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Immunology => Gene => Genetics
Genetics
INTRODUCTION
Genetics, scientific study of how physical, biochemical, and behavioural traits are transmitted from parents to their offspring. The word itself was coined in 1906 by the British biologist William Bateson. Geneticists determine the mechanisms of inheritance whereby the offspring of sexually reproducing organisms do not exactly resemble their parents, and 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.
EMERGENCE OF GENETICS
The science of genetics began in 1900, when several plant breeders independently discovered the work of the Austrian monk Gregor Mendel, which, although published in 1866, had been virtually ignored. Working with garden peas, Mendel described the patterns of inheritance in terms of seven pairs of contrasting traits that appeared in different pea-plant varieties. He observed that the traits were inherited as separate units, each of which was inherited independently of the others . He suggested that each parent has pairs of units but contributes only one unit from each pair to its offspring. The units that Mendel described were later given the name genes.
PHYSICAL BASIS OF HEREDITY
Soon after Mendel's work was rediscovered, scientists realized that the patterns of inheritance he had described paralleled the action of chromosomes in dividing cells, and they proposed that the Mendelian units of inheritance, the genes, are carried by the chromosomes. This led to intensive studies of cell division.
Every cell comes from the division of a pre-existing cell. All the cells that make up a human being, for example, are derived from the successive divisions of a single cell, the zygote, which is formed by the union of an egg and a sperm. The great majority of the cells produced by the division of the zygote are, in the composition of their hereditary material, identical to one another and to the zygote itself (assuming that no mutations occur; see below). Each cell of a higher organism is composed of a jellylike layer of material, the cytoplasm, which contains many small structures. This cytoplasmic material surrounds a prominent body called the nucleus. Every nucleus contains a number of minute, threadlike chromosomes. Some relatively simple organisms, such as cyanobacteria and bacteria, have no distinct nucleus but do have cytoplasm, which contains one or more chromosomes.
Chromosomes vary in size and shape and usually occur in pairs. The members of each pair, called homologues, closely resemble each other. Most cells in the human body contain 23 pairs of chromosomes, whereas most cells of the fruit fly Drosophila contain four pairs, and the bacterium Escherichia coli has a single chromosome in the form of a ring. Every chromosome in a cell is now known to contain many genes, and each gene is located at a particular site, or locus, on the chromosome.
The process of cell division by which a new cell comes to have an identical number of chromosomes as the parent cell is called mitosis . In mitotic division each chromosome divides into two equal parts, and the two parts travel to opposite ends of the cell. After the cell divides, each of the two resulting cells has the same number of chromosomes and genes as the original cell. Every cell formed in this process thus has the same genetic material. Simple one-celled organisms and some multicellular forms reproduce by mitosis; it is also the process by which complex organisms achieve growth and replace worn-out tissue.
Higher organisms that reproduce sexually are formed from the union of two special sex cells known as gametes. Gametes are produced by meiosis, the process by which germ cells divide. It differs from mitosis in one important way: in meiosis a single chromosome from each pair of chromosomes is transmitted from the original cell to each of the new cells. Thus, each gamete contains half the number of chromosomes that are found in the other body cells. When two gametes unite in fertilization, the resulting cell, called the zygote, contains the full, double set of chromosomes. Half of these chromosomes normally come from one parent and half from the other.
THE TRANSMISSION OF GENES
The union of gametes brings together two sets of genes, one set from each parent. Each gene-that is, each specific site on a chromosome that affects a particular trait-is therefore represented by two copies, one coming from the mother and one from the father (for exceptions to this rule, see Sex and Sex Linkage, below). Each copy is located at the same position on each of the paired chromosomes of the zygote. When the two copies are identical, the individual is said to be homozygous for that particular gene. When they are different-that is, when each parent has contributed a different form, or allele, of the same gene-the individual is said to be heterozygous for that gene. Both alleles are carried in the genetic material of the individual, but if one is dominant, only that one will be manifested. In later generations, however, as was shown by Mendel, the recessive trait may show itself again (in individuals homozygous for its allele).
For example, the ability of a person to form pigment in the skin, hair, and eyes depends on the presence of a particular allele (A), whereas the lack of this ability, known as albinism, is caused by another allele (a) of the same gene. (For convenience, alleles are usually designated by a single letter; the dominant allele is represented by a capital letter and the recessive allele by a small letter.) The effects of A are dominant; of a, recessive. Therefore, heterozygous people (Aa), as well as people homozygous (AA) for the pigment-producing allele, have normal pigmentation. People homozygous for the allele that results in a lack of pigment (aa) are albinos. Each child of a couple who are both heterozygous (Aa) has a probability of one in four of being homozygous AA, one in two of being heterozygous Aa, and one in four of being homozygous aa. Only the individuals carrying aa will be albino. Note that each child has a one-in-four chance of being affected with albinism; it is not accurate to say that one-quarter of the children in a family will be affected. Both alleles will be carried in the genetic material of heterozygous offspring, who will produce gametes bearing one or the other allele. A distinction is made between the appearance, or outward characteristics, of an organism and the genes and alleles it carries. The observable traits constitute the organism's phenotype, and the genetic makeup is known as its genotype.
It is not always the case that one allele is dominant and the other recessive. The four-o'clock plant, for example, may have flowers that are red, white, or pink. Plants with red flowers have two copies of the allele R for red flower colour and hence are homozygous RR. Plants with white flowers have two copies of the allele r for white flower colour and are homozygous rr. Plants with one copy of each allele, heterozygous Rr, are pink-a blend of the colours produced by the two alleles.
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 colour traits produce white flowers. Thus, the effects of a gene can depend on which other genes are present.
QUANTITATIVE INHERITANCE
Traits that are expressed as variations in quantity or extent, such as weight, height, or degree of pigmentation, usually depend on many genes as well as on environmental influences. Often the effects of different genes appear to be additive-that is, each gene seems to produce a small increment or decrement independent of the other genes. The height of a plant, for example, might be determined by a series of four genes: A, B, C, and D. Suppose that the plant has an average height of 25 cm (10 in) when its genotype is aabbccdd, and that each replacement by a pair of dominant alleles increases the average height by approximately 10 cm (4 in). In that case a plant that is AABBccdd will be 45 cm (18 in) tall, and one that is AABBCCDD will be 65 cm (26 in) tall. In reality, the results are rarely as regular as this. Different genes may make different contributions to the total measurement, and some genes may interact so that the contribution of one depends on the presence of another. The inheritance of quantitative characteristics that depend on several genes is called polygenic inheritance. A combination of genetic and environmental influences is known as multifactorial inheritence.
GENE LINKAGE AND GENE MAPPING
Mendel's principle that genes controlling different traits are inherited independently of one another turns out to be true only when the genes occur on different chromosomes. The American geneticist Thomas Hunt Morgan and his co-workers, in an extensive series of experiments using fruit flies (which breed rapidly), showed that genes are arranged on the chromosomes in a linear fashion; and that when genes occur on the same chromosome, they are inherited as a single unit for as long as the chromosome itself remains intact. Genes inherited in this way are said to be linked.
Morgan and his group also found, however, that such linkage is rarely complete. Combinations of alleles characteristic of each parent can become reshuffled 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, moulds, 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.
SEX AND SEX LINKAGE
Another contribution to genetic studies made by Morgan was his observation in 1910 of sexual differences in the inheritance of traits, a pattern known as sex-linked inheritance.
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 Xs: a female offspring. The union of an egg with a 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 disease called haemophilia, 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 haemophilia. 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 haemophilia. 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 haemophilia. 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 haemophilia. Many other conditions-including red-green colour blindness, hereditary nearsightedness, night blindness, and ichthyosis (a skin disease)-have been identified as sex-linked traits in humans.
GENE ACTION: DNA AND THE CODE OF LIFE
For more than 50 years after the science of genetics was established and the patterns of inheritance through genes were clarified, the largest questions remained unanswered: how are the chromosomes and their genes copied from cell to cell, and how do they direct the structure and behaviour of living things? Two American geneticists, George Wells Beadle and Edward Lawrie Tatum, provided one of the first important clues in the early 1940s. Working with the fungi Neurospora and Penicillium, they found that genes direct the formation of enzymes through the units of which they are composed. Each unit (a polypeptide) is produced by a specific gene. This work launched studies into the chemical nature of the gene and helped to establish the field of molecular genetics.
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. The four nitrogen bases are adenine (A), thymine (T), guanine (G), and cytosine (C).
In 1953, putting together the accumulated chemical knowledge, geneticists James Dewey Watson of the United States and Francis Harry Compton Crick of Great Britain worked out the structure of DNA. This knowledge immediately provided the means of understanding how hereditary information is copied. Watson and Crick found that the DNA molecule is composed of two long strands in the form of a double helix, somewhat resembling a long, spiral ladder. The strands, or sides of the ladder, are made up of alternating phosphate and sugar molecules. The nitrogen bases, joining in pairs, act as the rungs. Each base is attached to a sugar molecule and is linked by a hydrogen bond to a complementary base on the opposite strand. Adenine always binds to thymine, and guanine always binds to cytosine. To make a new, identical copy of the DNA molecule, the two strands need only unwind and separate at the bases (which are weakly bound); with more nucleotides available in the cell, new complementary bases can link with each separated strand, and two double helixes result. If the sequence of bases were AGATC on one existing strand, the new strand would contain the complementary, or "mirror image", sequence TCTAG. Since the "backbone" of every chromosome is a single long, double-stranded molecule of DNA, the production of two identical double helixes will result in the production of two identical chromosomes.
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. 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.
° The Genetic Code
Since proteins were shown to be products of genes, and each gene was shown to be composed of sections of DNA strands, scientists reasoned that a genetic code must exist by which the order of the four nucleotide bases in the DNA could direct the sequence of amino acids in the formation of polypeptides. In other words, a process must exist by which the nucleotide bases transmit information that dictates protein synthesis. This process would explain how the genes control the forms and functions of cells, tissues, and organisms. Because only four different kinds of nucleotides occur in DNA, but 20 different kinds of amino acids occur in proteins, the genetic code could not be based on one nucleotide specifying one amino acid. Combinations of two nucleotides could only specify 16 amino acids (42 = 16), so the code must be made up of combinations of three or more successive nucleotides. The order of the triplets-or, as they came to be called, codons-could define the order of the amino acids in the polypeptide.
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.
° Transcription
The production of a strand of messenger RNA by a particular sequence of DNA is called transcription. While the transcription is still taking place, the mRNA begins to detach from the DNA. Eventually one end of the new mRNA molecule, which is now a long, thin strand, becomes inserted into a small structure called a ribosome, in a manner much like the insertion of a thread into a bead. As the ribosome bead moves along the mRNA thread, the end of the thread may be inserted into a second ribosome, and so on. Using a very high-powered microscope and special staining techniques, scientists can photograph mRNA molecules with their associated ribosome beads.
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 fulfils within the organism.
In bacteria, viruses, and 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.
° Introns
A recent and unexpected discovery is that in higher organisms the genes are interrupted. Within the length of a sequence of nucleotides that codes a particular polypeptide may be one or more interruptions by noncoding sequences; within some genes as many as 50 or more of these intervening sequences, or introns, may be found. During transcription the introns are copied into RNA along with the coding sequences, producing an extra-large RNA molecule. The sequences corresponding to the introns are then exactly chopped out of the RNA, by special enzymes in the nucleus, to form the mRNA that is exported to the cytoplasm.
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 for Chemistry in 1980.
° 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, and their function is unknown. Among them are sequences that seem able to jump from place to place in a chromosome, or from one chromosome to another. These "transposons", or transposable elements, may cause mutations (see below) in the genes adjacent to their points of arrival or departure.
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.
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 (exclusively through the mother in the case of Homo sapiens), 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.
MUTATIONS
Although the replication of DNA is very precise, it is not perfect. Very rarely, mistakes do occur, and the new piece of DNA contains one or more changed nucleotides. A mistake of this kind, which is called a mutation, may happen in any part of the DNA. If it 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 haemoglobin and sickle-cell haemoglobin 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.
° 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 greatly increased 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 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. Others may be transposable elements.
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 to increase because of the propagation of new mutant individuals in a population, and the tendency to decrease because mutant individuals survive or reproduce less well than their peers. Recent human activities have tended to make the increase larger by exposure to medical X-rays, radioactive materials, and mutation-causing chemicals.
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.
° 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. People with Down's syndrome, for example, are trisomics, with three copies of the 21st chromosome.
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, such as most flowering plants and some invertebrate animals. Plant polyploids are usually larger and sturdier in form than their normal diploid ancestors. Polyploid foetuses sometimes occur in humans, but they die at an early stage of foetal development and are aborted.
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 law. 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.
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 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-favoured 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.
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 and the antigens involved in the rejection of transplanted organs, 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 schizophrenia, tuberculosis, malaria, several forms of cancer, migraine headaches, and high blood pressure. Many rare diseases are caused by recessive genes and a few by dominant genes.
The identification and study of genes are of great interest to biologists, and are also of medical importance when a particular gene is involved in disease. The human genome contains approximately 50,000 to 100,000 genes, of which about 4,000 may be associated with disease. A globally coordinated effort, called the Human Genome Project, was started in 1990 to characterize the entire human genome. The primary goal of the Human Genome Project is the generation of various genome maps, including the entire nucleotide sequence of the human genome. The Human Genome Project has been greatly assisted by the ability to clone large fragments of DNA into yeast artificial chromosome vectors for further analysis, and the automation of many techniques such as DNA sequencing.
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