Figure 514

A deletion mutation caused by the loss of a single base G in one of the two DNA strands causes a misreading of all code words beyond the point of the mutation.

Vander et al.: Human Physiology: The Mechanism of Body Function, Eighth Edition

PART ONE Basic Cell Functions would die. In contrast, if the active enzyme were involved in the synthesis of a particular amino acid, and if the cell could also obtain that amino acid from the extracellular fluid, the cell function would not be impaired by the absence of the enzyme.

To generalize, a mutation may have any one of three effects upon a cell: (1) It may cause no noticeable change in cell function; (2) it may modify cell function, but still be compatible with cell growth and replication; or (3) it may lead to cell death.

With one exception—cancer, to be described later—the malfunction of a single cell, other than a sperm or egg, as a result of mutation usually has no significant effect because there are many cells performing the same function in the individual. Unfortunately, the story is different when the mutation occurs in a sperm or egg. In this case, the mutation will be passed on to all the cells in the body of the new individual. Thus, mutations in a sperm or egg cell do not affect the individual in which they occur but do affect, often catastrophically, the child produced by these cells. Moreover, these mutations may be passed on to some individuals in future generations descended from the individual carrying the mutant gene.

DNA Repair Mechanisms Cells possess a number of enzymatic mechanisms for repairing DNA that has been altered. These repair mechanisms all depend on the damage occurring in only one of the two DNA strands, so that the undamaged strand can provide the correct code for rebuilding the damaged strand. A repair enzyme identifies an abnormal region in one of the DNA strands and cuts out the damaged segment. DNA polymerase then rebuilds the segment after base-pairing with the undamaged strand just as it did during DNA replication. If adjacent regions in both strands of DNA are damaged, a permanent mutation is created that cannot be repaired by these mechanisms.

This repair mechanism is particularly important for long-lived cells, such as skeletal muscle cells, that do not divide and therefore do not replicate their DNA. This means that the same molecule of DNA must continue to function and maintain the stability of its genetic information for as long as the cell lives, which could be as long as 100 years. One aspect of aging may be related to the accumulation of unrepaired mutations in these long-lived cells.

Mutations and Evolution Mutations contribute to the evolution of organisms. Although most mutations result in either no change or an impairment of cell function, a very small number may alter the activity of a protein in such a way that it is more, rather than less, active, or they may introduce an entirely new type of protein activity into a cell. If an organism carrying such a mutant gene is able to perform some function more effectively than an organism lacking the mutant gene, it has a better chance of reproducing and passing on the mutant gene to its descendants. On the other hand, if the mutation produces an organism that functions less effectively than organisms lacking the mutation, the organism is less likely to reproduce and pass on the mutant gene. This is the principle of natural selection. Although any one mutation, if it is able to survive in the population, may cause only a very slight alteration in the properties of a cell, given enough time, a large number of small changes can accumulate to produce very large changes in the structure and function of an organism.

The Gene Pool Given the fact that there are billions of people living on the surface of the earth, all carrying genes encoded in DNA and subject to mutation, any given gene is likely to have a slightly different sequence in some individuals as a result of these ongoing mutations. These variants of the same gene are known as alleles, and the number of different alleles for a particular gene in the population is known as the gene pool. At conception, one allele of each gene from the father and one allele from the mother are present in the fertilized egg. If both alleles of the gene are identical, the individual is said to be homozygous for that particular gene, but if the two alleles differ, the individual is heterozygous.

The set of alleles present in an individual is referred to as the individual's genotype. With the exception of the genes in the sex chromosomes, both of the homologous genes inherited by an individual can be transcribed and translated into proteins, given the appropriate signals. The expression of the genotype into proteins produces a specific structural or functional activity that is recognized as a particular trait in the individual and is known as the person's pheno-type. For example, blue eyes and black eyes represent the phenotypes of the genes involved in the formation of eye pigments.

A particular phenotype is said to be dominant when only one of the two inherited alleles is required to express the trait, and recessive when both inherited alleles must be the same—that is, the individual must be homozygous for the trait to be present. For example, black eye color is inherited as a dominant trait, while blue eyes are a recessive trait. If an individual receives an allele of the gene controlling black eye pigment from either parent, the individual will have black eyes. A single copy of the allele for black eye color is sufficient to express the proteins forming black eye pigment. In contrast, the expression of the blue-eyed phenotype occurs only when both alleles in the individual code for a protein able to form the blue-eyed

Vander et al.: Human Physiology: The Mechanism of Body Function, Eighth Edition

Genetic Information and Protein Synthesis CHAPTER FIVE

Genetic Information and Protein Synthesis CHAPTER FIVE

pigment. Although genes are often described as dominant or recessive, it is the activity or lack of activity of the proteins expressed by the genes that determines the phenotypic characteristics observed.

Genetic Disease Many diseases are referred to as "genetic"—that is, due to abnormal structure or function resulting from the inheritance of mutant genes, rather than the result of microbial infections, toxic agents, or improper nutrition. Over 4000 diseases are linked to genetic abnormalities, and these diseases are currently a major cause of infant mortality. Genetic diseases can be inherited as either a dominant or recessive trait. Let us look at a few examples.

Familial hypercholesterolemia is an autosomal dominant disease affecting 1 in 500 individuals. These individuals have elevated blood levels of cholesterol because of a defect in a plasma-membrane protein involved in cholesterol removal from the blood and are, therefore, at increased risk of developing heart disease. Inheritance of only a single mutant allele from either the mother or father is sufficient to produce this condition.

Cystic fibrosis, an autosomal recessive disease, is the most common lethal genetic disease among Caucasians, with a prevalence of about 1 in 2000 births. Because of a defective mechanism for the transfer of fluid across epithelial membranes (to be discussed in Chapter 6), various ducts in the lungs, intestines, and reproductive tract become obstructed, with the most serious complications generally developing in the lungs and leading to death from respiratory failure. An individual must inherit a mutant allele from both parents in order for this recessive disease to be expressed. Individuals who are heterozygous, having only one copy of the mutant allele, do not show the symptoms of the disease because a single copy of the normal allele is sufficient to produce the protein required to maintain epithelial fluid transport. However, such individuals are carriers who are able to transmit the mutant allele to their offspring.

Familial hypercholesterolemia and cystic fibrosis are examples of single gene diseases, as are sickle-cell anemia, hemophilia, and muscular dystrophy. Two other recognized classes of genetic disease are chromosomal and polygenic diseases, both of which require the expression or lack of expression of multiple genes to produce the phenotypic trait. Chromosomal diseases are the result of the addition or deletion of chromosomes or portions of chromosomes during the process of reducing the 46 chromosomes to 23 during the formation of egg and sperm cells (to be discussed in Chapter 19). The classic example of a chromosomal disease is Down's syndrome (trisomy 21), in which the fertilized egg has an extra copy, or translocation, of chromosome 21. This abnormality occurs in approxi mately 1 of every 800 births and is characterized by retardation of growth and mental function. Other forms of chromosomal abnormalities are the major cause of spontaneous abortions or miscarriages.

Polygenic diseases result from the interaction of multiple mutant genes, any one of which by itself produces little or no effect, but when present with other mutant genes produces disease. This category of genetic disease is involved in most forms of the major diseases in our modern society, such as diabetes, hypertension, and cancer.

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