Mutation, DNA Repair, and Recombination

Overview

This module looks at changes in the information stored in the genetic material, how they occur, what the consequences of such changes are, and strategies cells use to minimize DNA changes and damage.

Objectives

1. Understand the differences between somatic and gametic mutations, regarding where they occur, and what the consequences are.
2. Understand the difference between spontaneous and induced mutations.
3. Know the various possible effects of mutations of organisms.
4. Understand the molecular basis and possible consequences of base substitutions and frameshift mutations.
5. Understand the general concept of mutagenicity testing using the Ames test.
6. Know how thymine dimers form, and the various repair mechanisms (photoreactivation, excision repair, recombination repair, SOS repair) used to fix thymine dimers.
7. Understand how proofreading and mismatch repair are used to prevent base substitutions in DNA.
8. Understand the mechanism by which DNA molecules recombine.
9. Understand the concept of gene conversion, and how it can result from recombination.

Mutation

One of the properties of the genetic material, as outlined in the module on nucleic acids, is the ability to exhibit variation over time. This property was necessary to explain why individuals within a population are not all genetically identical, and to explain how organisms evolve. Mutation is defined as a failure to store genetic information faithfully. Changes in genetic information can be reflected in the expression of that information (i.e. in the proteins produced). In other words, mutation accounts for the variability in the genetic information.

Mutation is therefore a double-edged sword. One one hand, mutation is necessary to introduce variation into the gene pool of a population. Genetic variation has been shown to correlate with species fitness. On the other hand, most mutations are deleterious to the individuals in which they occur. So mutation is good for the population, but generally not so good for the individual.

Somatic vs. Gametic Mutations

The consequences of a mutation depend upon where in an individual they occur. Some mutations occur in regular body cells; these are somatic mutations. For example, someone who spends too much time suntanning might experience a mutation in a skin cell. The consequences of such a mutation are felt only by the individual. The skin cell may develop some problem (such as cancer, perhaps) as a result of the mutation, but because the mutation occurred only in a skin cell, it would not be passed on to subsequent generations.

Some mutations occur in germline cells. These cells produce the gametes; therefore, they are gametic mutations. In most cases, such mutations wouldn't even be noticed by the individual. After all, the gametes don't play a prominent role in the day-to-day function of the individual. These mutations, in contrast to the somatic mutations, will be passed on to the next generation, because they occur in the cells that produce the next generation.

Spontaneous vs. Induced Mutations

Some mutations arise as natural errors in DNA replication (or as a result of unknown chemical reactions); these are known as spontaneous mutations. The rates of such mutations have been determined for many species. E. coli has a spontaneous mutation rate of 1/10⁸ (one error in every 10⁸ nucleotides replicated). Humans have a higher spontaneous mutation rate: between 1/10⁶ and 1/10⁵ (probably as a result of the higher complexity of human replication).

Mutations can also be caused by agents in the environment; these are induced mutations. Induced mutations increase the mutation rate over the spontaneous rate. Looking at a single mutation in an individual, one cannot tell if the mutation was spontaneous or induced. Induced mutations can only be discerned by looking at the mutation rate in a population, and comparing it to the spontaneous mutation rate for the species. If the observed mutation rate is higher, then induced mutations can be assumed. Agents in the environment that cause an increase in the mutation rate are called mutagens.

Mutations: Random and Reversible

The spontaneity of many mutations should suggest to you that the process is random. Mutations do not occur in response to a stimulus. In other words, bacteria do not mutate to become antibiotic resistant as a response to exposure to antibiotics. Instead, out of all of the mutations occurring in a population of bacteria, some (a miniscule percentage) will cause antibiotic resistance. If that antibiotic is encountered, those bacterial cells with that particular mutation will survive; the vastmajority of the cells that do not have the mutation will die.

Mutations can be reversible. If a mutation occurs once in a gene, there is a very small probability that the mutated base could mutate back to its original form. Alternatively, there are occasions when a mutation in a second, separate gene will return the phenotype of the organism to a wild type appearance (a rare case of two wrongs making a right). This kind of mutation is known as a supressor mutation.

Effects of Mutation

Mutations can affect individuals in a variety of ways. Among the consequences of mutation are the following:

• Change in a morphological trait. This refers to an obvious change in some physical characteristic of an organism. Most of the mutant phenotypes we have observed in this course have been of this type (for example, short plants instead of tall).
• Nutritional or biochemical variation. A mutation may occur in a gene that encodes an enzyme involved in a metabolic pathway, such as an enzyme involved in the biosynthesis of an amino acid. If this occurs, the organism can no longer synthesize the amino acid, and must obtain from dietary sources.
• Change in behavior. These are hard to characterize, and there are few known examples of specific behaviors affected by a single gene. In one example, Drosophila mating behavior was found to be affected by a mutation. Mutant male flies were no longer able to distinguish between males and females, and tried to mate with any fly available!
• Changes in gene regulation. If a mutation occurs in a gene encoding a transcription factor, it could affect when and where the genes controlled by that transcription factor are expressed. This will be addressed in the modules on gene regulation.
• Lethality. Some mutations are lethal to an organism, like the yellow coat color allele in mice (as outlined in the module on extensions of Mendelism) or the Huntington's allele of humans.