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PRODIGY(R) interactive personal service 08/07/92 2:04 AM ACADEMIC AMERICAN ENCYCLOPEDIA GENETIC DISEASES Genetic diseases are inherited disorders reflecting gene MUTATIONS or abnormalities in chromosome structure or number and resulting in functional or anatomical changes. Common genetic diseases include deformities, such as cleft lip and palate; metabolic disorders, such as phenylketonuria, which results in mental retardation; and albinism, which results in lack of skin pigmentation. In the half-century between 1935 and 1985 infant mortality from infectious disease, primarily diarrhea, declined from 25% to 3%, and infant mortality from BIRTH DEFECTS increased from 5% to 15%. The frequency of chromosome abnormalities in the United States is 1 in about 200 live births. Approximately 50-60% of all recognized spontaneous abortions are chromosomally abnormal. Six in every 100 stillbirths have chromosome abnormalities, and 6 in every 100 neonatal deaths are associated with chromosome defects. GENE TRANSMISSION IN FAMILIES Gene transmission, or HEREDITY, in families is most often identified by the function of an altered GENE. Genetic diseases can be inherited in a manner similar to that of normal traits. These diseases include single-gene disorders that are autosomal dominant, autosomal recessive, or sex-linked recessive. They also include multifactorial disorders, resulting from more than one gene often interacting with environmental factors. Autosomal means that the gene pair is present in a chromosome pair other than the sex chromosomes. SINGLE-GENE DISORDERS Disorders caused by the mutation of a single gene are often called inborn errors of metabolism because they reflect alterations of a biochemical pathway. As a result of the mutation of a single gene, the gene product normally manufactured is absent or is present in low amounts. Therefore, either an important end product is not synthesized in sufficient quantity, or an excessive accumulation of intermediate products that may be toxic occurs. Many inborn errors of metabolism are fatal in early childhood or at best impair health to the extent that the maintenance of proper body function is difficult if not impossible. Autosomal Dominant Genes Copyright (c) 1992 Grolier Electronic Publishing, Inc. All rights reserved. PRODIGY(R) interactive personal service 08/07/92 2:04 AM ACADEMIC AMERICAN ENCYCLOPEDIA GENETIC DISEASES Autosomal dominant genes, of which more than a thousand are fully identified, are expressed in both heterozygous and homozygous individuals. Many are found to be lethal when the individual is homozygous. Dominant traits are usually expressed equally in both the male and the female. If one parent is affected, therefore, each pregnancy involves a 50% risk of recurrence. The sex of the parent contributing the gene can also play a role in the course of the disease (see GENETIC IMPRINTING). An example is HUNTINGTON'S CHOREA, which is characterized by ceaseless, involuntary jerky movements, dementia, and finally death. Symptoms are manifested after 35 years of age, usually after the affected person has had offspring, 50% of whom inherit the disease. Autosomal Recessive Genes Autosomal recessive traits, of which 600 are fully identified, are expressed phenotypically only in homozygotic individuals. Most of these traits, if not all, result from a single-gene mutation affecting a single step in a biochemical pathway. Most autosomal recessive traits are expressed to some extent in heterozygotic individuals, although their physical appearance and general health are normal. These people are known as carriers because they can transmit the gene to their children, who manifest the disease. Usually, affected children will have unaffected carrier parents. Frequently, parents who are closely related, like first cousins, transmit autosomal recessive disorders. The recurrence risk for heterozygous parents is 1 chance in 4, or 25%, for each pregnancy. TAY-SACHS DISEASE, GALACTOSEMIA, and PHENYLKETONURIA are examples of autosomal recessive disorders. In Tay-Sachs disease the affected gene does not produce an enzyme needed to metabolize lipids. As a result, they build up in the brain, causing neurologic deterioration and eventually death. In galactosemia the enzyme that converts the milk sugar galactose to glucose is not produced. Newborns with this disorder who are fed milk accumulate galactose in their blood. The infant develops cataracts, cirrhosis of the liver, and mental retardation. The disorder is reversible by omitting milk and milk products from the child's diet. Children having phenylketonuria (PKU) lack the ability to produce an enzyme that metabolizes the amino acid phenylalanine. Excess phenylalanine causes skin-pigment deficiency and mental Copyright (c) 1992 Grolier Electronic Publishing, Inc. All rights reserved. PRODIGY(R) interactive personal service 08/07/92 2:04 AM ACADEMIC AMERICAN ENCYCLOPEDIA GENETIC DISEASES retardation. Other such disorders include SICKLE-CELL DISEASE and thalassemia (see COOLEY'S ANEMIA). Sex-Linked Recessive Genes In most cases of sex-linked recessive traits, of which 125 are fully identified, the mother is heterozygous but unaffected--she is a carrier. She has a 50% chance of producing affected sons through transmission of an X chromosome carrying the gene mutation. Her daughters have a 50% chance of being heterozygous like the mother. If an affected male is able to reproduce, and marries a homozygous normal female, none of his children will be affected, but all of his daughters will be heterozygous for the sex-linked gene. His sons do not inherit the disease. MUSCULAR DYSTROPHY and HEMOPHILIA are representative sex-linked recessive disorders. In muscular dystrophy male children have weakness and degeneration of their muscles, progressing from extremities to the entire body. Hemophilia, which also affects male children with mothers who are unaffected carriers, is characterized by severe hemorrhaging and the inability of the blood to clot and heal a wound. Sex-Linked Dominant Genes Only a few disorders with sex-linked dominant inheritance are known, such as vitamin D-resistant rickets, which may produce severe bowing of the legs. Mutations occur on the X chromosome, so if the female carries the mutation, recurrence risks are 50% for both female and male progeny; if the male has the disorder, no sons but all of the daughters will be affected. MULTIFACTORIAL INHERITANCE Disorders that reflect the activity of several genes rather than one are known as multifactorial traits. In most cases the environment, especially during pregnancy, plays an important role in determining the severity of the disease in the child. Several relatively common disorders fall into this category; for example, cleft lip and palate, pyloric stenosis (obstruction of the stomach), and spina bifida (defect of the bony spinal column). In general, the recurrence risk for parents who have an affected child is in the range of 3-5%. If Copyright (c) 1992 Grolier Electronic Publishing, Inc. All rights reserved. PRODIGY(R) interactive personal service 08/07/92 2:04 AM ACADEMIC AMERICAN ENCYCLOPEDIA GENETIC DISEASES one parent is affected, the risk for any pregnancy is also in the 3-5% range. CHROMOSOME ABNORMALITIES Chromosome abnormalities constitute an increasing frequency of birth defects. The most common type of chromosome abnormality is a change in total chromosome number. In general, reduction of the total number of autosomes is incompatible with life. An infant with an extra chromosome involving virtually any autosome pair also has a limited life span, with multiple physical abnormalities and mental retardation. The most common chromosomal abnormality is DOWN'S SYNDROME, or mongolism, which involves the chromosome designated as number 21. This defect is termed Trisomy 21 because all cells in the infant's body carry an extra number 21 chromosome. This condition occurs in 1 out of 800 liveborn infants. Maternal age is a factor in the frequency of Down's syndrome; for example, 1 out of 300 mothers in their 30s, and 1 out of 40 mothers over 40 produce such infants. Other well-described trisomies in humans are Trisomy 13 (Patau's syndrome) and Trisomy 18 (Edward's syndrome). Both aberrations are associated with multiple birth defects, including mental retardation and limited life span. All human chromosome abnormalities can be detected in the developing fetus either through chorionic villus sampling, which can be done as early as the 9th week of gestation, or though amniocentesis, possible as early as the 14th to 16th week. Like autosomal abnormalities, aberrations of the sex chromosomes may result in impaired or absent fertility. For example, one abnormality is known as 45X, or Turner's syndrome. Individuals with this condition, who are classified as female, most commonly are short in stature and show impaired development of female genitalia and of such secondary sex characteristics as the breasts and distribution of body hair; they are also sterile. Another abnormality, called KLINEFELTER'S SYNDROME, occurs when the individual has 47 chromosomes in the cells of the body, with an XXY sex-chromosome composition. The individual is male in appearance, tall in stature, has sparse hair distribution over the body, and is sterile. Regardless of other sex-chromosome anomalies, when the Y Copyright (c) 1992 Grolier Electronic Publishing, Inc. All rights reserved. PRODIGY(R) interactive personal service 08/07/92 2:05 AM ACADEMIC AMERICAN ENCYCLOPEDIA GENETIC DISEASES chromosome is present the physical appearance is nearly always male. As the total number of sex chromosomes present increases, greater prevalence of associated birth defects and mental retardation results. Oliver W. Jones, M. D. GENE THERAPY One goal of recombinant-DNA technology (see GENETIC ENGINEERING) is the cure of human genetic diseases. Gene therapy may involve one or more of the following: (1) Gene Replacement Therapy, in which the normal form of a gene replaces a mutant gene. This type of gene therapy becomes important if the location of the gene at a specific point on a particular chromosome is essential for its proper functioning. (2) Gene Augmentation Therapy, in which the normal form of a gene is inserted in one of the cell's chromosomes without removal of the abnormal gene. This will be effective if the genetic disease is caused by a deleted gene or a gene with either reduced or no activity. (3) Gene Inactivation Therapy, in which the transferred gene produces a protein that neutralizes either a defective protein formed by a mutated gene or the excess number of proteins formed by an amplified gene (a gene that is duplicated abnormally to give many extra copies of itself). Therapeutic genes can be introduced directly into a cell through various chemical or physical processes that make the cell membrane temporarily permeable to foreign DNA. This method of gene transfer is called transfection. An indirect transfer method, called transduction, incorporates a beneficial gene into the genetic material of a virus, which is then allowed to infect the target cell. The most efficient method of transferring genes has been found to be transduction using a type of RNA virus called a RETROVIRUS. After infecting a host cell the retrovirus makes a DNA copy of itself, which is then inserted into the genetic material of the host cell. In 1990 the first trial of gene therapy was made, involving a child with lymphocytes that could not produce the enzyme adenosine deaminase (ADA), which is crucial for the normal development of the immune system. Using gene augmentation therapy, lymphocytes were removed from the child's blood and retrovirally altered by the addition of an ADA gene. These Copyright (c) 1992 Grolier Electronic Publishing, Inc. All rights reserved. PRODIGY(R) interactive personal service 08/07/92 2:05 AM ACADEMIC AMERICAN ENCYCLOPEDIA GENETIC DISEASES cells were then returned to the child's bloodstream. Early reports after monthly infusions showed improved immune function. A second gene therapy trial, involving two patients suffering from malignant melanoma skin cancer, began in early 1991. Trials using gene therapy to treat other genetic diseases, such as hemophilia, cystic fibrosis, and muscular dystrophy, are being developed. GENE MAPPING AND ANALYSIS In many cases where a person may be heterozygous for a disease-causing recessive gene or a carrier of a late-acting dominant gene, it is not yet possible to determine the presence or absence of the mutated gene directly. Instead it is necessary to look for some easily identifiable gene or section of DNA located nearby to act as a "marker" for the presence of the disease-causing gene. The genetic marker permits identification of a pattern of inheritance of the mutated gene in a family, a process known as linkage analysis. In 1983 a study of an extended family group with a high incidence of Huntington's chorea revealed that the gene was associated and passed along with a particular DNA fragment that could be located at a specific point on chromosome 4. The identification of this particular DNA fragment in a child of this extended family indicates the child has the gene for this disorder, many years before the first symptoms of the disease occur. In similar fashion the genes for Duchenne muscular dystrophy, cystic fibrosis, and neurofibromatosis have been mapped to specific locations on their chromosomes. As work in this field continues more and more disease-causing genes will be mapped to specific locations on particular chromosomes, permitting more precise GENETIC TESTING and counseling. Louis Levine Bibliography: Childs, B., et al., Molecular Genetics in Medicine (1988); Kirby, L.T., DNA Fingerprinting (1990); Nora, J.J., and Fraser, F.C., Medical Genetics, 3d ed. (1989); Pierce, B.A., The Family Genetic Sourcebook (1990); Verma, I.M., "Gene Therapy," Scientific American, November 1990; White, R., and Lalouel, J.M., "Chromosome Mapping with DNA Markers," Scientific American, February 1988. Copyright (c) 1992 Grolier Electronic Publishing, Inc. All rights reserved. PRODIGY(R) interactive personal service 08/07/92 2:06 AM ACADEMIC AMERICAN ENCYCLOPEDIA GENETICS Genetics is the area of biology concerned with the study of inheritance, the process by which certain characteristics of organisms are handed down from parent to offspring. Modern genetics began in 1865, when the Austrian monk Gregor MENDEL demonstrated the inheritance patterns of the garden pea, Pisum savitum, and provided a new way of looking at HEREDITY. Mendel's theories were based on hereditary factors, or genes (see GENE), the existence of which he deduced without seeing them or having any notion of what they were or where they were located. Gregor Mendel's results and theories, however, went unnoticed until 1900, when Hugo De Vries in the Netherlands, Carl Correns in Germany, and Erich von Ischermak-Seysenegg in Austria--who almost simultaneously rediscovered Mendel's work and independently performed similar experiments--arrived at the same conclusions reached by Mendel. It is now known that genes dictate the characteristic structures and functions of all organisms, from viruses to redwood trees and elephants, and that these characteristics are in turn passed on from parent to offspring. It is also known that the variety of hereditary traits are caused by variations in the genes themselves. MENDEL'S EXPERIMENTS Mendel studied seven characteristics of the garden pea and obtained experimental results that suggested a similar hereditary mechanism for all. In one experiment, he crossed plants that differed in the characteristic of plant height. He had previously obtained a line of pea plants that always produced tall plants and a line that always produced short plants, and he crossed them by transferring pollen from one plant to another. He found that the progeny (the first filial generation) were all tall. He then allowed these to self-pollinate and produce another generation of progeny (the second filial generation), three-quarters of which were tall and one-quarter short. Mendel's Laws From these results, Mendel deduced an explanation for the mechanism of inheritance and assumed certain principles to be true: (1) hereditary factors (genes) must exist; (2) two factors exist for each characteristic; (3) at the time of sex-cell formation, the hereditary factors of a pair separate equally into the gametes (law of segregation); (4) the gametes Copyright (c) 1992 Grolier Electronic Publishing, Inc. All rights reserved. PRODIGY(R) interactive personal service 08/07/92 2:06 AM ACADEMIC AMERICAN ENCYCLOPEDIA GENETICS bear only one factor for each characteristic; (5) hereditary factors for different traits sort independently of one another at gamete formation (law of independent assortment); and (6) gametes join randomly, irrespective of the factors that they carry. The characteristic that appeared in the first generation plants--in this case, tall plants--seemed to dominate over the one that did not appear. Mendel called tallness a dominant trait and shortness recessive; this phenomenon was referred to as the law of dominance. A capital A is now usually used to represent the gene that determines the dominant character, and a small a for one that determines the recessive character. When a pair of hereditary factors, or genes, are of the same type (AA), the condition is said to be homozygous for that character. On the other hand, if the two members of a pair are different (Aa), the condition is called heterozygous. The second generation plants of Mendel's experiment were composed of one-quarter AA, one-half Aa, and one-quarter aa. Since tallness is dominant, AA and Aa both appear tall, accounting for the three-quarter: one-quarter ratio of tall to short. The alternate forms of a gene, known as alleles, combine to produce different genetic types, or genotypes. Mendel demonstrated that the three-quarter: one quarter ratio existed for all seven characteristics of peas that he studied; he also showed that the separate gene pairs behaved independently of each other during gamete formation. CHROMOSOMES Mendel's knowledge of genes and their behavior was entirely theoretical. Subsequent studies of CELL structure and cell division have supplied physical evidence supporting his theories. It is now generally believed that genes behave as they do because of their location on chromosomes (see GENETIC CODE), structures found in the nucleus of each CELL of an organism. Chromosomes are not all the same length, and, when stained in the appropriate way, each may show characteristic bands, thickenings, or constrictions. The cells of each species contain a fixed and characteristic number of chromosomes. Some organisms, such as fungi and single-celled algae, have only a single set, or haploid number (n), of chromosomes in their cell nuclei. The somatic cells of Copyright (c) 1992 Grolier Electronic Publishing, Inc. All rights reserved. PRODIGY(R) interactive personal service 08/07/92 2:07 AM ACADEMIC AMERICAN ENCYCLOPEDIA GENETICS most higher organisms, including humans, contain two sets, or a diploid number (2n), of chromosomes. Still other organisms, such as mosses, ferns, and horsetails, alternate between diploid and haploid during different stages of their life cycles. Meiosis In diploid cells, gene pairs are located at specific sites (loci) on each chromosome. These gene pairs can be composed either of two identical genes or two alleles. A diploid cell therefore contains two genes for each hereditary characteristic. The gametes (sex cells) of diploid organisms, however, contain only a haploid (n) number of chromosomes; the union of two gametes, one from each parent, produces a diploid (2n) zygote, from which the offspring develops. The process of cell division by which such gametes are produced is called meiosis. It takes place in the testes and ovaries of animals, in the anthers and ovaries of higher plants, and in the sporophyte (2n) stage of organisms that alternate between haploid and diploid. In meiosis a single diploid cell divides into two diploid cells, each of which divides into two haploid cells. During this process, the two sets of chromosomes separate, thereby separating the members of the gene pairs. Each of the four resulting gametes therefore contains only one gene for each characteristic, and different gametes from the same parent may carry different alleles. Mendel's postulates may therefore be restated in physical terms as follows: (1) genes are located on chromosomes; (2) genes occur in pairs, occupying specific loci on a chromosome pair; (3) the first meiotic division separates the chromosome pairs, producing an equal division of the members of a gene pair in the product cells; (4) since there are two cell divisions and only one replication of chromosomes, the chromosome number is halved; (5) different gene pairs on separate chromosome pairs behave independently of each other; and (6) collision of egg and sperm is a chance process. Linkage and Crossing-Over In the early 1900s, Thomas Hunt MORGAN used the fruit fly Drosophila melanogaster to test a situation that Mendel did not encounter, in which two gene pairs are located on the same Copyright (c) 1992 Grolier Electronic Publishing, Inc. All rights reserved. PRODIGY(R) interactive personal service 08/07/92 2:07 AM ACADEMIC AMERICAN ENCYCLOPEDIA GENETICS chromosome pair. In this case they do not behave independently, since genes on the same chromosome tend to stay together during meiosis. This is called linkage. The combinations can be separated by the simultaneous breaking of homologous chromosomes during the first meiotic division, and the joining of the broken segments from each chromosome to the homologous broken segments. This process, called crossing-over, occurs regularly during meiosis and randomly between any chromosome pair in a bundle of four. Crossovers can be detected genetically if they involve two heterozygous gene pairs (the alleles producing distinct gene products). Under a microscope, they appear as cross-shaped structures called chiasmata. Mapping Crossing-over can be used to produce a chromosome map showing the relative positions of the loci of the known gene pairs. Two organisms having homozygous gene pairs are bred, and the offspring (first generation) has heterozygous gene peirs (AaBb). This heterozygote is then crossed with a tester strain of the genotype aabb, a standard tool known as a testcross. The progeny of a testcross are screened for the appearance of the genotype Aabb and aaBb, which can only arise from crossovers. The frequency of these types is a standard measure and is assumed to be proportional to the distance between the two loci on their chromosome. Using different combinations of gene pairs, an internally self-consistent map can be constructed in which the number of map units is defined as the percentage of progeny in a testcross derived from a crossover. The Role of Chromosomes It is now known that genes are lengths of a threadlike chemical called deoxyribonucleic acid (DNA) and form a continuous string that constitutes the chromosomes. Several researchers have attempted to explain the significance of the long assemblages of genes in chains, or chromosomes. First, some combinations of genes have adaptive value and need to be inherited as a package. Having them linked closely on one chromosome is one way of ensuring this. Second, genes with related functions often need to be activated simultaneously; their proximity allows them to be activated by one common switch mechanism. Third, the packaging of genes into units facilitates the orderly production of daughter cells in cell division. Copyright (c) 1992 Grolier Electronic Publishing, Inc. All rights reserved. PRODIGY(R) interactive personal service 08/07/92 2:07 AM ACADEMIC AMERICAN ENCYCLOPEDIA GENETICS Crossing-over and independent assortment of genes result in combinations of genes in progeny that are different from the parental arrangements. This process, called recombination, is believed to be an important mechanism for generating new genotypes. Recombination most frequently occurs among genes widely separated from each other; closely linked genes, however, have a random chance of rearrangement. POLYGENES AND GENE-ENVIRONMENT INTERACTION Mendel explained the phenomenon of discontinuous hereditary variation, which is expressed in separate and distinct forms that are associated with one kind of allele, such as tall versus short or wrinkled versus smooth. Continuous variations occur in many phenotypes, however, such as length or weight, is also commonly observed in nature and forms an apparently unbroken range from one extreme to another. This phenomenon, known as polygenic inheritance, results from the complex interaction among a set of genes. Human skin color, shades ranging from black through brown and yellow to white, is a good example of a trait determined by polygenes. Only an infinite number of polygenes, however, could give a perfectly continuous variation. The phenotype of an organism is shaped not only by its genotype but also by the interaction of that genotype with the environment. It is often difficult to determine the relative contribution of genetic and environmental variation to a particular phenotype. SEX DETERMINATION The sex of an organism is usually an inherited phenotype. In haploid forms, alleles of one gene pair can determine sex, but in higher organisms sex is often associated with a special pair of chromosomes called sex chromosomes. For example, human cells contain 22 pairs of autosomes, or nonsex chromosomes, and one pair of sex chromosomes. Women possess two identical sex chromosomes (X and X), and men possess two different sex chromosomes (X and Y). The presence or absence of the Y chromosome determines sex in humans; therefore, the Y contains the genes for male sex determination, called the "testis determining factor" (tdf). In many higher plants, anthers and ovaries are located on separate plants (dioecism), and some of these have an X/Y-like chromosomal determination of sex. Copyright (c) 1992 Grolier Electronic Publishing, Inc. All rights reserved. PRODIGY(R) interactive personal service 08/07/92 2:07 AM ACADEMIC AMERICAN ENCYCLOPEDIA GENETICS In humans, the X chromosome bears genes that affect traits having nothing to do with the sex. Because they are located on the X, however, they show a special inheritance pattern different from autosomal gene inheritance; the Y chromosome apparently has no counterpart to these genes. Red-green color blindness and hemophilia are two genetic traits determined by X-linked genes. The X and the Y genes are able to separate into equal numbers of sperm in the male and produce a 1:1 ratio of males to females in the eggs that they fertilize. THE NATURE OF THE GENE The genetic material for most organisms, DNA, is a double-stranded helix comprising a long chain of nucleotide bases with a sugar-phosphate backbone, as proposed by James D. WATSON and Francis H. C. CRICK in 1953. Eukaryotic cells contain two kinds of DNA sequences: unique DNA, one copy present in a haploid gene set; and repetitive DNA, identical copies (one million or more) found dispersed throughout the chromosome. The unique segments probably contain regular genes. The function of repetitive DNA segments is not known, although they may be involved either in the process of chromosome pairing or in regulating the activity of the unique sequence. DNA of eukaryotic organisms appears to be wound around nucleosomes--small, beadlike units that each consist of about 200 base pairs of DNA and a complex structure of proteins known as histones. Nucleosomes help package the DNA into the chromosome--an average human chromosome is about 0.005 mm in length and contains 50 mm of DNA. During mitotic cell division chromosomal replication produces two identical daughter cells, each of which contains identical DNA, assuring the stability of the hereditary material. The DNA replication is semiconservative. This means that free nucleotides hydrogen-bond to each half of the separate DNA strands, resulting in two new DNA double helices each consisting of one-half old and one-half newly formed strands. Genes of the DNA in eukaryotic organisms (RNA in some viruses) control phenotype by coding for the structure of PROTEINS, which are the main structural and catalytic molecules in an organism; hair, muscle, skin, tendons, and enzymes are all proteinaceous. The order of the nucleotide bases in DNA dictates the corresponding order of amino acids that give Copyright (c) 1992 Grolier Electronic Publishing, Inc. All rights reserved. PRODIGY(R) interactive personal service 08/07/92 2:08 AM ACADEMIC AMERICAN ENCYCLOPEDIA GENETICS proteins their specific shape and function during PROTEIN SYNTHESIS. The protein-building information in DNA is copied into a single-stranded molecule, called messenger RNA (mRNA), that then moves to the cytoplasm, where protein synthesis occurs. The nucleotides in mRNA can be thought of as letters that are read in groups of three, called codons, each codon standing for an amino acid. The amino acids are transported to the mRNA by transfer RNA molecules, and the protein is assembled on the surface of ribosomes. In humans the DNA in each cell contains about 3 billion base pairs, distributed among 22 sets of autosomal chromosomes and one set of sex chromosomes in the nucleus as well as one set of chromosomes in each mitochondrion. If all of this DNA were stretched out, it would have a length of about 1 m (3 ft), but the DNA is tightly compressed into the chromosome. Only about 2 percent of a person's DNA forms the actual genes, as well; the rest constitutes either noncoding "spacer" regions between genes or noncoding "intron" regions within genes. The amount of DNA per cell varies tremendously within both animal and plant kingdoms and is unrelated to the taxonomic group concerned (see GENETIC CODE; GENOME). MUTATION MUTATION is the process by which genes change from one form to another. Mutations may be caused by such mutagens as X rays, ultraviolet rays, nitrous acid, ethyl methane sulfonate, and nitrosoguanidine; less frequently, mutations may occur spontaneously as a result of accidental changes in the chemistry of the cell. Because mutation is random, haphazard change, most mutants contain damaged genes that are nonfunctional. Mutants usually do not live long in nature; geneticists and breeders, however, may keep mutants alive for study or for use in producing new plant and animal forms in agriculture. A mutation in DNA usually results in an altered nucleotide sequence, either by substitution, addition, deletion, or insertion, which is translated into an altered amino-acid sequence that usually produces a change in the organism's normal body function. The alteration of amino acids can have a drastic effect on function, as in the case of sickle-cell hemoglobin. A mutation of the chromosome by transposition, translocation, or insertion can cause similar effects. Mutations of cells other than sex cells are considered to be a Copyright (c) 1992 Grolier Electronic Publishing, Inc. All rights reserved. PRODIGY(R) interactive personal service 08/07/92 2:08 AM ACADEMIC AMERICAN ENCYCLOPEDIA GENETICS primary cause of cancer in those tissues. All humans carry quite a large number of deleterious and lethal mutant genes that are recessive. Each mating is a kind of a lottery, in which the offspring reveal whether or not the parents' mutations are at identical loci. For example, if both parents are heterozygous (Aa) for a gene pair in which the recessive allele is deleterious, then one-fourth of their children will show genetic disease of the kind controlled by that locus. Genetic counseling can often help prospective mates in determining whether such diseases will manifest in their offspring (see also GENETIC IMPRINTING). GENES IN DEVELOPMENT Most organisms start life as single cells (zygotes) and grow into massive multicellular bodies with cells of considerable differences in form and function. This process, which involves growth and differentiation, is called DEVELOPMENT. Although skin cells, liver cells, brain cells, and so on, are highly differentiated, they are all derived from the original zygote as a result of the high-fidelity copying of DNA during mitotic division. This is achieved by a complex, little-understood process whereby different genes are active in different tissues. The best examples of gene regulation are found in bacteria, where genes of related function are grouped on the chromosome together with a special class of regulatory genes to form an operon, which is a kind of control unit. The operon theory was proposed by Francois Jacob and Jacques Monod in 1961. Regulatory genes, usually responding to environmental cues, either assist or prevent the passage of the mRNA synthesis enzyme, RNA polymerase, along the operon, thereby controlling gene activity. No satisfactory examples of operons have been found at present in higher organisms, but several examples of regulatory genes are known, although these are not necessarily linked to a controlled locus. Repetitive DNA that is interspersed between unique DNA has been postulated as a site of a vast system of regulatory genes. GENES IN CYTOPLASMIC ORGANELLES Although most genes are found in the chromosomes of the nucleus, two kinds of cytoplasmic organelles, mitochondria and Copyright (c) 1992 Grolier Electronic Publishing, Inc. All rights reserved. PRODIGY(R) interactive personal service 08/07/92 2:08 AM ACADEMIC AMERICAN ENCYCLOPEDIA GENETICS chloroplasts, also contain certain genes. Phenotypes determined by these genes are inherited through the female parent. Maternal or uniparental inheritance has been extensively studied in microorganisms, notably the unicellular algae, chlamydomonas, and several fungi. In Chlamydomonas, a variety of drug-resistant and morphological phenotypes are involved. In fungi, sensitivity to certain drugs, such as erythromycin, paramomycin, and oligoomycin, can be cytoplasmically inherited, as can some kinds of poor growth phenotypes ("petites" in yeast and "poky" in the bread mold Neurospora). The mitochondria and chloroplasts carry their own DNA, which is circular and unlike nuclear DNA in nucleotide composition. They also contain their own autonomous protein-synthesizing system, many parts of which are coded by organellar DNA genes. Many other components of the mitochondria and chloroplasts, such as cytochromes, are coded by genes of nuclear DNA. These organelles are therefore composed of a mixture of components with DNA blueprints located in both the nucleus and the organelle. The specific synthesizing machinery of mitochondrion, together with its shape and size, have suggested to some that the mitochondrion is a vestige of a primitive symbiotic association with bacteria. Similarly, the structure and functions of a chloroplast are reminiscent of the primitive blue-green algae. This kind of evolution, in which complexity results from the adoption of an internal collection of simpler cells, is called hereditary symbiosis and may have been important in the development of modern cells. GENES IN POPULATIONS Mendelian genetics can predict the inheritance patterns within families, but one should not expect to see similar patterns and ratios in populations, which are complex mixtures of different families. A different approach, sometimes called population genetics, is used to analyze genetic distribution in populations. Each locus contains two alleles (A and a) of one gene. The gene pool of a population is derived by considering each diploid individual to be one cell bearing two genes at that locus. The total number of A and a genes in a population is calculated and an allele frequency for each is obtained. Usually, the frequency of A is called p, and the frequency of a Copyright (c) 1992 Grolier Electronic Publishing, Inc. All rights reserved. PRODIGY(R) interactive personal service 08/07/92 2:08 AM ACADEMIC AMERICAN ENCYCLOPEDIA GENETICS is called q, where p + q = 1 (or 100%). The allele frequencies are the main determinants of the genetic structure of populations. If mating is random for example, there will be pp of AA, 2 pq of Aa, and qq of aa. This genotype distribution, which is stable if all other factors are constant, is called Hardy-Weinberg equilibrium, named after its discoverers. At its most fundamental level, evolution is little more than a change in relative allele frequencies. The actual values of p and q at each locus are determined by the complex interaction of many forces, including mutation from A to a, mutation from a to A (reversion, which is usually less frequent than forward mutation), chance fluctuation due to small populations (producing genetic drift of allele frequencies), and natural selection for or against certain genotypes. In turn, selection can be directional, ultimately eliminating one allele from the population, or stabilizing, favoring intermediate genotypes and tending to maintain several alleles and phenotypes in an interbreeding population, a phenomenon called genetic polymorphism. Preliminary results of a different form of genetic study of human evolution aroused controversy at the 1987 meeting of the American Anthropological Association. The research involved analyses of mitochondrial DNA in placental samples from women with a worldwide distribution of ancestry. Such DNA is inherited only from the mother, and through mutation studies the researchers hoped to trace human ancestry back to a "single" source--some generation of first humans. The results of a team of geneticists working at the University of California, Berkeley, suggested a human family tree with roots in sub-Saharan Africa some 140,000 to 200,000 years ago. Another team, at Emory University, proposed a common ancestor of similar age but in southeastern Asia. Anthropologists expressed considerable skepticism, however, about these results of what came to be known as the "Eve" hypothesis. Most anthropologists consider that the first true humans appeared much longer ago (see PREHISTORIC HUMANS). MODERN GENETICS Genetics is an important aspect of many areas of pure and applied biology. Viral genetics, microbial genetics, plant Copyright (c) 1992 Grolier Electronic Publishing, Inc. All rights reserved. PRODIGY(R) interactive personal service 08/07/92 2:08 AM ACADEMIC AMERICAN ENCYCLOPEDIA GENETICS genetics, animal genetics, and human genetics focus research on specific types of organisms. Research in molecular genetics involves studies on chemical structure and function; cytogenetics on location of the genetic material in cells and on cell division; developmental genetics on the genetic function in embryological phenomena; behavior genetics on the role of the gene in regulating behavior; and population genetics on the evolutionary process. At the applied level, genetics is of direct use in understanding genetic diseases and environmental mutation. It is used in plant and animal breeding to improve the quality and quantity of food. It also is a tool in basic research by which complex biological processes can be analyzed, often at the molecular level. A. J. W. Griffiths Bibliography: Ayala, F. J., Population and Evolutionary Genetics (1982); Briggs, David, and Walters, Max, Plant Variation and Evolution (1969); Burnet, Frank Macfarlane, Endurance of Life: The Implications of Genetics for Human Life (1978); Dobzhansky, Theodosius, Genetics of the Evolutionary Process (1970); Goodenough, U., Genetics, 3d ed. (1983); Lerner, I. Michael, and Libby, William J., Heredity, Evolution, and Society, 2d ed. (1976); Levine, Louis, Biology of the Gene, 3d ed. (1980); Lewontin, R. C., Rose, Steven, and Kamin, L. J., Not in Our Genes: Biology, Ideology and Human Nature (1984); McKusick, V. S., Mendelian Inheritance in Man, 7th ed. (1986); Mertens, Thomas R., ed., Human Genetics: Readings on the Implications of Genetic Engineering (1975); Scandalious, J. G., Molecular Genetics of Development (1987); Smith, Anthony, The Human Pedigree (1976); Spiess, E. B., Genes in Populations (1977); Suzuki, David T., and Griffiths, A. J., An Introduction to Genetic Analysis, 3d ed. (1986); Stent, G. S., and Calendar, R., Molecular Genetics (1978); Watson, James D., The Double Helix (1968); Watson, J. D., et al, The Molecular Biology of the Gene, 2 vols. (1987). Copyright (c) 1992 Grolier Electronic Publishing, Inc. All rights reserved.