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126 THE LIFE SCIENCES HEREDITY AND EVOLUTION When the Origin of Species was published in 1859, Darwin convinced biologists that all living forms are related to life in the past, from which they evolved by small changes preserved by natural selection. But the fundamental mechanism of this process eluded him. This was provided in the formulation of the rules of inheritance by Gregor Mendel, based on his observations with garden peas, which led to understanding that heredity is particulate in nature. Shortly thereafter, observations of the behavior of chromosomes, particularly the manner in which the chromosome number is halved during the formation of sperm and egg, made it apparent that the chromosomes were the carriers of these particulate genetic factors, later called "genes." In the 1920's, as a result of a large body of ingenious, elegant experimentation with the fruit fly Drosophila melanogaster, genes were shown to be arranged in single file on the chromosomes. By 1940, the chromosomal mechanisms of genetic transmission were thoroughly understood, and the concept of mutation a heritable change in a gene or chromosome so that it produces a new effect-was well established. The rules of mutation were well understood by 1950 that any individual occurrence is essentially unpredictable although the average can be mea- sured, that most mutations are harmful, and that the rate of mutation can be increased by raising the temperature, by radiation, and by a variety of chemicals. But the chemical nature of the gene itself and of the mutation process was not understood. The chemical structure of DNA, and the concept of mutation as a process involving the substitution of one of the four bases of DNA for one of the others, or of deletion of some portion of the DNA, or inversion of some portion of the molecule, or crossing-over by exchange between two genes or chromosomes, was established in the last two decades. Fundamental theory and the detailed mechanisms of genetics now rest on rather secure grounds. Population Genetics An Extension of Mendelism A new field, population genetics, is addressed to more detailed understand- ing of how mutation, selection, migration, population size, environmental conditions, and other factors influence the distribution of individuals, the character of populations, and the evolutionary process. To date, however, available methods permit the study of only microevolutionary change- changes within species rather than the study of the origin of higher cate- gories such as genera or families. The first step was to determine the rela

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FRONTIERS OF tionship between the proportions of genes in the population and the proportions of the various genetic types of individuals (genotypes) that arise by random combinations of these genes. Thus, if Pi, P.,, P3 . . . repre- sent the proportions of alternative genes at a single chromosomal locus, the genotype frequencies are given by appropriate terms in the quadratic ex- pression OPT + p., + p3 ....~2. .. . .. . ~. ,, Many natural populations are sufficiently large, and mating Is sumc~enny random for a number of traits, to demon- strate that this principle applies remarkably well. It has been a powerful tool for analyzing natural populations and determining the mode of inheri- tance of genetic traits in populations in which experimental matings are not possible, viz., man. One of the earliest demonstrations of the validity of the Drinciole was the finding that the distribution of the major blood groups of r ~ -r ~ man, A-B-O, conforms to the above rule. Because the potential number of genotypes in the population is vastly larger than the number of genes, a considerable simplification is achieved by considering changes in gene frequencies rather than genotype frequencies. In any case, in a sexually reproducing population, the genes are reasserted by the Mendelian shuffle that occurs in each generation; the effects of such reassortment are transi- tory because gene combinations are put together and taken apart with each generation. Thus, the value of considering gene frequencies rather than genotype frequencies is that the genes perpetuate themselves as intact units, whereas the genotypes are constituted anew each generation. The weakness of this simplification relates to the fact that individual genes are not completely randomized in each generation. Genes close to one another on the same chromosome often tend to be linked together in inheritance. Accordingly, a truly sufficient mathematical theory requires extremely complex models. One of the earliest contributions of population genetics was to provide understanding of the disadvantage of inbreeding. Sibling mating had long been discouraged in human tradition, and many biologists had noted the weakening effect of inbreeding. It was recognition of the fact that harmful recessive genes usually produce their effects only when present in duplicate and that the occurrence of such duplication is enormously increased by inbreeding, as evident in the occurrence of human hereditary disorders, that led to objections to inbreeding on scientific rather than social grounds. Observational and experimental population genetics started with field studies of natural populations. Although most evolutionary change is too slow to be witnessed in a human lifetime, some examples of unusually rapid evolution have been described. Among these is the evolution of "industrial melanism." As smoke from factories gradually darkened tree trunks, the light-colored forms of moths that rest on these trunks were replaced by darker forms, a phenomenon possible only under rather intensive selection ~, BIOLOGY 127

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128 THE LIFE SCIENCES pressure. This pressure was demonstrated experimentally by the observa- tion that birds selectively caught light moths from the darker tree trunks found in industrial areas and dark moths from the lighter tree trunks found in rural areas. A more recent and more unfortunate demonstration of the operation of such processes is the development of insects resistant to com- mon insecticides and of micro-organisms resistant to antibiotics. The large numbers of individual organisms of varied genotypes and the rapid rates of reproduction make possible rapid selection of such resistant mutants, which then grow out and replace the original susceptible strains. One of the greatest contributions of experimental population genetics has been the demonstration of the large amount of hidden genetic varia- bility, which is concealed in relatively constant natural populations. Cytogenetics Not long after discovery of the chromosomal basis of heredity it became apparent that, for normal development, there must be exactly the right number of chromosomes in the fertilized egg. Most species are diploid, having two representatives of each chromosome in the fertilized egg and in all the body cells derived from it. Some are polyploid having four, six, or eight chromosomes of each type. For the diploid species in particular, when there are too many or too few chromosomes, or even if there is an excess or deficiency of only a part of a chromosome, the resulting animal or plant will exhibit abnormalities and frequently cannot survive. A classic demonstration of this phenomenon was obtained by breeding studies with the common jimsonweed, Datura stramonium, which normally has 12 pairs of chromosomes in each cell. If an organism has three representatives of a particular chromosome instead of two, it is said to be trisomic. Each of the 12 possible trisomic types of jimsonweed was found to have a char- acteristic abnormal appearance. Monosomic plants with only a single representative of a given chromosome were also discovered, and these, too, had characteristic abnormalities, usually considerably more severe than the corresponding trisomics. Such data were not expected. From them came understanding of the great importance of the correct balance among genes on each chromosome. If an organism is to develop normally, not only must the genes be normal, but there must be the correct numerical balance among them. Unbalanced chromosome combinations arise because of an accident in the process of meiosis, the reduction division that yields egg or sperm cells containing half the normal complement of chromosomes of somatic cells. Such accidents are not common but neither are they exceedingly rare, and whenever they have been systematically sought they have been found.

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FRONTIERS OF BIOLOGY In agricultural practice trisomic and monosomic types have been of great practical utility. They permit the determination of both the conse- quences of a specific gene and its chromosomal location. Application of this knowledge facilitates the transfer of useful genes e.g., those for resistance to diseases, insects, or poor soil from one variety to another. It was with such techniques that the gene for rust resistance was transferred from the common weed, goat grass, into commercial wheat and, in a recent tour de force, that a useful gene was transferred from rye to wheat. Simi- larly, polyploidy can be exploited as in the creation of a new cereal crop, Triticale, an octoploid with six sets of chromosomes from wheat and two from rye. HUMAN CYTOGENETICS Adequate techniques for the study of human chromosomes were invented only a dozen years ago. In fact, they are quite unsophisticated, and it is difficult to understand the long delay in their development; even the correct number of human chromosomes was unknown until a little more than a decade ago. But because of the large body of material and great interest, human cytogenetics has advanced extremely rapidly. With the new tech- niques, a few drops of blood suffice, and knowledge of human cytology is now comparable to that of the best-studied plants. The overriding question was to what extent chromosome anomalies are responsible for human disease, malformation, or early death. The first trisomic disease, discovered in 1959, turned out to be the already familiar "mongolism" or Down's syndrome, characterized by severe mental retardation, a number of characteristic physical abnormalities, and a face that appeared to Down to resemble the mongoloid peoples, a fact that resulted in his unfortunate choice of a name for this disease. About one infant in 700 is born with this disorder, and such patients constitute as much as one third of the population in institutions for the most severely retarded. A long-standing puzzle was created by the fact that mongolism is associated with a remarkable variety of seemingly unrelated abnormali- ties. Now that the cause is known, this is not surprising, for there must be many genes on the responsible chromosome and any gene that produces an abnormal result if present three times in the genome rather than the normal two would produce this effect. This suggested an approach to finding other chromosomal diseases, and the study of patients with mental retardation and other superficially unre- lated abnormalities led almost immediately to the discovery of two other trisomic types, both new conditions previously unknown to clinical medi- cine. But nc other examples of trisomic types have been found in several years of subsequent study. Since the three known types all involve quite

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130 THE LIFE SCIENCES small chromosomes, it appears likely that trisomy for the other chromo- somes of man is simply incompatible with the development of the embryo and fetus. Experience with experimental plants and animals indicated that monosomv is more harmful than trisomy for the same chromosomes. In confirmation, a study of miscarried human embryos indicated that more than a third of spontaneous abortions are caused by tnsomy, monosomy, and more complex chromosome anomalies. An exception to the rule that chromosomes occur in identical pairs is found in the sex chromosomes X and Y (Figure 30~. Moreover, these are also the basis for the exception to the rule that monosomy is lethal since monosomic individuals with a single X chromosome and no Y chromo- some turned out to have the well-known but previously not understood No rma I Fema le lou _ |8 l~ X' f F Al I] XX XX x~ }6 tI XA &6 7 ~ 'A 10 11 1;' h' ~Ss se zz an sa 19 Tu rner's Synd rome 1 10~ '8 I! X' lA I' 11 x 1 2 3 4 S 6 X X' X' ;iX Ia ah X' .d Ah ad x! x' &. t3 14 15 16 4x AX &A ^& 19 20 2 1 22 Normal Male ,0 ~ is ax ~8 46 t hK 2 ~ If. 3 ~ 5 it X HA b' I] d~ h' l' Bitt l,6 Ace. x~ no a~ 13 t4 15 1~.; t7 1h, Ix X~ 44 ^^ I) 20 2 ~ 22 Klinefelter's Syndrome ,0u |' ~' l' dA AA X~ ~l ~2 3 4 5 6 X HA X~ ^8 AA MA ^^ FIGURE 30 Human chromosomes of the normal female and the normal male, and in Turner's syndrome and Klinefelter's syndrome. (From Metabolic and Endocrine Physiology by Jay Tepperman. Copyright (I) 1968, Year Book Medical Publishers, Inc. Used by permission. Photograph courtesy of Mary Voorhess and Lytt Gardner.)

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FRONTIERS OF BIOLOGY Turner's syndrome (small stature, amenorrhea, absence of secondary sex characteristics), while the trisomic XXY type has turned out to be the known condition, Klinefelter's syndrome (apparent male with feminine stig- mata and very small gonads). In individuals with chromosomes that have broken and been reattached, there may be no immediate abnormality, but such abnormal chromosomes complicate the normal process of sperm and egg formation, markedly increasing the likelihood of unbalanced chromo- some combinations in the next generation. This imposes a serious burden on the prospective parents, who should be made clearly aware of the poten- tial consequences. Polymorphism Naturalists have long noted that some species of animals are polymorphic, i.e., they exist in two or more quite distinct forms such as black and cinnamon bears or red and silver foxes in the same litters. Population geneticists have sought to understand this process in a general way for any gene locus. If the heterozygous individual (A,A,) is somehow selectively advantageous in comparison with either form of homozygote (A,A, or ALA, j, then both types of genes persist in the population in a stable equi- librium determined by the relative fitnesses of the two homozygotes. This has been demonstrated amply with many forms; fruit flies have been most thoroughly studied, but polymorphisms are found throughout the animal and plant kingdoms. Sickle cell anemia is perhaps the classical human example. Individuals with "normal" hemoglobin are susceptible to malaria, those with two genes for the sickle cell trait are subject to a profoundly debilitating anemia, while the heterozygote is resistant to malaria and only slightly incapacitated by having half his hemoglobin abnormal; hence, the heterozygote has a selective advantage. Accordingly, both genes flourish in African populations. As man is investigated more intensively, an increas- ing number of polymorphisms, usually detectable only at the molecular level, have become apparent; presumably all are maintained by the same . . principle. Some Recent Accomplishments A primary accomplishment of population genetics is the understanding it has provided of the nature of the evolutionary process, of the value of the sexual reproduction mechanism, and of the relation of man to all other . . . ~v~ng organisms. 131

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THE LIFE SCIENCES No chapter in modern biochemistry is of greater interest than the accumu- lated demonstration of the kinship of man to other living forms. The primary datum is the universality of the genetic code and of the operation of the genetic apparatus. The fact that the genetic code is a constant from bacteria to man to higher plants is the most cogent available argument supporting the concept that all living forms derive from a single common ancestor. At the same time, by tracing the amino acid sequences of specific proteins with essentially identical functions, it has been possible to illustrate how the process of mutation causes divergence from an original form. The most thoroughly studied such protein is the electron carrier cytochrome c. Amino acid sequences of this protein from more than 30 species are now available, and of the 105 residues in this protein, only a quarter of the positions remained filled by the same amino acid in all species. Strikingly, at what is considered to be the binding site of cytochrome c to the enzyme responsible for its oxidation, there is a run of 12 amino acids where no substitutions have occurred in recorded history. Moreover, in a general way, the number of differences in amino acid sequence between the cyto- chromes c of any two species is a function of the time since the two species separated from a common ancestral form, as indicated by the paleontologi- cal record. Accordingly, the cytochromes c of the primates, like the hemoglobins of the primates, are virtually identical, which is convincing proof on the molecular level of our common origin. In contrast to the great variability of most of the amino acids of the proteins studied to date is the remarkable constancy of structure of a histone (a basic protein bound to DNA in cell nuclei). Of the 115 amino acids in this molecule, only at one position does the histone of the garden pea differ from that of the cow, testifying to their common ancestry. One other aspect of such studies is particularly noteworthy. As one ascends the phylogenetic ladder, the DNA content of cells increases, as does the number of proteins that such organisms synthesize. How did this increase in DNA come about? The answer derives from comparative studies of amino acid sequences of diverse proteins within a given species. For example, it is apparent that much of the structure of the digestive enzymes trypsin, chymotrypsin, and elastase, as well as one enzyme that operates in the blood-clotting process, is identical. Similarly, the poly- peptide hormones of the pituitary are very much alike, and a protein hor- mone produced in the gastrointestinal tract closely resembles one produced in the pancreas. Yet all of these are quite distinct proteins at the present time. The first observation in this area was the fact that although four different types of protein chains are involved in the structure of normal human hemoglobins, these are essentially of equal length and show very large areas of identity. For each such related group, one can only conclude