Variation is the essence of life, and mutations are the source of all genetic variation. A staggering number and variety of alterations, rearrangements, and duplications of genetic material have occurred since the first living cells, in which there is an incredible range of life forms, from single-celled amoebas and fruit flies to giant dinosaurs and humans. These dramatically different life forms were all produced using genetic material that was present and reproduced from the first living cells. They resulted from the process of mutation, an alteration in genetic material.
Perhaps because of their negative depiction in science fiction and horror films, there is a widespread common misperception that all mutations are harmful, dramatic, and deleterious. Most mutations are not harmful, and the same limited number of mutations has probably been recurring in each species for millions of years. Many helpful mutations have already been incorporated into the normal genotype through natural selection. Harmful mutations do occur, and while they tend to be eliminated through natural selection, they do recur randomly. It is, however, a mistake to consider mutation as sudden or exclusively harmful. Mutation cannot generate sudden, drastic changes—it requires many generations to generalize throughout a species population. Furthermore, if the changes caused by mutation did not favor survival, natural selection would work against their generalization throughout the species population. In the absence of mutation, there would have been no development of life and no evolution would have occurred.
The impact of mutation varies greatly. Though mutations are changes in genetic material, they do not necessarily affect an individual organism's phenotype. When phenotype is affected, it is because the code for protein synthesis has been changed. Whether mutation will affect phenotype and the extent to which it will be influenced depends on how protein manufacture is affected, when and where the mutation occurs, and the complexity of the genetic controls governing the selected trait.
When a trait is governed by the interaction of many genes, with each exerting about the same influence, the impact of a mutation might be negligible. In traits controlled by a single pair of genes, mutation is likely to exert a much greater influence. For traits governed by the interaction between a major controlling gene pair and several other less influential gene pairs, the location of the mutation will determine its impact. Other considerations such as whether the mutated gene is dominant or recessive also determine whether it will directly act on an individual's phenotype—a mutated recessive gene might not appear in the phenotype for several generations.
Mutation can occur in any cell in an organism's body, but only germinal mutations (those that affect the cells that give rise to sperm or eggs) are passed to the next generation. When mutation occurs in somatic (other than sperm and egg) cells in the body such as muscle, liver, or brain cells, only cells that derive from mitotic division of the affected cell will contain the mutation. Although mutations in somatic cells can cause disease, most do not have a significant impact because if the mutated gene is not involved in the specialized function of the affected cell, these "silent mutations" will not be detected. Furthermore, mutations that appear only in somatic cells disappear when the organism dies; they are not passed on to subsequent generations and do not enter the gene pool that is the source of genetic variation for the species.
Another reason that many mutations are not expressed in the phenotype is that they affect only one copy of the gene, leaving diploid organisms with an intact copy of the gene. These types of mutations have a recessive inheritance pattern and do not affect phenotype unless an individual inherits two copies of the mutation. There is also the question of the probability of a mutation in a gamete affecting offspring. The mutation may occur in a single gamete and so may only be passed on if that particular gamete is involved in conception. For example, human semen contains more than fifty million sperm per ejaculate, so it is highly unlikely that a mutation carried by a single sperm will be passed on. When mutation occurs during embryonic (before birth) development and all gametes are affected, there is a greater chance that it might influence the phenotype of future generations. Alternatively, if, like many mutations, the gene defect occurs with advancing age, and the affected individuals are beyond their reproductive years, then it will have no impact on future generations.
How Different Types of Genetic Mutations Occur
Mutation is a normal and fairly frequent occurrence, and the opportunity for a mutation to take place exists
every time a cell replicates. In general the cells that divide many times throughout the course of an organism's life are at greater risk for mutation than those that divide less frequently.
While DNA nearly always reproduces itself accurately, even a minor alteration produces a mutation that may alter a protein, prevent its production, or have no effect at all. There are four broad classes, and within them many varieties, of mutations, and each is named for the error or action that causes it. "Point mutations" are substitutions, deletions, or insertions in the sequence of DNA bases in a gene.
The most common point mutation in mammals is called a base substitution and occurs when an A-T pair replaces a G-C pair. Base substitutions are further classified as either transitions or transversions. Transitions occur when one pyrimidine (C or T) is substituted for the other and one purine (A or G) is substituted on the other strand of DNA. Transversions occur when a purine replaces a pyrimidine. Sickle-cell anemia results from a transversion in which T replaces A in the gene for a component of hemoglobin.
Structural chromosomal aberrations occur when the DNA in chromosomes is broken. The broken ends may remain loose or join those occurring at another break to form new combinations of genes. When movement of a chromosome section from one chromosome to another takes place, it is called translocation. Translocation between human chromosomes 8 and 21 has been implicated in the development of a specific type of leukemia (cancer of the white blood cells). It also has been shown to cause infertility (inability to sexually reproduce) by hindering the distribution of chromosomes during meiosis.
Numerical chromosomal aberrations are changes in the number of chromosomes. In a duplication mutation genes are copied, so the new chromosome contains all of its original genes plus the duplicated one. Polyploidy is a numerical chromosomal aberration in which the entire genome has been duplicated and an individual that is normally diploid (having two of each chromosome) becomes tetraploid (containing four of each chromosome). Polyploidy is responsible for the creation of thousands of new species, acting to increase genetic diversity and produce species that are bigger, stronger, and more able to resist disease.
Aneuploidy refers to occasions when just one or a few chromosomes are involved and also describes the loss of a chromosome. Examples of aneuploidy are Down's syndrome (multiple, characteristic physical and cognitive disabilities), in which there is an extra chromosome 21—usually caused by an error in cell division called nondisjunction—and Turner's syndrome, in which there is only one X chromosome. Common characteristics of Turner's syndrome include short stature and lack of ovarian development. Women with Turner's syndrome are also prone to cardiovascular problems, kidney and thyroid problems, skeletal disorders such as scoliosis (curvature of the spine) or dislocated hips, and hearing and ear disturbances.
Transposon-induced mutations involve sections of DNA that copy and insert themselves into new locations on the genome. Transposons, also known as a kind of "jumping genes," usually disrupt and inactivate gene function. In humans selected types of hemophilia have been linked to transposon-induced mutations.
The Frequency and Causes of Mutation
In the absence of external environmental influences, mutations occur very rarely and are very seldom expressed because many forms of mutation are expressed by a recessive allele. The most common naturally occurring mutations arise simply as accidents. Susceptibility to mutation varies during the life cycle of an organism. For example, among humans mutation of egg cells increases with advancing age—the older the mother the more likely she is to carry gametes with mutations. Susceptibility also varies among members of a species such as humans based on their geographic location and ethnic origin.
The mutation rate is the frequency of new mutations per generation in an organism or a species. Mutation rates vary widely from one gene to another within an organism and between organisms. The mutation rate for bacteria is one per 100 million genes per generation. Despite this relatively low rate, the enormous number of bacteria—there are more than twenty billion produced in the human intestines each day—translates into millions of new mutations to the bacteria population every day. The human mutation rate is estimated at one per 10,000 genes per generation, and human mutation rates are comparable throughout the world. The only exceptions are populations that have been exposed to factors known as mutagens that cause a change in DNA structure and as a result increase the mutation rate. With more than 30,000 genes, a typical human contains three mutations. Considering the fact that human genes mutate approximately once every 30,000 to 50,000 times they are duplicated, and in view of the complexity of the gene replication process, it is surprising that so few "mistakes" are made.
Gene size, gene base composition, and the organism's capacity to repair DNA damage are closely linked to how many mutations occur and remain in the genome. Larger genes are more susceptible than smaller ones because there are more opportunities and potential sites for mutation. Organisms better able to repair and restore DNA sequences will be less likely to have high mutation rates.
The overwhelming majority of human mutations arise in the father, as opposed to the mother. There are more opportunities for mutation during the more numerous cell divisions needed to produce sperm compared to egg cells. Sperm are produced late in the life of males, while females produce eggs earlier—during embryonic development and are born with their full complement of eggs. Thus, the frequency of mutations that are passed to the next generation increases with parental age.
The mutation rate is partly under genetic control and is strongly influenced by exposure to environmental mutagens. Some mutagens act directly to alter DNA, and others act indirectly, by triggering chemical reactions in the cell that result in breakage of a gene or group of genes. Radiation or ultraviolet light—from natural sources like the sun or radioactive material in the earth, or from manmade sources such as X-rays—can significantly accelerate the rate of mutations.
The link between radiation and mutation was first identified in the 1920s by Hermann Muller, a student of Thomas Hunt Morgan, who worked in the famous "fly room." Muller discovered that he could increase the mutation rate of fruit flies more than a hundredfold by exposing reproductive cells to high doses of radiation. His pioneering work prompted medical and dental professionals to exercise caution and minimize patients' exposure to radiation. Since mutagens in the reproductive cells are likely to affect heredity, special precautions such as donning a lead apron to block exposure are used when dental X-rays or other diagnostic imaging studies are performed. Similarly, special care is taken to prevent radiation exposure to the embryo or fetus because a mutation during this period of development when cells are rapidly proliferating might be incorporated in many cells and could result in birth defects.