Mutation

• BIOLOGY
• ANATOMY OR SYSTEM INVOLVED: Cells, immune system

DEFINITION: An error in the process that copies genetic information for each new generation, resulting in an alteration in the organism that can be beneficial, harmful, or neutral.

The Function of Genes

An individual is not a random assortment of characteristics. An individual's appearance, physiological makeup, susceptibility to disease, and even how long they may live are determined by information received from their parents. The smallest unit of information for inherited characteristics is the gene. An individual inherits two copies of each gene, one from each parent.

The different forms a gene takes are called alleles. In many cases, alleles can be classified as either dominant or recessive. For example, imagine that eye color is determined by a single gene with only two alleles: one designated B, for brown eyes, and one designated b, for blue eyes. (In fact, eye color is determined by several genes, each with multiple possible alleles; depending on the mix of dominant and recessive alleles for each gene involved, eye color can range from pale blue to dark brown, while other combinations produce green eyes.) In this example, B is dominant, while b is recessive. Thus, an individual's genotype, or genetic makeup, for eye color can be one of three types: BB, bb, or Bb. A BB individual will have brown eyes. A bb person will have blue eyes. A Bb individual will also have brown eyes, because when a dominant allele (B) is combined with a recessive allele (b), the dominant allele will always be the one expressed. For a recessive allele to be expressed, an individual must have two recessive alleles (bb).

When a person reproduces, they pass on one allele for each gene to the child. Therefore, the child also has two alleles for each gene, one from each parent. A person with two identical alleles for a given gene is said to be for that trait and can pass on only one kind of allele. Someone with two different alleles for a particular gene is said to be heterozygous. A person has a 50 percent chance of passing on the dominant allele and a 50 percent chance of passing on the recessive allele.

Alleles are passed to offspring in the sex cells, the eggs (or ova) and the sperm. Eggs and sperm undergo a special type of cell division called meiosis, which produces four daughter cells that carry half the amount of genetic information—that is, half the number of chromosomes—contained in the parent cell. (Non-sex cells divide via mitosis, which produces daughter cells with the same number of chromosomes as the parent cell.) When an egg is fertilized by a sperm cell, the amount of genetic information is once again doubled. After fertilization, the egg cell divides repeatedly by mitosis to produce the millions of cells that make up the embryo—and, later, the adult organism.

If the genetic makeup of a couple for a given trait is known, the probable characteristics of their children for this trait can be predicted. For example, returning to the simplified example of eye color, one can predict the eye color for children of a brown-eyed father and a blue-eyed mother. Because the mother has blue eyes, and blue is recessive, she must be homozygous for this trait (bb). If the father is homozygous for the other allele (BB), their children will each have a brown allele from their father and a blue allele from their mother; they will all be heterozygous (Bb). Since brown is dominant, they will all have brown eyes.

If, on the other hand, the father is heterozygous (Bb), then one can predict the likely eye colors of their children using a simple diagram called a Punnett square. By dividing a square into a grid, with the possible alleles from the sperm cells (B and b) along the top and those from the eggs (b and b) down the side, one can show all the possible combinations of inherited alleles. In this case, the combination of Bb and bb results in two possible Bb genotypes and two possible bb genotypes. Therefore, each child born to these parents will have a 50 percent chance of having brown eyes (Bb) and a 50 percent chance of having blue eyes (bb). Because each act of conception is statistically independent from those preceding it, this does not necessarily mean that half the couple's children will have brown eyes and half will have blue eyes. Nevertheless, the more children they have, the closer the actual percentage of brown-eyed or blue-eyed children will be to half.

In most cases, genetic inheritance is not quite so simple. Many traits—including eye color, as mentioned above—are controlled by multiple genes, a phenomenon known as polygenic inheritance. In addition, many genes do not show complete dominance. For example, evidence shows that height is controlled by several genes that exhibit incomplete dominance. One homozygous individual (TT) will be tall, the other (tt) will be short, and the heterozygous individual (Tt) will be of medium height. The laws that determine how the alleles may be passed on from generation to generation, however, are exactly the same. One can use a simplified example of two people who are heterozygous for a hypothetical height gene. If both parents are heterozygous, each will be able to produce two kinds of sex cells, those with “tall” alleles and those with “short” alleles. From all the possible outcomes shown in the boxes of the Punnett square, one would predict 25 percent tall (TT), 25 percent short (tt), and 50 percent medium-height (Tt) children.

If several genes are involved, a wide range of heights is possible. A person who is homozygous for the “tall” alleles in most of the height genes will be very tall. Someone homozygous for most of the “short” alleles will be short. Someone who is heterozygous in most of these genes will be of medium height. Since even relatively short people will have some “tall” alleles, and since chance determines which sex cells are actually used, it is possible for two short people to have a tall child, if the egg and sperm that unite have more than the usual share of “tall” alleles.

The preceding examples posited genes with only two alleles: brown or blue, tall or short. In most cases, however, a gene will have more than two possible alleles, although any one individual will still have only two alleles for that gene in his or her genetic makeup. A good example of such a gene is the one that controls human blood type. There are three alleles: A, B, and O. The A and B alleles are dominant, while the O allele is recessive. This allows for the various types of blood. A person with an A allele produces a particular chemical in the blood, a person with a B allele produces a different chemical, and a person with an O allele produces no chemical at all. If a chemical not already present in the blood is introduced, such as during a blood transfusion, the body will react against it, destroying the new blood. Since people with type O blood produce neither chemical, they are sometimes referred to as “universal donors.” Their blood can be given safely to anyone. Similarly, people with AB blood can receive any other blood type because their bodies already contain both types of chemical.

One can also use blood type to show how parents can produce children who are genetically unlike both parents. If the mother is heterozygous for type A blood (AO) and the father is heterozygous for type B blood (BO), their child could have any of the four blood types (AO, BO, AB, or OO). Although blood type is not an obvious visible feature, many genes that express themselves in an individual’s appearance behave in a similar manner. Therefore, one should not be surprised to see two parents with a child who resembles neither of them.

The genes that control heredity actually consist of strands of deoxyribonucleic acid (DNA) that make up the chromosomes. Humans have twenty-three pairs of in each cell, or forty-six chromosomes total. This explains how an individual can have two alleles for each gene: each allele is located in the same position, or locus, on each chromosome of a pair. The exception to this rule is the sex chromosomes, which are different in males and females. Sex chromosomes come in two kinds, a relatively large X and a small Y. The X chromosomes can carry many more genes than the Y. Females have two X chromosomes (XX) and thus have two alleles for every gene found on the X chromosome. Males have one X chromosome and one Y chromosome (XY); therefore, they only have one allele for those genes carried on the X. (The Y chromosome has been shown to carry very little genetic information, although what it does carry is important.)

Genes carried on the X or Y chromosome are called sex-linked, since they typically are expressed in only one sex—the male—while females often carry but do not express such traits. For example, if a disease is caused by a recessive X-linked allele, any male who inherits that allele will express the disease because they will not have a second, dominant allele to suppress it; meanwhile, a female may carry the same recessive allele but not express it if her other X chromosome carries a dominant allele. And, of course, any allele carried on the Y chromosome can only be expressed in those who inherit a Y chromosome.

One sex-linked trait is the disorder hemophilia. A hemophiliac fails to produce a chemical that allows the blood to clot. This disorder is usually fatal if the hemophiliac is not constantly supplied with the clotting factor; such an individual would simply bleed to death following even the slightest injury. Suppose that a woman who carries the allele for hemophilia marries a man who does not have the disorder. Hemophilia is a recessive condition; therefore, assuming that the woman does not herself have hemophilia—which is very rare (though not impossible) because she would have to have two copies of the same defective allele—she has one normal X chromosome and one bearing the recessive allele (denoted by Xh). Since the normal allele directs the production of the clotting factor, her blood can clot normally. Since her husband is not a hemophiliac, his one X chromosome must bear the normal allele. One can use a Punnett square to predict the likelihood of their children inheriting the disease. Each of their daughters will have a 50 percent chance of being a carrier for the trait, but without genetic testing there is no way of knowing whether they actually are. Each of their sons, meanwhile, will have a 50 percent chance of suffering from hemophilia.

How Mutations Occur

There is a variety of genetic information in the human population, leading to a diversity of internal and external features. The process of sexual reproduction randomly selects among that variety for each new individual who is born. Mutation is the continual process that created the variety originally.

A human being begins as a single fertilized cell. That cell contains the two alleles for each gene (potentially barring the sex-linked genes) in its twenty-three pairs of chromosomes. The cell divides constantly during growth and development to produce the millions of cells that make up an adult. Each one of those cells, with very few exceptions, also has twenty-three pairs of chromosomes. For each cell to have its own double copy of information, the DNA that makes up the chromosomes must replicate, once for each cell division. This process of DNA replication must ensure that the information contained in the DNA is copied exactly, and for the most part, it is.

To understand how a mistake can occur, one must look at the structure of DNA, the genetic blueprint. The DNA resembles a spiral staircase. The outside rails are strings of sugar molecules hooked together by phosphate groups. The steps are made of nucleobases, or bases, that project from each sugar-phosphate backbone toward the middle. The information is contained in the sequence of base pairs that make up the steps of the staircase. The bases that can form such a pair are determined by their shape and bonding properties. Of the four bases, only two pairs are possible. Adenine (A) always pairs with thymine (T), leaving cytosine (C) and guanine (G) to form the other pair. This structure explains the accuracy with which DNA replicates. During replication, the original molecule unwinds from its spiral structure. The two strands separate, and a new, complementary strand forms on each of the original strands. The order of bases on the new strand is determined by the original strand and the base-pairing rules. Where there is an A in the old strand, there must be a T in the new one. The other bases will not fit because they do not have the correct shape or bonding properties. Similarly, where the old strand has a C, the new one must have a G. Each base is attached to a deoxyribose sugar and a phosphate group, all three forming a nucleotide. Once all proper nucleotides are linked together, the new strand is complete, the original DNA is rewound, and there are two molecules where there once was one.

The accuracy with which the DNA template is copied is impressive. It has been estimated that an error occurs only once for every 100,000 nucleotides copied. The replication of DNA is a chemical process that relies on random movements of molecules to put the correct ones together. There are enzymatic systems to make sure that only the correct nucleotides end up as part of the new DNA strand. There are also error detection and correction mechanisms that can remove an incorrect and replace it with the correct one. This correction process reduces the error rate to one in 10 billion. Nevertheless, with the amount of DNA that has to be copied, mistakes do occur. If a mistake is made in a gamete (sperm or egg cell), the mutated DNA can be passed to future generations.

A mistake in replication will not be detected until the section of DNA that contains it is actually used by the cell to synthesize a protein molecule. At the molecular level, a gene is a section of DNA that has the information necessary to make a particular protein molecule. Proteins are the working molecules of the body; they make up flesh and bone and the enzymes that speed up chemical reactions. The sequence of bases on a DNA molecule codes for the sequence of amino acids that makes up a protein molecule. Since there are twenty commonly used amino acids, and a protein can contain thousands of amino acids, there is an almost infinite number of different protein molecules. A mutation on a DNA molecule will usually mean that one in the protein for which it codes is changed.

Changing one unit in a thousand may not seem very significant, and usually it is not. Such a small change in a protein molecule generally has very little effect on the functioning of that molecule. Perhaps this mutation will make the molecule able to withstand a slightly higher temperature before breaking down. If the protein is an enzyme, the change may speed or slow its reaction time by a little bit. Perhaps an individual may be able to live slightly longer if the mutated protein is slightly improved in function. The longer that individual lives, the greater the chance that he or she could produce offspring who would also have the mutated gene. In this way, positive, useful mutations become more common in the population. A change that makes the protein less functional is less likely to be reproduced, since the individual possessing the mutation may not live long enough to have children. This is the basic mechanism underlying evolution.

However, a slight change in a protein can potentially make a big difference. The hemoglobin (the oxygen-carrying protein in red blood cells) of a person with sickle-cell disease differs from normal hemoglobin by one amino acid. That amino acid is in a critical position; when it is changed, the hemoglobin clumps uselessly in the cell and does not carry oxygen. This is a lethal mutation, as a person afflicted with sickle-cell disease cannot live very long. One would assume that this mutation would not survive in the human population. Yet, in some parts of Africa, the mutant allele is carried by as much as 20 percent of the population. To understand how this can be, one must consider the heterozygous individual. With one normal allele and one mutant one, such an individual would make both kinds of hemoglobin, including enough normal hemoglobin to be able to live comfortably under normal conditions. Moreover, the presence of the altered hemoglobin confers significant resistance to malaria. Because the heterozygous individual has a selective advantage over both homogeneous genotypes, this mutant allele not only has been maintained, but has even increased in the African population.

Perspective and Prospects

The modern study of is conducted mostly at the molecular level. One project has identified every human gene and mapped its location on a specific chromosome. Dubbed the Human Genome Project, it was a cooperative venture among scientists worldwide. This map tells researchers where each gene is located, and it is hoped that the defective copies in people with genetic diseases can be repaired using this knowledge. Genetic engineering techniques have already isolated many genes. For example, the gene for the production of insulin has been identified and extracted from human cells in culture. The gene has been inserted into the chromosomes of bacteria, which are then grown in large quantities in commercial cultures. The insulin that they produce is harvested, purified, and made available to diabetics. This genuine human insulin is more potent than the insulin extracted from animals. In addition, such a process is essential for diabetics who suffer adverse reactions to the inevitable impurities that are found in insulin extracted from animals.

Ultimately, it should be possible to insert a functioning gene, like the one for insulin, directly into an afflicted person’s chromosomes—thus curing the genetic disease. The cured individual, however, would still be able to pass the defective allele on to their children. The possibility of splicing genes into the chromosomes of sex cells does not seem likely in the near future.

More traditional genetics is also of value to prospective parents. A woman with a history of hemophilia in her family would want to know the chances that her children could inherit the disease. A genetic counselor would analyze the family tree of the woman and calculate a statistical probability. Some other genetic diseases can be detected in a still in the womb. For example, a condition called phenylketonuria (PKU) can cause severe mental disabilities and other medical problems. A genetic analysis of prospective parents with a family history of the condition could indicate the likelihood of PKU occurring in their children. If the chances are high, cells of the couple’s child can be extracted and tested early in pregnancy. In the case of PKU, early detection can be used to prevent the effects of the disease. If the diet of the mother and then the newborn are carefully regulated, the toxic chemical that causes the disease will not accumulate in the fetus or newborn.

Genetic mutations continue to occur in modern society. In fact, they are more likely. Many environmental factors have been shown to increase the mutation rate in animals. Several types of radiation and many chemicals can increase the mutation rate. This is why an X-ray technician will place a lead apron over the of a patient being X-rayed. Lead prevents the X-ray from penetrating to the genital organs, where actively dividing DNA is particularly sensitive to the radiation. Such care should always be taken to protect the genetic makeup of future generations.

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