Genetics, scientific study of how physical, biochemical, and behavioral traits are transmitted from parents to their offspring. The word itself was coined in 1906 by the British biologist William Bateson. Geneticists are able to determine the mechanisms of inheritance (see Heredity) because the offspring of sexually reproducing organisms do not exactly resemble their parents, and because some of the differences and similarities between parents and offspring recur from generation to generation in repeated patterns. The investigation of these patterns has led to some of the most exciting discoveries in modern biology.
BASIS OF HEREDITY
TRANSMISSION OF GENES
The action of genes is seldom a simple matter of a single gene controlling a single trait. Often one gene may control more than one trait, and one trait may depend on many genes. For example, the action of at least two dominant genes is required to produce purple pigment in the purple-flowered sweet pea. Sweet peas that are homozygous for either or both of the recessive alleles involved in the color traits produce white flowers. Thus, the effects of a gene can depend on which other genes are present.
LINKAGE AND GENE MAPPING
Morgan and his group also found, however, that such linkage is rarely complete. Combinations of alleles characteristic of each parent can become reassorted among some of their offspring. During meiosis, a pair of homologous chromosomes may exchange material in a process called recombination, or crossing-over. (The effect of crossing-over can be seen under a microscope as an X-shaped joint between the two chromosomes.) Crossovers occur more or less at random along the length of the chromosomes, so the frequency of recombination between two genes depends on their distance from each other on the chromosome. If the genes are relatively far apart, recombinant gametes will be common; if they are relatively close, recombinant gametes will be rare. In the offspring produced by the gametes, the crossovers show up as new combinations of visible traits. The more crossovers that occur, the greater the percentage of offspring that show the new combinations. Consequently, by arranging suitable breeding experiments, scientists can plot, or map, the relative positions of the genes along the chromosome.
In recent years geneticists have used organisms such as bacteria, molds, and viruses, which rapidly produce extremely large numbers of offspring, to detect recombinations that occur only rarely. Thus, they are able to make maps of genes that are quite close together. The method introduced at Morgan’s laboratory has now become so exact that differences occurring within a single gene can be mapped. These maps have shown that not only do the genes occur in linear fashion along the chromosome, but they themselves are linear structures. The detection of rare recombinants can reveal the existence of structures even smaller than those observed through the most powerful microscopes.
Studies of fungi, and more recently of fruit flies, have shown that recombination of alleles can sometimes take place without reciprocal exchanges between chromosomes. Apparently, when two different versions of the same gene occur together (in a heterozygote), one of them may be "corrected" to match the other. Such corrections may take place in either direction (for example, the allele A may be changed to a, or vice versa). This process has been called gene conversion. Occasionally, several adjacent genes may undergo conversion together, and the likelihood of two genes being coconverted is related to their distance apart. This provides another way of mapping the relative positions of genes on the chromosome.
The most recent techniques of gene mapping, known as physical mapping, use genetic material cloned by high-technology methods such as polymerase chain reaction (PCR) and combine robotics, lasers, and computers to measure the distance between genetic markers on the chromosome (see Human Genome Project).
AND SEX LINKAGE
Sex is usually determined by the action of a single pair of chromosomes. Abnormalities of the endocrine system or other disturbances may alter the expression of secondary sexual characteristics, but they almost never completely reverse the sex. A human female, for example, has 23 pairs of chromosomes, and the members of each pair are much alike. A human male, however, has 22 similar pairs and one pair consisting of two chromosomes that are dissimilar in size and structure. The 22 pairs of chromosomes that are alike in both males and females are called autosomes. The remaining chromosomes, in both sexes, are called the sex chromosomes. The two identical sex chromosomes in the female are called X chromosomes. One of the sex chromosomes in the male is also an X chromosome, but the other, shorter one is called the Y chromosome. When gametes are formed, each egg produced by the female contains one X chromosome, but the sperm produced by the male can contain either an X or a Y chromosome. The union of an egg, which always bears an X chromosome, with a sperm also bearing an X chromosome produces a zygote with two X’s: a female offspring. The union of an egg witha sperm that bears a Y chromosome produces a male offspring. Modifications of this mechanism occur in various plants and animals.
The human Y chromosome is approximately one-third as long as the X, and apart from its role in determining maleness, it appears to be genetically inactive. Thus, most genes on the X have no counterpart on the Y. These genes, said to be sex-linked, have a characteristic pattern of inheritance. The hereditary blood disease hemophilia, for example, is usually caused by a sex-linked recessive gene (h). A female with HH or Hh is normal; a female with hh has hemophilia. A male is never heterozygous for the gene because he inherits only the gene that is on the X chromosome. A male with H is normal; with h he has hemophilia. When a normal man (H) and a woman who is heterozygous (Hh) have offspring, the female children are normal, but half of them carry the h gene—that is, none of them is hh, but half of them bear the genotype Hh. The male children inherit only the H or the h; therefore, half the male children have hemophilia. Thus, in normal circumstances a female carrier passes on the disease to half her sons, and she also passes on the recessive h gene to half her daughters, who in turn become carriers of hemophilia. Many other conditions—including red-green color blindness, hereditary nearsightedness, night blindness, and ichthyosis (a skin disease)—have been identified as sex-linked traits in humans.
ACTION: DNA AND THE CODE OF LIFE
That chromosomes were almost entirely composed of two kinds of chemical substances, protein and nucleic acids, had long been known. Partly because of the close relationship established between genes and enzymes, which are proteins, protein at first seemed the fundamental substance that determined heredity. In 1944, however, the Canadian bacteriologist Oswald Theodore Avery proved that deoxyribonucleic acid (DNA) performed this role. He extracted DNA from one strain of bacteria and introduced it into another strain. The second strain not only acquired characteristics of the first but passed them on to subsequent generations. By this time DNA was known to be made up of substances called nucleotides. Each nucleotide consists of a phosphate, a sugar known as deoxyribose, and any one of four nitrogen-containing bases (see Acids and Bases). The four nitrogen bases are adenine (A), thymine (T), guanine (G), and cytosine (C).
The DNA backbone is actually a great deal longer than the chromosome but is tightly coiled up within it. This packing is now known to be based on minute particles of protein known as nucleosomes, just visible under the most powerful electron microscope. The DNA is wound around each nucleosome in succession to form a beaded structure. The structure is then further folded so that the beads associate in regular coils. Thus, the DNA has a "coiled-coil" configuration, like the filament of an electric light bulb.
After the discoveries of Watson and Crick, the question that remained was how the DNA directs the formation of proteins, compounds central to all the processes of life. Proteins are not only the major components of most cell structures, they also control virtually all the chemical reactions that occur in living matter. The ability of a protein to act as part of a structure, or as an enzyme affecting the rate of a particular chemical reaction, depends on its molecular shape (see Molecule). This shape, in turn, depends on its composition. Every protein is made up of one or more components called polypeptides, and each polypeptide is a chain of subunits called amino acids. Twenty different amino acids are commonly found in polypeptides.The number, type, and order of amino acids in a chain ultimately determine the structure and function of the protein of which the chain is a part.
Ten years after Watson and Crick reported the DNA structure, the genetic code was worked out and proved biologically. Its solution depended on a great deal of research involving another group of nucleic acids, the ribonucleic acids (RNA). The specification of a polypeptide by the DNA was found to take place indirectly, through an intermediate molecule known as messenger RNA (mRNA). Part of the DNA somehow uncoils from its chromosome packing, and the two strands become separated for a portion of their length. One of them serves as a template upon which the mRNA is formed (with the aid of an enzyme called RNA polymerase). The process is very similar to the formation of a complementary strand of DNA during the division of the double helix, except that RNA contains uracil (U) instead of thymine as one of its four nucleotide bases, and the uracil (which is similar to thymine) joins with the adenine in the formation of complementary pairs. Thus, a sequence adenine-guanine-adenine-thymine-cytostine (AGATC) in the coding strand of the DNA produces a sequence uracil-cytosine-uracil-adenine-guanine (UCUAG) in the mRNA.
Ribosomes are made up of protein and RNA. A group of ribosomes linked by mRNA is called a polyribosome or polysome. As each ribosome passes along the mRNA molecule, it "reads" the code, that is, the sequence of nucleotide bases on the mRNA. The reading, called translation, takes place by means of a third type of RNA molecule called transfer RNA (tRNA), which is produced on another segment of the DNA. On one side of the tRNA molecule is a triplet of nucleotides. On the other side is a region to which one specific amino acid can become attached (with the aid of a specific enzyme). The triplet on each tRNA is complementary to one particular sequence of three nucleotides—the codon—on the mRNA strand. Because of this complementarity, the triplet is able to "recognize" and adhere to the codon. For example, the sequence uracil-cytosine-uracil (UCU) on the strand of mRNA attracts the triplet adenine-guanine-adenine (AGA) of the tRNA. The tRNA triplet is known as the anticodon.
As tRNA molecules move up to the strand of mRNA in the ribosome beads, each bears an amino acid. The sequence of codons on the mRNA therefore determines the order in which the amino acids are brought by the tRNA to the ribosome. In association with the ribosome, the amino acids are then chemically bonded together into a chain, forming a polypeptide. The new chain of polypeptide is released from the ribosome and folds up into a characteristic shape that is determined by the sequence of amino acids. The shape of a polypeptide and its electrical properties, which are also determined by the amino acid sequence, dictate whether it remains single or becomes joined to other polypeptides, as well as what chemical function it subsequently fulfills within the organism.
In bacteria, viruses, and cyanobacteria (formerly known as blue-green algae), the chromosome lies free in the cytoplasm, and the process of translation may start even before the process of transcription (mRNA formation) is completed. In higher organisms, however, the chromosomes are isolated in the nucleus and the ribosomes are contained only in the cytoplasm. Thus, translation of mRNA into protein can occur only after the mRNA has become detached from the DNA and has moved out of the nucleus.
The functions (if any) of introns are not understood, although the suggestion has been made that the processing of RNA by chopping out the intervening sequences may be involved in regulating the quantity of polypeptide produced by the gene. Introns have also been found in genes that code for special RNAs, such as those that are components of the ribosomes. The discovery of introns was made possible by new methods of determining the exact sequence of nucleotides in molecules of DNA and RNA. These methods were developed by the British molecular biologist Frederick Sanger; for this work he received a second Nobel Prize in chemistry in 1980.
D Repeated Sequences Direct studies of DNA have also shown that, in higher organisms, some sequences of nucleotides are repeated many times throughout the genetic material. Some of these repeated sequences represent multiple copies of genes that code polypeptides, or of genes that code special RNAs (almost always, there are many copies of genes that produce the RNA components of ribosomes). Other repeated sequences do not seem to code polypeptides or RNAs. Among them are sequences that seem able to jump from place to place in a chromosome, from one chromosome to another, and even from one species to another. These transposons, or transposable elements—informally known as jumping genes—are able to attach to other DNA sequences, causing mutations in the genes adjacent to their points of arrival or departure. Transposons were first discovered in the 1940s by Nobel laureate Barbara McClintock in her research on maize but have since been found in every species. Much research is now focused on transposons, and many scientists suspect that these transposable elements may be a key to evolutionary change, helping to increase the genetic variation of a species.
IX GENE REGULATION Knowing how protein is made allows scientists to understand how genes can produce specific effects on the structures and functions of organisms. This does not explain, however, how organisms can change in response to changing environmental circumstances, or how a single zygote can give rise to all the different tissues and organs that make up a human being. Most of the cells in these tissues and organs contain identical sets of genes but nevertheless make different proteins; clearly, in the cells of any one tissue or organ some genes are acting but others are not. Different tissues have different arrays of genes in the active state. Thus, part of the explanation for the development of a complex organism must lie in the ways by which genes are specifically activated.
The processes of gene activation in higher organisms are still obscure, but through the work of the French geneticists François Jacob and Jacques Lucien Monod, a good deal is known about these processes in bacteria. Near each bacterial gene is a segment of DNA known as the promoter. This is the site at which RNA polymerase, the enzyme responsible for the production of mRNA, sticks to the DNA and starts transcription. Between the promoter and the gene there is often a further segment of DNA called the operator, where another protein—the repressor—can stick. When the repressor is attached to the operator, it stops the RNA polymerase from moving along the chromosome and producing mRNA; consequently, the gene is inactive. The presence of a chemical substance in the cell, however, may cause the repressor to become detached and the gene to become active. Other substances may affect the degree of gene activity by altering the ability of the RNA polymerase to bind to the promoter. The repressor protein is produced by a gene called the regulator.
In bacteria, several genes may be controlled simultaneously by one promoter and one or more operators. The entire system is then called an operon. Apparently, operons do not occur in complex organisms, but quite possibly each gene has its own individual system of promoters and operators, and introns and repeated sequences may also play a role.
X CYTOPLASMIC INHERITANCE Some constituents of the cell besides the nucleus contain DNA. They include the cytoplasmic bodies known as mitochondria (the energy producers of the cell) and the chloroplasts of plants, where photosynthesis takes place. These bodies are self-reproducing. The DNA is replicated in a manner similar to that in the nucleus, and sometimes its code is transcribed and translated into proteins. In 1981 the entire sequence of nucleotides in the DNA of a mitochondrion was determined; apparently, mitochondria use a code only slightly different from that used by the nucleus.
The traits determined by cytoplasmic DNA are more often inherited through the mother than through the father, because sperm and pollen usually contain less cytoplasmic material than do eggs. Some cases of apparent maternal inheritance are actually due to the transmission of viruses from mother to offspring through the egg cytoplasm.
XI MUTATIONS Although the replication of DNA is very precise, it is not uniformly perfect. Very rarely, changes occur in DNA during replication, and the new piece of DNA contains one or more changed nucleotides. Such a change, known as a mutation, may take place in any part of the DNA. If a mutation occurs in the sequence of nucleotides that codes for a particular polypeptide, it may change an amino acid in the polypeptide chain. This change may seriously alter the properties of the resulting protein. For example, the polypeptides distinguishing normal hemoglobin and sickle-cell hemoglobin (see Sickle-Cell Anemia) differ by only a single amino acid. When a mutation occurs during the formation of gametes, it will be passed on to the following generation.
A Gene Mutation Mutations were first reported in 1901 by the Dutch botanist Hugo De Vries, one of Mendel’s rediscoverers. In 1929 the American biologist Hermann Joseph Muller found that the rate of mutation can be increased greatly by X rays. Later, other forms of radiation, as well as high temperatures and various chemicals, were also found to be capable of inducing mutations. The mutation rate can also be increased by the presence of particular alleles of certain genes, known as mutator genes, some of which seem to cause defects in the mechanisms maintaining the fidelity of DNA replication. Gene mutations can also occur as the result of transposons.
Most gene mutations are harmful to the organisms that carry them; the function of a complex system such as a protein is more easily destroyed than improved by a random change. Thus, the number of individuals carrying a particular mutant gene at any time is usually the consequence of two opposing forces: The tendency for the number to increase because of the reproduction of new mutant individuals in a population, and the tendency for the number to decrease because mutant individuals survive or reproduce less well than their peers. Human activities have tended to make the increase in the number of individuals carrying mutant genes larger because of exposure to medical X rays, radioactive materials (see Radioactivity), and mutation-causing chemicals.
Gene mutations due to transposons seem to follow a different rule. Recent research has shown that such genetic mutations are more likely to improve the evolutionary fitness of a species than are other types of mutations.
Mutations are usually recessive, and their harmful effects are not expressed unless two of them are brought together into the homozygous condition. This is most likely to occur as a result of inbreeding, the mating of closely related organisms that may have inherited the same recessive mutant gene from a common ancestor. For this reason, inherited diseases are more common among children whose parents are cousins than they are in the human population as a whole.
B Chromosome Mutations The substitution of one nucleotide for another is not the only possible kind of mutation. Sometimes a nucleotide may be entirely lost or one may be gained. In addition, more dramatic and obvious changes may occur, or the chromosomes themselves may alter in form or number. A section of chromosome may become detached, turn over, and then reattach to the chromosome at the same site. This is called an inversion. If the detached section unites with a different chromosome, or a different part of the original chromosome, it is called a translocation. Sometimes a piece of chromosome will be lost from one member of a pair of homologous chromosomes and gained by the other member. One of the pair is then said to have a deficiency and the other a duplication. Deficiencies are usually lethal in the homozygous condition, and duplications are often so. Inversions and translocations are more frequently viable, although they may be associated with mutations in genes near the points where the chromosomes have been broken. Most of these chromosomal rearrangements are probably the consequences of errors in the process of crossing over.
Another kind of mutation occurs when a pair of homologous chromosomes fails to separate at meiosis. This can produce gametes—and hence zygotes—with extra chromosomes and others with one or more chromosomes missing. Individuals with an extra chromosome are known as trisomics, and those with a missing chromosome as monosomics. Both conditions tend to result in severe disabilities. For example, people with three copies of the 21st chromosome are born with Down syndrome.
Sometimes an entire set of chromosomes may fail to separate at meiosis; thus, a gamete with twice the normal number of chromosomes is produced. If such a gamete fuses with one containing the normal number of chromosomes, the offspring will have three homologous sets rather than the normal two. If two gametes with twice the normal number fuse, the offspring will have four homologous sets. Organisms with additional sets of chromosomes are known as polyploids. Polyploidy is the only known process by which new species may arise in a single generation. Viable and fertile polyploids are found almost exclusively in hermaphroditic organisms (see Hermaphroditism), such as most flowering plants and some invertebrate animals. Plant polyploids are usually larger and sturdier in form than their normal diploid ancestors. Polyploid fetuses sometimes occur in humans, but they die at an early stage of fetal development and are aborted (see Genetic Disorders).
XII GENES IN POPULATIONS Population genetics, which investigates how genes spread through populations of organisms, was given a firm basis by the work of the English mathematician Godfrey H. Hardy and the German obstetrician Wilhelm Weinberg. In 1908 they independently formulated what is now known as the Hardy-Weinberg rule. This states that if two alleles of one autosomal gene (A and a) exist in a population, if their frequencies of occurrence (expressed in decimals) are p and q, respectively (p + q = 1), and if mating between individuals occurs at random with respect to the gene, then after one generation the frequencies of the three genotypes AA, Aa, and aa will be p2, 2pq, and q2, respectively. These frequencies, in the absence of disturbances, will then remain constant from generation to generation. Any change of frequency, which signals an evolutionary change, must therefore be due to disturbances. These disturbances may include mutation, natural selection, migration, and breeding within small populations that may lose particular alleles by chance, or random genetic drift (see Evolution).
Evidence indicates that most populations are a great deal more variable genetically than was supposed. Studies of the polypeptide products of genes have suggested that, on the average, about one-third of them have genetic variants at frequencies higher than could be expected from the balance between their generation by mutation and the selective disadvantage of the mutants. This has led to increased interest in the ways by which alternate alleles may be actively maintained in a state of balance so that neither replaces the other. One such balancing mechanism is heterozygous advantage, when the heterozygote survives better than either of the homozygotes. Another balancing mechanism, called frequency-dependent selection, depends on the relative advantage of rare varieties, for example, in populations subject to predators. Predators tend to concentrate on the variety that is common and to disregard rarer types. Thus, a variety can be at an advantage when it is rare but may begin to lose the advantage as natural selection for the protective trait makes it more common. Predators then begin to kill off the once-favored variety until at last an equilibrium is reached between the alleles in the population. Parasites may act in a similar fashion, becoming specialized to attack whichever is the commonest variety of host and thereby maintaining genetic variability in host populations.
XIII HUMAN HEREDITY Most physical characteristics of humans are influenced by multiple genetic variables as well as by the environment. Some characteristics, such as height, have a relatively large genetic component. Others, such as body weight, have a relatively large environmental component. Still other characteristics, such as the blood groups (see Blood Type) and the antigens involved in the rejection of transplanted organs (see Transplantation, Medical), appear to involve entirely genetic components; no environmental condition is known to change these characteristics. The transplantation antigens have recently been extensively studied because of their medical interest. The most important ones are produced by a group of linked genes known as the HLA complex. This group of genes not only determines whether transplanted organs will be accepted or rejected, it is also involved in the body’s resistance to various diseases (including allergies, diabetes, and arthritis).
Susceptibility to various other diseases has an important genetic element. These diseases include Huntington’s disease (see Chorea), Alzheimer’s disease, diabetes mellitus, multiple sclerosis (MS), schizophrenia, malaria, several forms of cancer, migraine headaches, alcoholism, obesity, and high blood pressure. Many rare diseases are caused by recessive genes and a few by dominant genes.
See also Gene; Genetic Engineering; Heredity; Hybrid; Natural Selection; Plant Breeding.
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