cells. The red blood cells of a person carrying the mutant allele are abnormally sensitive to an antimalarial drug called primaquine; when such people are treated with this drug, their red blood cells rupture. People with the normal allele have no such problem. Before the drug came into use, no one was aware that such a mutation existed. In bacteria, because of their small sizes and simpler morphologies, distinguishing a mutant from a normal bacterium usually requires sophisticated chemical methods, not just visual inspection. Some mutations cause their phenotypes only under certain restrictive conditions. They are not detectable under other, permissive conditions. These phenotypes are known as conditional mutants. Many conditional mutants are temperature- sensitive, able to grow normally at a permissive temperature—say, 30°C—but unable to grow at a restrictive temperature — say, 37°C. The mutant allele in such an organism may code for an enzyme with an unstable tertiary structure that is altered at the restrictive temperature. All mutations are alterations in the nucleotide sequence of DNA. At the molecular level, we can divide mutations into two categories:

- Point mutationsare mutations of single base pairs and so are limited to single genes: One allele (usually dominant) becomes another allele (usually recessive) because of an alteration (gain/loss or substitution) of a single nucleotide (which, after DNA replication, becomes a mutant base pair).

- Chromosomal mutationsare more extensive alterations than point mutations. They may change the position or orientation of a DNA segment without actually removing any genetic information, or they may cause a segment of DNA to be irretrievably lost.

Point mutations are changes in single nucleotides

Point mutations result from the addition or subtraction of a nucleotide base, or the substitution of one base for another, in the DNA, and hence in the mRNA. Point mutations can be caused by errors in chromosome replication that are not corrected in proofreading or by environmental mutagens such as chemicals and radiation. Changes in the mRNA may or may not result in changes in the protein. Silent mutations have no effect on the protein; missense and nonsense mutations will result in changes in the protein, some of them drastic.

Silent mutations

Because of the redundancy of the genetic code, some point mutations result in no change in amino acids when the altered mRNA is translated; for this reason, they are called silent mutations. For example, there are four mRNA codons that code for proline: CCA, CCC, CCU, and CCG. If the template strand of DNA has the sequence CGG, it will be transcribed to CCG in mRNA, and proline-charged tRNA will bind to it at the ribosome. But if there is a mutation such that the codon in the template DNA now reads AGG, the mRNA codon will be CCU—the tRNA that binds it will still carry proline: Silent mutations are quite common, and they result in genetic diversity that is not expressed as phenotypic differences.

Missense mutations

In contrast to silent mutations, some base substitution mutations change the genetic message such that one amino acid substitutes for another in the protein. These changes are called missense mutations:

A missense mutation may cause a protein not to function, but often its effect is only to reduce the functional efficiency of the protein. Therefore, individuals carrying missense mutations may survive, even though the affected protein is essential to life. Through evolution, some missense mutations even improve functional efficiency.

Nonsense mutations

Nonsense mutations, another type of mutation in which one base is substituted for another, are more often disruptive than missense mutations. In a nonsense mutation, the base substitution causes a stop codon, such as UAG, to form in the mRNA product: Think again of codons as three-letter words, each corresponding to a particular amino acid. Translation proceeds codon by codon; if a base is added to the message or subtracted from it, translation proceeds perfectly until it comes to the one-base insertion or deletion. From that point on, the three-letter words in the message are one letter out of register. In other words, such mutations shift the “reading frame” of the genetic message. Frame-shift mutations almost always lead to the production of nonfunctional proteins.

Chromosomal mutations are extensive changes in the genetic material

Changes in single nucleotides are not the most dramatic changes that can occur in the genetic material. Whole DNA molecules can break and rejoin, grossly disrupting the sequence of genetic information. There are four types of such chromosomal mutations: deletions, duplications, inversions, and translocations. These mutations can be caused by severe damage to chromosomes resulting from mutagens or by drastic errors in chromosome replication.

- Deletionsremove part of the genetic material. Like frame-shift point mutations, their consequences can be severe unless they affect unnecessary genes or are masked by the presence, in the same cell, of normal alleles of the deleted genes. It is easy to imagine one mechanism that could produce deletions: A DNA molecule might break at two points, and the two end pieces might rejoin, leaving out the DNA between the breaks.

- Duplicationscan be produced at the same time as deletions. Duplication would arise if homologous chromosomes broke at different positions and then reconnected to the wrong partners. One of the two molecules produced by this mechanism would lack a segment of DNA (it would have a deletion), and the other would have two copies (a duplication) of the segment that was deleted from the first.

- Inversionsalso result from breaking and rejoining. A segment of DNA may be removed and reinserted into the same location in the chromosome, but “flipped” end over end so that it runs in the opposite direction (Figure). If the break site for an inversion includes part of a DNA segment that codes for a protein, the resulting protein will be drastically altered and almost certainly nonfunctional.

- Translocationsresult when a segment of DNA breaks off, moves from its chromosome, and is inserted into a different chromosome. Translocations may be reciprocal, or nonreciprocal, as the mutation involving duplication and deletion in Figure illustrates. Translocations often lead to duplications and deletions, and may result in sterility if normal chromosome pairing in meiosis cannot occur.