What is mutation?

The Function of Genes

An
individual is not a random assortment of characteristics. The way individuals look, their physiological makeup, their 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. For each characteristic, an individual has two copies of the gene controlling that characteristic. The gene can have two forms, called alleles. For example, the alleles for eye color can be designated using the letters B and b, with the B allele carrying the information for brown eyes and the b allele specifying blue eyes. Thus the genotype, or genetic makeup, of an individual 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 have brown eyes since the brown allele is dominant over the blue one. The dominant allele will always be expressed, whether present as two copies or only one. For a recessive allele to be expressed, an individual must have two recessive alleles (bb).

When a person reproduces, he or she passes 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 homozygous 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 heterozygous person will pass on the dominant allele to 50 percent of his or her children, on average; the other 50 percent will receive the recessive allele. Alleles are passed on in the sex cells—the eggs and sperm. Eggs and sperm are produced by a special type of cell division, meiosis, that reduces by half the amount of genetic information carried by the cell. When an egg is fertilized by a sperm cell, the amount of genetic information is once again doubled. In “normal” cell division, called mitosis, the amount of genetic material in each cell is kept constant. 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, one can predict the eye color for children of a brown-eyed husband and blue-eyed wife. Assuming that the husband comes from a family of only brown-eyed people, one can be fairly certain that he is homozygous for this trait (BB). Since his wife has blue eyes, and blue is recessive, she must be 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.

One can take this example a step further and predict the outcome for the next generation. If one of this couple’s brown-eyed sons marries a blue-eyed woman, then one can predict the eye colors of their children using a simple diagram called a Punnett square. (Reginald Crundall Punnett contributed much to the early study of genetics.)

Using this simple tool, with the possible alleles in the sperm cells along the top and those from the eggs down the side, one can show all the possible combinations of inherited alleles (see figure 1). These boxes represent the genotypes of the fertilized eggs. In this case, one would expect about half of their children to have brown eyes (the Bb boxes) and half to have blue eyes (the bb boxes). Since chance determines exactly which sperm actually fertilizes the egg in every conception event, however, such a prediction is not always accurate. Nevertheless, the more children they have, the closer the actual percentage of brown-eyed or blue-eyed children will be to half.

Actually, the inheritance of eye color is somewhat more complicated than it is described above. Several genes contribute to eye color. Depending on the mix of dominant and recessive alleles for each gene involved, eye color can range from pale blue to dark brown. Other combinations produce green eyes.

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: By chance, the egg and sperm that united had more than the usual share of “tall” alleles.

The preceding examples have used genes that have only two alleles: brown or blue, tall or short. There are genes, however, for which more than two alleles are possible—although any one individual may have only two alleles in his or her genetic makeup. A good example of such a gene is the one that controls human blood type. There are three blood type 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. Similarly, the B allele causes the production of a different chemical. The O allele produces no chemical at all. If a chemical not already present in the blood is introduced, such as in 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 a blood type example to show how parents can produce children who are genetically unlike both parents. The mother has type A blood and is heterozygous (AO), while the father has type B blood and is also heterozygous (BO). Their child could have any of the four blood types.

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
chromosomes in each cell. This explains how an individual can have two alleles for each gene, one on each chromosome of a pair. The exception 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 and thus have two alleles for every gene found on the X chromosome. Males have only one X chromosome; therefore, they only have one allele for those genes carried on the X. The Y chromosome of the male has been shown to carry very little, although important, genetic information. Genes carried on the X chromosome are called sex-linked, since they typically are expressed in only one sex—the male. Females may be merely carriers of a sex-linked trait.

One sex-linked trait is the disorder called 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 trait for hemophilia marries a man who does not have the disorder. Hemophilia is a recessive condition; therefore, the woman 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 and she is perfectly normal. 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. About half of them will be carriers for the trait, but there is no way of knowing which ones they are. Of the sons, one half will be normal and the other half will suffer 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 process that created the variety originally, and it can continue to add to it today.

A human being begins as a single fertilized cell. That cell contains two copies of the genetic information 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. In order 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 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 molecule resembles a spiral staircase. The outside rails are strings of sugar molecules hooked together by phosphate groups. The steps are made of 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 nucleotide 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 on to future generations.

The mistake will not be detected until the section of DNA that contains it is actually used by the cell to make a specific 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 amino acid 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. During human evolution, an individual may have been able to live slightly longer if the mutated protein was slightly improved in function. The longer that he or she lived, the greater was the chance that the individual could produce offspring—who would also have the mutated gene. In this way, positive, useful mutations became more common in the population. A change that made the protein less functional was less likely to be reproduced since the individual possessing the mutation may not have lived long enough to have children.

A slight change in a protein can make a very 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. The amino acid, however, is in a critical position. With the changed amino acid, 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 black population. To understand how this can be, one must consider the heterozygous individual. With one normal allele and one mutant one, such an individual makes 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 the other
two genotypes, this mutant allele not only has been maintained but even has increased in the black population in Africa.

Perspective and Prospects

The modern study of genetics is conducted mostly at the molecular level. One project has identified every human gene and 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, and the bacteria 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 his or her 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 fetus still in the womb. For example, a condition called
phenylketonuria (PKU) can cause severe mental retardation 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 have not stopped occurring 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 abdomen of a patient being x-rayed. Lead prevents the x-rays 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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