mutation: Definition, Synonyms and Much More from Answers.com
- ️Wed Jul 01 2015
Concept
A word familiar to all fans of science fiction, mutation refers to any sudden change in DNA—deoxyribonucleic acid, the genetic blueprint for an organism—that creates a change in an organism's appearance, behavior, or health. Unlike in the sci-fi movies, however, scientists typically use the word mutant as an adjective rather than as a noun, as, for example, in the phrase "a mutant strain." Mutation is a phenomenon significant to many aspects of life on Earth and is one of the principal means by which evolutionary change takes place. It is also the cause of numerous conditions, ranging from albinism to cystic fibrosis to dwarfism. Mutation indicates a response to an outside factor, and the nature of that factor can vary greatly, from environmental influences to drugsto high-energy radiation.
How It Works
Dna, Chromosomes, and Mutations
Deoxyribonucleic acid, or DNA, is a molecule in the cells of all life-forms that contains genetic codes for inheritance. DNA, discussed elsewhere in this book, is as complex in structure as it is critically important in shaping the characteristics of the organism to which it belongs, and therefore it is not surprising that a subtle alteration in DNA can produce significant results. Alterations to DNA are called mutations, and they can result in the formation of new characteristics that are heritable, or capable of being inherited.
Every cell in the body of every living organism contains DNA in threadlike structures called chromosomes. Stretches of DNA that hold coded instructions for the manufacture of specific proteins are known as genes, of which the human race has approximately 40,000 varieties. If the DNA of a particular gene is altered, that gene may become defective, and the protein for which it codes also may be missing or defective. Just one missing or abnormal protein can have an enormous effect on the entire body: albinism, for instance, is the result of one missing protein.
Mutations also can be errors in all or part of a chromosome. Humans normally have 23 pairs of chromosomes, and an extra chromosome can have a tremendous negative impact. For example, there should be two of chromosome 21, as with all other chromosomes, but if there are three, the result is Down syndrome. People with Down syndrome have a unique physical appearance and are developmentally disabled. Nor is an extra chromosome the only chromosomal abnormality that causes problems: if chromosomes 9 and 22 exchange materials, a phenomenon known as translocation, the result can be a certain type of leukemia. Down syndrome also results from translocation.
Germinal mutations are those that occur in the egg or sperm cells and therefore can be passed on to the organism's offspring. Somatic mutations are those that happen in cells other than the sex cells, and they cannot be transmitted to the next generation. This is an important distinction to keep in mind in terms of both the causes and the effects of mutation. If only the somatic cells of the organism are affected, the mutation will not appear in the next generation; on the other hand, if a germinal mutation is involved, what was once an abnormality may become so common in certain populations that it emerges as the norm.
The Role of Mutation in Evolution
Most of the forms of mutation we discuss in this essay appear suddenly (i.e., in a single generation) and affect just a few generations. Yet even such seemingly "normal" characteristics as our ten fingers and ten toes or our two eyes or our relatively hairless skin (compared with that of apes) are ultimately the product of mutations that took shape over the many hundreds of millions of years during which animal life has been evolving. Evolution, in fact, is driven by mutation, along with natural selection (see Evolution).
Over the eons, advantageous mutations, examples of which we look at later, have allowed life to develop and diversify from primitive cells into the multitude of species—including Homo sapiens—that exist on Earth today. If DNA replicated perfectly every time, without errors, the only life-forms existing now would be those that existed about three billion years ago: single-cell organisms. Mutations, therefore, are critical to the development of diverse life-forms, a phenomenon known as speciation (see Speciation). Mutations that allow an organism to survive and reproduce better than other members of its species are always beneficial, though a mutation that may be beneficial in some circumstances can be harmful in others. Mutations become especially important when an organism's environment is changing—something that has happened often over the course of evolutionary history. And though we cannot watch evolution taking place, we can see how mutations are used among domesticated plants and animals, as discussed later.
Real-Life Applications
Ethnicity and Mutation
Every single human trait—blue eyes, red hair, cystic fibrosis, a second toe longer than the big toe, and so on—is the result of some genetic mutation somewhere back down the line. Traits that are shared by all people must have arisen long ago, while other traits occur only in certain populations of people. Traits may be as innocuous as eye color or hair texture or as grave as a shared tendency toward a particular disease. Cystic fibrosis, for instance, is most common in people of northern European descent, while sickle cell anemia (see Amino Acids) occurs frequently in those of African and Mediterranean ancestry. A fatal disorder known as Tay-Sachs is found primarily in Jewish people whose ancestors came from Eastern Europe. In many cases, the particular mutation, while harmful in one regard, proved to be a useful one for that population. We know, for example, that while two copies of the mutant sickle cell anemia gene cause illness, one copy confers resistance to malaria—a very useful trait to people living in the tropics, where malaria is common.
The Pima "fat-Storage Mutation."
Researchers have noted a high incidence of obesity among the Pima, a Native American tribe whose ancestral homeland is along the Gila and Salt rivers in Arizona. The Pima tend to eat a diet that is no more fatty than that of the average American—which, of course, means that it is plenty fatty, complete with chips, bologna, ice cream, and all the other high-calorie, low-nutrient foods that most Americans consume. But whereas the average American is over-weight, the average Pima is more dramatically so. This suggests that long ago, when the ancestors of the Pima had to face repeated periods of famine in the dry lands of the American Southwest, survival favored the individual or individuals who had a mutation for fat storage. It so happens that today, there is more than enough food at the local supermarket, but by now the Pima as a group has the fat-storage gene. Therefore, many members of the tribe have to undergo strict dietary and exercise regimens so as not to become grossly overweight and susceptible to heart disease and other ailments.
Favorable Mutations
As with other mutations relating to ethnic groups, scientists have hypothesized that some advantage must be conferred upon people with single copies of the cystic fibrosis gene or the Tay-Sachs disease gene. Though many mutations are harmful, others prove to be beneficial to a species by helping it adapt to a particular environmental influence. Useful mutations, in fact, are the driving force behind evolution.
The processes of evolution are usually much too slow for people to discern, but it is possible to observe the effects of selective breeding when applied to domesticated animals and plants. The artificial selection of pigeons by breeders, in fact, provided the English naturalist Charles Darwin (1809-1882) with a model for his theory of natural selection, discussed in Evolution. Likewise, animal and plant breeders use mutations to produce new or improved strains of crops and livestock. Careful breeding in this manner has spawned the many different breeds of dogs, cats, and horses—each with their characteristic coloring, size, temperament, and so on—that we know today. It also has resulted in crops that are resistant to drought or insects or which have a high yield per acre. Likewise, goldfish, yellow roses, and Concord grapes are all descendants of ancestors with specific mutations.
Diseases and Mutation
The majority of mutations, however, are less than favorable, and this is illustrated by the relationship between mutation and certain hereditary diseases. An example is Huntington disease, a condition that strikes people in their forties or fifties and slowly disables their nervous systems. It produces shaking and a range of other symptoms, including depression, irritability, and apathy, and is usually fatal. The gene associated with Huntington's is dominant.
The horrible degenerative brain condition known as Creutzfeldt-Jakob disease, discussed in Diseases, is usually caused by another mutation. (Though it can be caused by infection, most cases of the disease are the result of heredity.) As with some of the other conditions we have mentioned, this one seems to affect particular groups more than others. Whereas the worldwide incidence of this rare condition is about one in one million, among Libyan Jews the rate is higher. The disease is a type of spongiform encephalopathy, so named because it produces characteristic spongelike patterns on the surface of the brain. Spongiform encephalopathies are caused by the appearance of a prion, a deviant form of protein whose production typically is caused by a mutation.
Most hereditary diseases are, by definition, linked with a mutation. Such is the case with hemophilia, for instance (see Noninfectious Diseases), and with cystic fibrosis, a lethal disorder that clogs the lungs with mucus and typically kills the patient before the age of 30 years. Cystic fibrosis, like Huntington, occurs when a person inherits two copies of a mutated gene. In 1989 researchers found the source of cystic fibrosis on chromosome 7, where an infinitesimal change in the DNA sequence leads to the production of an aberrant protein.
Congenital Disorders
In the past, all manner of superstitions arose to explain why a child was born, for instance, with a cleft palate, a situation in which the two sides of the roof of the mouth fail to meet, causing a speech disorder that may be mild or severe. Once known as a harelip, the cleft palate was said to have formed as a result of the mother's being frightened by a hare while she was carrying the child. In fact, it is just one example of a congenital disorder, an abnormality of structure or function or a disease that is present at birth. Congenital disorders, which also are called birth defects, may be the result of several different factors, mutation being one of the most significant. Among the many examples of congenital disorder are the hereditary diseases we have already mentioned, as well as dwarfism, Down syndrome, albinism, and numerous other conditions.
Dwarves and Midgets
The term dwarf has many associations from fairy tales—an example of the combined fascination and revulsion with which people with congenital disorders have long been treated—but it also is used to describe persons of abnormally short stature. A dwarf is distinguished from a midget in a number of ways, all of which indicate that the features of a midget are less removed from the norm. Midgets, while small, have bodies with proportions in the ordinary range. Likewise, the intelligence and sexual development of an adult midget are similar to those of other adults, and a midget or midget couple typically produces children of ordinary size. Pygmies, a group of people in southern Africa, appear to be midgets through a germinal mutation, but in many populations the mutation is somatic, occurring only occasionally in families whose other members are of ordinary size.
Dwarfs, by contrast, have several different disorders. One variety of dwarfism, known in the past as cretinism, is characterized by a small, abnormally proportioned body and an impaired mind. On the other hand, several forms of hereditary dwarfism carry with them no ill effect on the mental capacity. For example, people with the type of dwarfism known as achondroplasia have short limbs and unusually large heads, but the life span and intelligence of someone with this condition are quite normal. In the case of diastrophic dwarfism, the brain is fine, but the skeleton is deformed, and the risk of death from respiratory failure is high in infancy. Persons with diastrophic dwarfism who survive early childhood, however, are likely to enjoy a normal life span.
Down Syndrome
Like people with many other congenital disorders, those with Down syndrome used to be called by a name that now is considered crude and insensitive: mongoloid. The term, when used with a capital M, refers to people of east Asian descent and is analogous to other broad racial groupings: Caucasoid, Negroid, and Australoid. In the case of people with Down syndrome, mongoloid referred to the unusual facial features that mark someone with that condition.
A person with Down syndrome (caused by an extra chromosome in the 21st chromosomal pair) is likely to have a wide, flat face and eyes that are slanted, sometimes with what is known as an inner epicanthal fold—all facial characteristics common among people who are racially Mongoloid. Numerous other facial features identify a person with Down syndrome as someone who suffers from a specific congenital disorder, including a short neck, ears that are set low, a small nose, large tongue and lips, and a chin that slopes. People with Down syndrome are apt to have poor muscle tone and possess abnormal ridge patterns on their palms and fingers and the soles of their feet. Heart and kidney problems are common with Down syndrome as well, but one feature is most common of all: mental retardation. The condition occurs in about one of 1,000 live births among women under age 40 but about one in 40 live births to older women. Overall, the incidence is about one in 800 live births. As noted earlier, the cause of Down syndrome is translocation, but the reason translocation occurs is not known.
Albinism
Compared with dwarfism or Down syndrome, albinism is not nearly as severe in terms of its effect on a person's functioning. A condition that results from an inherited defect in melanin metabolism (melanin is responsible for the coloring of skin), albinism is marked by an absence of pigment from the hair, skin, and eyes. The hair of an albino tends to be whitish blond, the skin an extremely pale white, and the eyes pinkish. Albinism occurs among other animals: hence the white rats, rabbits, and mice almost everyone has seen. Domestic white chickens, geese, and horses are partial albinos that retain pigment in their eyes, legs, and feet. As was once true of people with other congenital disorders, human albinos once inspired fear and awe. Sometimes they were killed at birth, and in the mid-nineteenth century, albinos were exhibited in carnival sideshows. In these cruel spectacles, sometimes whole families were put on display, touted as a unique race of "night people" who lived underground and came out only when the light was dim enough not to hurt their eyes.
On the other hand, some ethnic groups experience enough albino births that another one causes no excitement. For example, among the San Blas Indians of Panama, one in approximately 130 births is an albino, compared with one in 17,000 for humans as a whole. Albinism comes about when melanocytes (melanin-producing cells) fail to produce melanin. In tyrosinase-negative albinism, the most common form, the enzyme tyrosinase (a catalyst in the conversion of tyrosine to melanin) is missing from the melanocytes. When the enzyme is missing, nomelanin is produced. In tyrosinase-positivealbinism, a defect in the body's tyrosine transportsystem impairs melanin production. One inevery 34,000 persons in the United States has tyrosinase-negative albinism. It is equally common among blacks and whites, while more blacksthan whites are affected by tyrosinase-positivealbinism. Native Americans have a particularlyhigh incidence of both forms of albinism.
Mutagens and Other Causes
As might be expected, cells that divide many, many times in a lifetime are more at risk of errors and mutations than cells that divide less frequently. In a human female, egg cells are fully formed at birth, and they never divide thereafter. By contrast, sperm cells are being produced constantly, and the older a man is, the more frequently his sperm-producing cells have divided. By age 20 they will have divided 200 times and by age 45 about 770 times. This has led scientists to hypothesize that when a baby is born with a congenital disorder caused by an error in cell division, the father is the parent more likely to have contributed the gene with the mutation.
This is just one example of why mutation occurs. Many mutations are caused by mutagens—chemical or physical factors that increase the rate of mutation. Some mutagens occur naturally, and some are synthetic. Cosmic rays from space, for instance, are natural, but they are mutagenic. Some naturally occurring viruses are considered mutagenic, since they can insert themselves into host DNA. Hydrogen and atomic bombs are man-made, and they emit harmful radiation, which is a mutagen. Recreational drugs, tobacco, and alcohol also can be mutagens in the bodies of pregnant women. The first mutagens to be identified were carcinogens, or cancer-causing substances. Carcinogens in chimney soot were linked with the chimney sweep's cancer of late eighteenth-century England, discussed in Noninfectious Diseases. In fact, cancer itself is a kind of mutation, involving uncontrolled cell growth. Other environmental factors that are known to bring about mutations include exposure to pesticides, asbestos, and some food additives, many of which have been banned.
Where to Learn More
"Are Mutations Harmful?" Talk. Origins (Web site). <http://www.talkorigins.org/faqs/mutations.html>.
Human Gene Mutation Database, Institute of Medical Genetics, University of Wales College of Medicine (Web site). <http://archive.uwcm.ac.uk/uwcm/mg/hgmd0.html>.
Kimball, Jim. Mutations. Kimball's Biology Pages (Web site). <http://www.ultranet.com/~jkimball/Biology-Pages/M/Mutations.html>.
"Mutations." Brooklyn College, City University of New York (Web site). <http://www.brooklyn.cuny.edu/bc/ahp/BioInfo/SD.Mut.HP.html>.
Patterson, Colin. Evolution. Ithaca: Comstock Publishing Associates, 1999.
Reilly, Philip. Abraham Lincoln's DNA and Other Adventures in Genetics. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press, 2000.
Twyman, Richard M. Advanced Molecular Biology: A Concise Reference. Oxford, UK: Bios Scientific Publishers, 1998.
Weinberg, Robert A. One Renegade Cell: How Cancer Begins. New York: Basic Books, 1998.
Any alteration capable of being replicated in the genetic material of an organism. When the alteration is in the nucleotide sequence of a single gene, it is referred to as gene mutation; when it involves the structures or number of the chromosomes, it is referred to as chromosome mutation, or rearrangement. Mutations may be recognizable by their effects on the phenotype of the organism (mutant).
Gene mutations
Two classes of gene mutations are recognized: point mutations and intragenic deletions. Two different types of point mutation have been described. In the first of these, one nucleic acid base is substituted for another. The second type of change results from the insertion of a base into, or its deletion from, the polynucleotide sequence. These mutations are all called sign mutations or frame-shift mutations because of their effect on the translation of the information of the gene. See also Nucleic acid.
More extensive deletions can occur within the gene which are sometimes difficult to distinguish from mutants which involve only one or two bases. In the most extreme case, all the informational material of the gene is lost.
A single-base alteration, whether a transition or a transversion, affects only the codon or triplet in which it occurs. Because of code redundancy, the altered triplet may still insert the same amino acid as before into the polypeptide chain, which in many cases is the product specified by the gene. Such DNA changes pass undetected. However, many base substitutions do lead to the insertion of a different amino acid, and the effect of this on the function of the gene product depends upon the amino acid and its importance in controlling the folding and shape of the enzyme molecule. Some substitutions have little or no effect, while others destroy the function of the molecule completely.
Single-base substitutions may sometimes lead not to a triplet which codes for a different amino acid but to the creation of a chain termination signal. Premature termination of translation at this point will lead to an incomplete and generally inactive polypeptide.
Sign mutations (adding or subtracting one or two bases to the nucleic acid base sequence of the gene) have a uniformly drastic effect on gene function. Because the bases of each triplet encode the information for each amino acid in the polypeptide product, and because they are read in sequence from one end of the gene to the other without any punctuation between triplets, insertion of an extra base or two bases will lead to translation out of register of the whole sequence distal to the insertion or deletion point. The polypeptide formed is at best drastically modified and usually fails to function at all. This sometimes is hard to distinguish from the effects of intragenic deletions. However, whereas extensive intragenic deletions cannot revert, the deletion of a single base can be compensated for by the insertion of another base at, or near, the site of the original change. See also Gene; Genetic code.
Chromosomal changes
Some chromosomal changes involve alterations in the quantity of geneticmaterial in the cell nuclei, while others simply lead to the rearrangement ofchromosomal material without altering its total amount. See also Chromosome.
Origins of mutations
Mutations can be induced by various physical and chemical agents or can occur spontaneously without any artificial treatment with known mutagenic agents.
Until the discovery of x-rays as mutagens, all the mutants studied were spontaneous in origin; that is, they were obtained without the deliberate application of any mutagen. Spontaneous mutations occur unpredictably, and among the possible factors responsible for them are tautomeric changes occurring in the DNA bases which alter their pairing characteristics, ionizing radiation from various natural sources, naturally occurring chemical mutagens, and errors in the action of the DNA-polymerizing and correcting enzymes.
Spontaneous chromosomal aberrations are also found infrequently. One way in which deficiencies and duplications may be generated is by way of the breakage-fusion-bridge cycle. During a cell division one divided chromosome suffers a break near its tip, and the sticky ends of the daughter chromatids fuse. When the centromere divides and the halves begin to move to opposite poles, a chromosome bridge is formed, and breakage may occur again along this strand. Since new broken ends are produced, this sequence of events can be repeated. Unequal crossing over is sometimes cited as a source of duplications and deficiencies, but it is probably less important than often suggested.
In the absence of mutagenic treatment, mutations are very rare. In 1927 H. J. Muller discovered that x-rays significantly increased the frequency of mutation in Drosophila. Subsequently, other forms of ionizing radiation, for example, gamma rays, beta particles, fast and thermal neutrons, and alpha particles, were also found to be effective. Ultraviolet light is also an effective mutagen. The wavelength most employed experimentally is 253.7 nm, which corresponds to the peak of absorption of nucleic acids.
Some of the chemicals which have been found to be effective as mutagens are the alkylating agents which attack guanine principally although not exclusively. The N7 portion appears to be a major target in the guanine molecule, although the O6 alkylation product is probably more important mutagenically. Base analogs are incorporated into DNA in place of normal bases and produce mutations probably because there is a higher chance that they will mispair at replication. Nitrous acid, on the other hand, alters DNA bases in place. Adenine becomes hypoxanthine and cytosine becomes uracil. In both cases the deaminated base pairs differently from the parent base. A third deamination product, xanthine, produced by the deamination of guanine, appears to be lethal in its effect and not mutagenic. Chemicals which react with DNA to generate mutations produce a range of chemical reaction products not all of which have significance for mutagenesis.
Significance of mutations
Mutations are the source of genetic variability, upon which natural selection has worked to produce organisms adapted to their present environments. It is likely, therefore, that most new mutations will now be disadvantageous, reducing the degree of adaptation. Harmful mutations will be eliminated after being made homozygous or because the heterozygous effects reduce the fitness of carriers. This may take some generations, depending on the severity of their effects. Chromosome alterations may also have great significance in evolutionary advance. Duplications are, for example, believed to permit the accumulation of new mutational changes, some of which may prove useful at a later stage in an altered environment.
Rarely, mutations may occur which are beneficial: Drug yields may beenhanced in microorganisms; the characteristics of cereals can be improved.However, for the few mutations which are beneficial, many deleterious mutationsmust be discarded. Evidence suggests that the metabolic conditions in thetreated cell and the specific activities of repair enzymes may sometimespromote the expression of some types of mutation rather than others. See also Deoxyribonucleic acid (DNA).
A mutation is any heritable change in the genome of an organism. For a population, heritable mutations provide the source of genetic variation, without which evolution could not occur: If all individuals of a species were genetically identical, every subsequent generation would be identical regardless of which members of the species reproduced successfully. For an individual organism, mutations are rarely beneficial, and many cause genetic diseases, including cancer. For researchers, mutations (either spontaneous or introduced) provide important clues about gene location and function.
Phenotypic Effects and Evolution
Mutations in the germ-line cells are heritable and provide the raw material upon which natural selection operates to produce evolution. Mutations in somatic cells, which are cells that are not germ line, are not heritable but may lead to disease in the organism possessing them.
Most mutations do not cause disease and are said to be "silent" mutations. This is for at least two reasons. First, most DNA does not code for genes, so changes in the sequence do not affect the types or amounts of protein made and there is no change in the phenotype of the organism. Second, most sexually reproducing organisms are diploid, meaning they possess two copies of every gene. Many types of mutation simply disable one copy, leaving the other intact and functional. Therefore these mutations display a recessive inheritance pattern, with no effect on phenotype unless an individual inherits two copies of the mutation. Diploid species can accumulate a large pool of such recessive mutations, which are mostly disadvantageous and thus contribute to the burden of genetic disease.
Some mutations lead to detrimental alterations of the normal pheno-type and are, therefore, selected against. Very occasionally, the mutant phenotype is superior and provides a selective advantage, which leads to an increase in the frequency of this mutant allele and, thus, to evolution of the population. Alternatively, a disadvantageous mutation in one environment may become advantageous in another, again leading to increased frequency of this allele.
Molecular Basis of Mutations
DNA is composed of a double helix, each side of which is a long string of four types of nucleotides. Each nucleotide possesses identical sugar-phosphate groups that contribute to the DNA backbone but differs in the structure of the base suspended between the two backbones. The bases are adenine, thymine, cytosine, and guanine (A, T, C, G). Because of their structure, A pairs only with T across the double helix, and C only with G.
Within genes, the sequence of DNA encodes a sequence of amino acids used to build a protein. The DNA is read in triplets of bases, with each triplet coding for an amino acid. With the recognition that the genetic information lies in the sequence of bases in the DNA, it became possible to understand the chemical nature of gene mutations and how these could be as stable as the original allele of the gene.
Consideration of the genetic code linking DNA and amino acids reveals how mutations can either alter a protein, have no effect, or prevent it from being produced entirely. Mutations fall into four broad categories (point mutations, structural chromosomal aberrations, numerical chromosomal aberrations, and transposon-induced mutations), each of which may be subdivided further.
Point Mutations
"Point mutations" are small changes in the sequence of DNAbases within a gene. These are what are most commonly meant by the word "mutation." Point mutations include substitutions, insertions, and deletions of one or more bases.
If one base is replaced by another, the mutation is called a base substitution. Because the DNA is double-stranded, a change on one strand is always accompanied by a change on the other (this change may occur spontaneously during DNA replication, or it can be created by errors during DNA repair. Consequently, it is often difficult to know which base of the pair was mutated and which was simply the result of repairing the mismatch at the mutation.
For example, the most common mutation in mammalian cells is the substitution of a G-C pair with an A-T pair. This could arise if G is replaced by A and subsequently the A is replicated to give T on the other strand. Alternatively, the C could be replaced by a T and the T could then be replicated to give an A on the complementary strand, the final result being the same. It is believed that the G-C to A-T conversion most commonly begins with a C-to-T mutation. This is because most of these mutations occur at DNA sequences in which C is methylated (i.e., chemically modified by the addition of a-CH3 group). The methylated form of C can be converted to a base that resembles T (and thus pairs with A) by removal of an-NH2 group (deamination)—a relatively common event.
Base substitution mutations are classified as transitions or transversions. Transitions are mutations in which one pyrimidine (C or T) is substituted by the other and one purine (G or A) is substituted on the complementary strand. The G-C to A-T conversion is a transition mutation, since C becomes T.
Transversions are mutations in which a purine is replaced by a pyrimidine or vice versa. Sickle cell anemia is caused by a transversion: T is substituted for A in the gene for a hemoglobin subunit. This mutation has arisen numerous times in human evolution. It causes a single amino acid change, from glutamic acid to valine, in the β subunit of hemoglobin. Sickle cell anemia was the first genetic condition for which the change in the protein was demonstrated in 1954 by Linus Pauling (a Nobel laureate from the California Institute of Technology) and subsequently shown to be a single amino acid difference by Vernon Ingram (a Nobel laureate from the Massachusetts Institute of Technology).
Base substitutions are sometimes silent mutations—mutations that do not change the amino acid sequence in the protein encoded by the gene. Silent mutations are possible because the original and mutated sequences can code for the same amino acid, given the redundancy of the genetic code. In the divergence between sea urchins and humans, for example, one of the histone proteins has only two amino acid substitutions, although the gene has many base pair substitutions. Histones are proteins around which DNA is wrapped in chromosomes. The very close similarity in sequence between such distantly related organisms is an indication of how critical the structure is for the function: Most mutations that change it are very disadvantageous.
One type of substitution mutation that almost always inactivates the gene is mutation to a stop codon. A stop codon ends the assembly of the protein, and a truncated protein is usually not active biochemically. Many recessive genetic diseases occur when a mutation converts a coding triplet to a stop codon.
Other mutations involve the insertion or deletion of one or more base pairs in the DNA. When they occur in genes, such mutations typically inactivate the encoded protein, because they change the "reading frame" of the gene. The DNA sequence is translated in groups of three nucleotides. Insertion or deletion of a nucleotide changes the sets of triplets, and thus every subsequent amino acid is altered, changing the protein completely, as shown in Figure 2. Stop codons also frequently arise from insertions or deletions.
Naturally occurring trinucleotide repeat sequences (e.g., CAGCAG CAGCAG) are hot spots for certain important human mutations that involve the insertion of more copies of the repeated sequence. For example at the locus for Huntington's disease, a sequence of 10-29 copies of CAG is normal and stable, but if there are 30-38, there is a high rate of mutation to increased numbers of copies, and if there are 39 or more copies, middle-age dementia called Huntington's disease results.
Functional Consequences and Inheritance Patterns
Mutations can be classified by their functional consequences. Mutations that inactivate the resulting protein, or prevent it from being made at all, are called loss-of-function mutations. These are usually recessive, since the organism still retains one functional copy on the other chromosome. Loss-of-function mutations may be dominant if the organism cannot compensate for the loss by using the other gene copy. Gain-of-function mutations are those in which the protein takes on a new function, or loses the ability to be regulated by other proteins. These mutations are typically dominant, since the new function may be deleterious even in the presence of a normal protein, encoded by the other gene copy.
Chromosomal Aberrations and Transposons
"Structural chromosomal aberrations," the second category of mutations, arise when DNA in chromosomes is broken. The broken ends may remain unrepaired or may be joined with those of another break, to form new combinations of genes, such as translocations. A translocation between chromosomes 8 and 21 in humans causes acute myeloid leukemia by increasing the activity of c-myc, a gene involved in cell replication.
Translocations often cause human infertility, because they interfere with the normal distribution of chromosomes during meiosis. Chromosomes pair up before separating, as eggs or sperm are formed, and the correct pairing depends on matching sequences between them. Structural aberrations also include inversions and duplications of pieces of chromosomes.
Most chromosomal aberrations lead to the formation of chromosomal fragments without centromeres. Centromeres are crucial for proper chromosomal division, during both mitosis and meiosis. Therefore a chromosomal fragment is likely to be lost from one of the daughter cells formed after cell division.
Structural aberrations are nonetheless common in evolutionary history. As a result, although the chromosomes of mouse and man are quite different in appearance, most genes have the same neighbors in the two species, representing the ancestral mammalian arrangement, even if they have been moved to another chromosome as shown in Figure 3.
"Numerical chromosomal aberrations," the third category of mutations, are changes in the number of chromosomes. In some cases, the whole genome has been duplicated (called polyploidy) and the mutant has, for example, four of each chromosome (and is thus tetraploid) rather than the usual two (diploid, as in humans). These are much more common in the evolution of plants than animals. In other cases, only one or a few of the chromosomes are involved, which is referred to as aneuploidy. Down syndrome, in which a person has an extra chromosome 21, is an example of such a mutation. Aneuploidy may also involve the loss of a chromosome. The absence of one of the sex chromosomes, X or Y, is a mutation in humans that results in Turner's syndrome, in which there is only one X.
"Transposon-induced mutations" are the fourth category of mutations. Transposable genetic elements (transposons) are pieces of DNA that can copy themselves and insert into a new location in the genome. They were first discovered by Barbara McClintock, a U.S. geneticist and Nobel laureate in 1950. When transposons jump into a new position, the insertion may disrupt a gene and thus mutate it, usually inactivating it. Sometimes the transposon jumps again, and the activity of the gene it leaves is restored. Often, however, the transposon stays in the original position, permanently disrupting the gene. Some forms of hemophilia are due to transposon insertion. Transposon mutations have been extremely common in human evolution, and such mutations are still occurring.
Mutations in Research and Medicine
Early geneticists treasured mutations in the organisms they studied, since no characteristic can be studied genetically unless heritable variants exist. If, for example, everyone had brown eyes, nothing could be learned about the inheritance of eye color, as all generations would have the same color of eyes. For this reason, geneticists collected and propagated all the mutants they could find, and methods were developed to deliberately induce mutations, a process called mutagenesis. Such techniques include exposing their experimental organisms to X rays and chemicals.
Transposons can also be deliberately used to introduce mutations in model organisms. In the plant Arabidopsis thaliana and in the fruit fly Drosophila melanogaster, transposon mutagenesis is often used to induce mutations, as the mutation can be very rapidly cloned and mapped with the transposon's DNA sequence as starting point.
Comparing existing mutations can help determine the evolutionary relatedness of two organisms. During evolution, there has been a relatively constant rate of accumulation of mutations in genes for a number of proteins, so the number of changes can be used to estimate the time since two species had a common ancestor. This is called the molecular clock and is illustrated in Figure 1. Each gene has evolved at a characteristic rate—the result of mutation rates, selection, and chance changes in the gene pool.
Advances in genetics have only intensified the search for mutations, especially in complex traits such as behavior and cancer, as the key to finding the genes involved and then unraveling the underlying mechanisms. This involves mapping the mutations, cloning the genes, and studying the mutants to discover what biochemical processes are changed in the mutants.
Mutations are believed to underlie most, if not all cancers. Cancer-causing mutations found so far include genes involved in communication between cells (signal transduction) and in the control of cell division. Many of these genes have been categorized into two broad classes: oncogenes and tumor suppressor genes. The mutation that has been found most often, in a tumor suppressor gene called p53, usually arises as a somatic mutation but can also be inherited as Li Fraumeni syndrome.
Xeroderma pigmentosum is an autosomal recessive condition in which the ability to repair DNA damage induced by UV light is defective. Many mutations are produced, and the affected people have large numbers of skin cancers.
Bibliography
Drake, John W. "Spontaneous Mutation." Annual Review of Genetics 25 (1991): 125-46.
Hartwell, Leland H., et al. Genetics: From Genes to Genomes. Boston: McGraw-Hill,2000.
Lewis, Ricki. Human Genetics: Concepts and Applications, 4th ed. Boston: McGraw-Hill,2001.
Pauling, Linus, et al. "Sickle Cell Anemia, a Molecular Disease." Science 110 (1949):543-548.
Internet Resource
International Agency for Research on Cancer. http://www.iarc.fr/.
—John Heddle