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Downloaded from symposium.cshlp.org on September 12, 2016 - Published by Cold Spring Harbor Laboratory Press Evolution of Genes and Genes in Evolution THEODOSIUS DOBZHANSKY Department of Zoology, Columbia University, New York City "Even though the genius of man might make various inventions, attaining the same end by various means, it will not invent anything more beautiful, or more economical, or more direct than nature, for in nature's inventions nothing is wanting and nothing is superfluous." Leonardo da Vinci HUMAN DIVERSITY AND THE GENETIC CODE Modern man is disinclined to concede to nature as unstintingly as Leonardo did a sweeping superiority over human invention. The suppleness of the genetic mechanisms which transmit heredity from one generation to the next is, however, unequalled among human exploits. The evidence now available is overwhelmingly in favor of the view that the genetic information transmitted through the gametes is encoded primarily, though perhaps not exclusively, in deoxyribonucleic acids. The volume of these extraordinary substances in a human gamete amounts, according to the figure quoted by Muller (1958), to about four cubic microns, and the weight to a mere 4 X 10-~2 grams. The number of persons living will soon reach three billion, or 3 X 109 people. They will have arisen from 6 N 109 gametes. It follows that the total volume of the physical carriers of the genetic information which the species Homo sapiens will have received from its ancestors will amount to a paltry 2.4 mm ~, and the aggregate weight will be some 24 mg. This is about equal to a raindrop. How can the genetic individuality and distinetiveness of every human being in the whole world reside in so minute an amount of material? To resolve this mystery has been, and still continues to be, the main task, or at any rate one of the main tasks, of genetics. The efforts of Mendel, Morgan, Muller, and of many other geneticists, biologists, and biochemists, extending for almost a century up to the present, have cleared up large segments of the mystery, or at ]east made them less baffling. It will be convenient for our purpose to begin the consideration of the problem with one of the most recent advances, rather than in the historical order. A detailed exposition of the brilliant hypothesis of Watson and Crick (1953) and Crick (1954, 1957) is quite unnecessary for our present purpose. Its essentials are that deoxyribonucleic acids (DNA) consist of a double helix of polynueleotide chains; the two chains of the helix are held together by hydrogen bonds between their component purine and pyrimidine bases; two purines, adenine and guanine, and two pyrimidines, cytosine and thymine, are found; adenine in one chain is always linked to thymine in the other, and guanine to cytosine. Analysis of DNA from different organisms has shown that the adenine: guanine and thymine:cytosine ratios vary from species to species, while the adenine:thymine and guanine:cytosine ratios are always close to unity. According to Dunn and Smith (1958), a part of the adenine in the DNA of at least some strains of the bacteria Escherichia colt, Aerobacter, Mycobacterium, and some others is replaced by a related compound, 6-methytaminopm'ine. Similarly, a part of the cystosine in the DNA of some higher animals is replaced by 5-methylcytosine. Innumerable words can all be represented by different combinations of the 26 letters of the Latin alphabet. The genetic "alphabet" contains only four "letters"--the four nucleotide bases. It is nevertheless capable of specifying the differences between countless genes. Suppose that a gene is a section of the helix covering only ten nucleotide-pairs. The number of possible permutations of four letters in a ten-letter "word" is 4'% or 1,048,576. A gene may actually contain hundreds or even thousands of linearly arranged nucleotides. Provided that there are no restrictions on the proportions or on the order of the nucleotide-pairs, the numbers of the possible variant structures (alleles) of genes is immense. Muller (1958) goes daringly much beyond this, basing his speculation on Benzer's (1955, 1957) brave hypothesis that a mutation, at least in the bacteriophage, may involve substitution, loss, or insertion of a single nucleotide-pair in the WatsonCrick double helix. Muller assumes that the entire 4 N 10-12 grams of DNA in the haploid chromosome set in a human gamete is uniquely represented genetic material (concerning the validity of this assumption see, however, below). Since the mass of one nucleotide pair is about l 0 -2' grams, there must be some 4 X 109, or four billion, nucleotide pairs in a human gamete. With four kinds of nucleotides, and making the same assumptions as above, this makes four to the four-billionth power, or about 102,~~176176176176 possible genetic endowments. This is as good an "infinity" as ever envisaged for anything. 15 Downloaded from symposium.cshlp.org on September 12, 2016 - Published by Cold Spring Harbor Laboratory Press 16 DOBZHANSKY ORGANIC DIVERSITY Mankind is certainly not the most numerous species on earth. Dr. C. B. Williams (private communication) estimates that the number of existing species of insects may be of the order of 2 • 106, and of living individual insects of the order of 1018. This would mean an average of about 5 X 101I individuals per insect species, but some species are undoubtedly much more numerous, and many others much less numerous than the average. Both the numbers of species and of individuals of animals which stand in the zoological system higher than insects is virtually negligible compared to the diversity and the abundance of the insects. I can find no estimates, however rough, of numbers of individuals of higher plants, but they can hardly exceed the insect populations by more than one or two orders of magnitude. Lower animals at least equal the insects in numbers of individuals, though certainly not of species. Thus, soil nematodes seem to be, according to some counts, more numerous than insects in at least some climates. Among microorganisms, the numbers of individuals are surely much greater than among the higher forms of life. And yet, the potentialities of genetic mechanisms to generate a diversity of genotypes are more than ample to confer genetic individuality even on microorganisms. Thus Benzer (1957) estimates that the genetic material of the bacteriophage T-4 particle consists of between 2 X 105 and 8 X 10 ~ nucleotide pairs. Even if every bacteriophage particle had a genotype different from every other, they would embody only an insignificantly small fraction of the possible genotypes (48~176176176 or more, using Muller's method of computation). Of course where asexual reproduction is the usual or the exclusive method of propagation, as it is in many lower organisms, clones are formed which consist of individuals which, barring mutation, have the same genes. The four-letter "genetic alphabet" is, to use Leonardo's words, a beautiful, economical, and direct means to create an ample supply of genetic raw materials from which evolutionary changes can be constructed. This is evident despite the many uncertainties in the above speculations and calculations. Perhaps one of the gravest uncertainties concerns the assumed identity of the entire mass of D N A in a gamete, or in a cell in unicellular organisms, with the unique carriers of the genetic information. We see nothing strange in the assumption that a human gamete carries some four billion nucleotide pairs, or at least 10,000 times as much as is found in a bacteriophage. Man, the crown of creation, is entitled, we feel, to have more, and more complex, genes than a lowly bacteriophage. However, comparison of a wider variety of organisms discloses some unexpected situations, as illustrated by Table 1 (compiled from the publications of Mirsky and Ris, 1951, and Vendrely, 1958). TABLE 1. D N A CONTENT, IN MG X 10-9, PER DIPLOID NUCLEUS IN DIFFERENT ANIMALS (After M i r s k y a n d Ris, a n d Vendrely) Organism Sponge Jellyfish Sea urchin Limpet Crab Shark Sturgeon Carp Trout Lungfish Amphiuma Necturus Frog DNA 0.11 0.66 1.96 1.00 2.98 5.46 3.2 3.5 4.9 100 168 48 15 Organism Toad Green turtle Alligator Fowl Goose Rabbit Guinea pig Rat Horse Cattle Pig Dog Man DNA 7.3 5.3 5.0 2.3 2.9 5.3 5.9 5.7 5.8 6.4 5.1 5.3 6.0 Man and other mammals have about twice as much D N A in their nuclei as a crab has, three times as much as a sea urchin, five to six times as much as a limpet, and some fifty times as much as a sponge. So far so good; but the frog exceeds man by a factor of more than two, the lungfish Protopterus by at least sixteen, and the urodele amphidian, Amphiuma, by more than twenty five. The D N A contents of the nuclei tend, on the whole, to parallel the cell size, and the cells of Necturus, Protopterus, and Amphiuma are remarkably large. Cells are usually larger in polyploids than in the diploids from which they are derived. There is, however, no reason to believe that any of these animals are high polyploids, and it is hard to make sense of the supposition that they need more numerous or more complex and larger genes than man does. Other possible surmises are about equally unattractive. One may suppose that only a part of the D N A contained in a chromosome is the carrier of the genetic information which replicates itself, while the remainder is not replicated. Or else, a part of the DNA, though it does replicate itself, represents "nonsense combinations" of the nueleotides, a sort of a useless ballast in the chromosome. It is also possible that, at least in some organisms, chromosomes contain not one double helix of polynucleotie chains but several or many replicate helices held together like separate wires in an electric cable. The first of these conjectures is not easily reconciled with certain observations on the autoradiographic behavior of chromosomes labeled with tritiated thymidine (Taylor, Woods, and Hughes 1957). The third is not in accord with the fact that most gene mutations induced in the gametes by X rays and other means alter the whole bodies, and not only parts, of the bodies of the zygotes which arise from such m u t a n t gametes. One can only conclude that as yet no satisfactory understanding of the situation has been reached. Downloaded from symposium.cshlp.org on September 12, 2016 - Published by Cold Spring Harbor Laboratory Press EVOLUTION OF GENES AND GENES IN EVOLUTION CONCEPT OF PARTICULATE HEREDITY Unfashionable though such an idea may be in this day of molecular biology, it should be kept in mind that a living body is more than a container for a mixture of chemicals. Knowledge of the chemical composition would, by itself, tell us about the organism roughly as much as a chemical analysis of an automobile would about the motor vehicle. This is obviously not to deny that the component parts of an automobile must be made of proper materials to function properly. Organization as well as composition of the protoplasm are essential for life, and both have developed and become perfected in the process of evolution. The methods used to secure an understanding of the nature of the genetic code fall into two classes. The first is the Mendel-Morgan method of crossing and analysis of hybrid generations, from which inferences are drawn concerning the architecture of the germinal materials. The second is the method of chemical and physical investigation of these materials. An entirely satisfactory synthesis of the results of these two types of studies is probably not yet in the realm of what is achievable. However, it is not premature to survey the outlines of the situation which is emerging, and such surveys have been attempted from time to time, with varying degrees of success by many geneticists. One of the most recent and most successful is that of Pontecorvo (1958). In the present Symposium, our interest in this matter is perhaps tangential but nevertheless very real. Since evolution is a change in the genetic structure of living matter, an at least provisional genetic theory free of overt contradictions is an indispensable part of the twentieth century Darwinism. The enduring achievement of Mendelian-Morganian genetics is the demonstration that the hereditary materials transported in the gametes are arrays of discrete units known as genes. ("Mendelian-Morganian" genetics is sometimes contrasted with Michurinist-Lysenkoist pseudogenetics. Since the latter belongs to the category of superstition rather than science, MendelianMorganian is a fair label to describe that part of genetics which uses analysis of hybrid generations as its most distinctive tool). Even though the gene-particles are not quite the windowless monads envisaged by classical geneticists, at least some discontinuity in the germinal materials is incontrovertible. The raw materials of evolution are, accordingly, changes in structure, number, or relative position of the genes. These raw materials are acted upon by sexual recombination, natural selection, and random genetic drift. Interactions of these factors lead to changes of frequencies, or to substitutions of one or more genes in living populations. Such alterations are the elementary evolutionary events. (Not enough is known about changes in the cytoplasmic germinal materials to have their proper places assigned 17 among the raw materials of evolution and among the elementary evolutionary events. It appears likely that most, or even all, cytoplasmic genetic materials will be shown to be self-reproducing particles. If so, their eventual inclusion among the components of the evolutionary process should present no great difficulty). Mendelian-Morganian genetics has made it exceedingly probable that evolutionary changes are reducible ultimately to gene changes. This indeed is important enough. But genetics has accomplished something else as well; it has clarified the evolutionary role of sexual reproduction. A majority of species of organisms now living reproduces sexually; this has been the case apparently since Cambrian times, or earlier. Mechanisms which bring about exchanges of germinal materials between different strains within a species have in recent years been discovered even in forms in which true sexual reproduction is lacking. What, however, are the consequences of such exchange? Seeing that children are usually intermediate between the parents, pre-Mendelian biologists inferred that the heredities of the parents commingle and blend in the offspring. This seemed reasonable enough to many physiologists, even to so brilliant a one as Jacques Loeb. Darwin, though very reluctantly, made the same inference. But if the parental heredities really blended in the offspring, then sex would be a conservative force, a great leveler, and at least a brake if not a complete checkmate on evolution. A newly arisen mutation would, in a few generations, be dissolved in the prevalent type, like a drop of ink in a sea. Worse still, starting with a genetically variable population, for example a population containing large and small, or dark and light individuals, some generations of sexual interbreeding would yield a genetic uniformity-an intermediate pure race. The concept of particulate heredity changes the situation completely. Particles do not blend or dissolve, they segregate. This is a direct corollary of Mendel's discovery. To us, having the advantage of hindsight, this deduction seems crystal-clear, almost to the point of banality. It was, in fact, arrived at but slowly. As is generally known, Hardy and Weinberg, independently but in the same year, 1908, pointed out that the genetic composition of a sexually-reproducing population should remain constant through a series of generations. The full evolutionary implications of this constancy were first realized, and clearly expounded, in a remarkable but little known work of Chetverikov, in 1926. The constancy, the genetic equilibrium discovered by Hardy and Weinberg, describe the statics of the population. They obtain in the absence of disturbing factors, mutation, selection, and random genetic drift. These disturbers of the equilibrium are the dynamic forces acting on populations. They are the causes of evolution. A translation of a part of Chetverikov's work is Downloaded from symposium.cshlp.org on September 12, 2016 - Published by Cold Spring Harbor Laboratory Press 18 DOBZHANSKY found in an appendix to the present article. The same ground was traversed again, with much mathematical elegance and refinement, in Fisher's well-known book in 1930. This was followed by Wright's analysis in 1931. Population genetics was thus launched. Heredity being particulate, sex is not only exculpated of any suspicion of being a brake on evolutionary change; sexual reproduction becomes one of the most important evolutionary mechanisms. Under asexual reproduction, every mutational change yielding the components of a new adaptive genotype must arise in the same line of descent. In sexual Mendelian populations, mutants arisen in different places and at different times may be combined in a single genotype, owing to Mendelian recombination. Furthermore, astronomical numbers of genotypes become potentially possible. Recombination in the progeny of hybrids heterozygous for n genes may yield 3" genotypes, 2 n of them homozygous ones. 1 Be it noted that Hardy-Wemberg-Chetverikovian deductions are valid regardless of whether genes are absolutely discrete "beads-on-string", as they were pictured in classical genetics, or merely functional blocks of nucleotide pairs in the Watson-Crick double helix. The point crucial for these deductions is that the genes segregate and recombine, as shown by Mendel and as seen in countless experiments made following the Mendelian discovery. Nevertheless, genes are not only atoms of evolution but are themselves evolving organic systems. The nature of these systems is clearly one of the modern evolutionist's concerns. CONTINUITY AND DISCONTINUITY OF GENES The ideas held by geneticists concerning the genes have been undergoing a progressively accelerating, and on the whole progressive, evolution for almost a century. Mendel's great work describes the inheritance of "characters"--colors, shapes, and sizes of pea plants. He realizes, however, that the "characters" must be somehow present in the generative elements as well as in the mature plants: " . . . . The theory is confirmed that the pea hybrids form eggs and pollen cells which, in their constitution, represent in equal numbers all constant forms which result from the combination of the characters united in fertilization." And towards the end of his paper, almost 1Pontecorvo (1958), p. 134) writes: " . . . T h e discovery of the versatility of recombination has made nonsence of the specious arguments which used to be produced for reconciling with neo-Darwinism the widespread occurrence of asexual microorganisms. We realize now that, if in an organism there is no obvious sexual cycle, we had better find out which other process of recombination is operating". This, I submit, is a misunderstanding. Gene recombination, by whatever process, may unite genetic variants arising in different lines. If, however, organisms in which no genetic recombination takes place are frequent, then the "specious arguments" remain necessary. If they are rare the problem ceases to exist. as an afterthought, Mendel adds: " T h e differentiating characters of two plants can finally, however, only depend upon differences in the composition and grouping of the elements which exist in the foundation cells of the same in vital interaction." After the rediscovery of Mendel's work in 1900, his chaste "characters" did not long remain unentangled with doctrines of a cruder material sort. In 1903, Sutton and Boveri independently guessed that the Mendelian "characters" must be borne in the chromosomes of cell nuclei. This was a remarkably lucky guess, considering the time when it was made; it served to open a whole new field of studies, cytogenetics. Johannsen, who coined the word gene in 1909, wanted, however, to be as puritanical about his gene concept as a crusty Calvinist elder. To him, " T h e word gene is, thus, fully free from every hypothesis. It expresses only the fact that at least many properties of the organism are determined by special, at least partly separable, and therefore to some extent independent "states", "factors", "units", or "elements", in short by what we shall call genes, which are present in the gene cells." The puritanical, abstract genes rapidly got out of fashion. In 1919, Morgan wrote that "We are led, then, to the conclusion that there are elements in the germplasm that are sorted out independently of one another . . . . These elements we call genes, and what I wish to insist on is that their presence is directly deducible from the genetic results (segregation in hybrids), quite independently of any further attributes or loealizations that we may assign to them. It is this evidence that justifies the theory of particulate inheritance." But further attributes are assigned to the genes on the very next page: " . . . . The gene is a certain amount of material in the chromosome that may separate from the chromosome in which it lies, and be replaced by a corresponding part (and by none other) of the homologous chromosome." Moreover, Morgan definitely broke away from the old preformlst notion, that a gene "represents" in germplasm a part, or a "character", of the adult body. He wrote that "first, each gene may have manifold effects on the orgamsm, and, second, that every part of the body, and even each particular character, is the product of many genes . . . . I t m a y also be well to point out that even if the whole germ plasm, the sum of all the genes, acts in the formatmn of every detail of the body, still the evidence from heredity shows that this same material becomes segregated into two parts during the maturation of the egg and sperm, and that at this time individual elements separate from each other largely independently of the separation of other pairs of elements. It is in this sense, and in this sense only, that we are justified in speaking of the particulate composition of the germ plasm and of particulate inheritance." The "bead-on-string" analogy, representing the Downloaded from symposium.cshlp.org on September 12, 2016 - Published by Cold Spring Harbor Laboratory Press EVOLUTION OF GENES AND GENES IN EVOLUTION genes as wholly independent particles, packed in chromosomes in a fortuitous linear order, arose perhaps as a text book oversimplification of Morgan's conception. But it is only fair to point out that, in the twenties and the early thirties, this notion probably had the virtues of a working hypothesis. It was pushed as far as it could go without meeting stubborn resistance of incompatible facts. Such faets began to appear with Sturtevant's discovery in 1925 and 1928 of the position effects at the Bar "locus" in Drosophila, which a few years later was shown, by Bridges and by Muller, Prokofieva-Belgovskaia, and Kossikov, to be aetually a duplication for a short segment of a chromosome. In the thirties, the discovery that chromosomal aberrations are induced by X rays opened up new possibilities of genetic and eytogenetic studies. Many transloeations and inversions were obtained in Drosophila, which carried the same genes as "normal" flies, but arranged in different linear orders in the chromosomes. In many eases these genes were observed to act differently when their arrangement in the chromosomes was altered. This began to look like real interdependenee of genes which were neighbors in the same chromosome. A personal reminiscence may be in order here. Late in 1932, I had an opportunity to demonstrate to Professor R. Goldsehmidt some translocations in Drosophila which yietded perceptible position effects. His reaction was emphatic: such an hypothesis would mean the overthrow of the gene theory! His repudiation of the gene theory came soon thereafter (Goldschmidt 1935, 1938). Other geneticists refused, however, to be impaled on the horns of the dilemma--absolutely independent genes or no genes at all. As instances of position effects multiplied more and more (see especially Dubinin and Sidorov 1934 and Lewis 1945), two types of explanations of these phenomena were ventured. Muller and Prokofieva (1935) pointed out the possibility of " . . . . a higher degree of interaction between locally more concentrated products of gene aetivity than between more distantly produced and either more diluted or changed produets" (see also Lewis 1950). The present writer (Dobzhansky 1936) ventured what at that time seemed a less orthodox surmise, namely that, "The genes may be pictured as organic molecules united with each other in the longitudinal direetion to form micelles, after the fashion of the eellulose micelles. Breakage of such a mieelle, and the formation of a new mieelle, may involve modifications of the intergenic bonds which may or may not be reversible in ease the original gene order is restored." Beginning particularly in the forties, genetic studies on bacteria, viruses, and lower fungi rapidly led to a tremendous refinement of what Ponteeorvo (1958) aptly describes as the resolving power of genetic analysis. We have seen above that the Morganian genes were elements "sorted out independently of one another." 19 In other words, they were units of Mendelian segregation. But the segregation is observed in heterozygotes which carry two variant forms, two alleles, of a gene. Alleles arise by mutation, and genes came to be regarded as units of mutation. When a gene is observed to mutate repeatedly, its different mutant alleles affect, as a rule, the same trait or function of the body. Genes were believed to be also units of function. This oversimplification has crumbled under the impact of the battering ram of the higher resolving power of genetic analysis. The units of segregation, of mutation and of function are not neeessarily coincident. It would do injustice to the many ingenious studies of the structure and function of the genetic units which have appeared in reeent years to attempt to single some of them out for review here. I prefer rather to refer the reader to the short but informative book of Ponteeorvo (1958), to the relevant parts of the Cold Spring Harbor Symposia on Quantitative Biology held in 1951, 1953, 1956, and 1958, to the Symposium on the Chemical Basis of Heredity (W. D. MeElroy and Bentley Glass, Editors, 1957), and to the collection of papers by Demeree et al. (1956). It should also be pointed out that essentially convergent information bearing on the problem of gene structure has been obtained in organisms as diverse as mice, Drosophila, maize, cotton, Aspergillus, Neurospora, yeast, Escherichia, Salmonella, bacteriophage T4 and others. The smallest genetical variables appear to be mutational "sites". The lower limit of a mutational site is, as mentioned above, a single "letter" of the "genetic alphabet", i.e., a single nucleotide pair in a Watson-Crick double helix. The units of recombination may or may not be larger than the mutational sites. If they will prove to be larger, this will mean that crossing over does not occur indiscriminately between any two nucleotide pairs but only between certain fixed blocks of them. And finally, the genes as functional units contain, at least sometimes and possibly always, several to many units of recombination. Different changes in the same gene were recognized in classical genetics because they behaved as Mendelian alleles in crosses. Suppose that we have several recessive mutants which more or less resemble each other in phenotype. Recessive mutants are regarded as allelic if they do not complement each other's action in heterozygotes, i.e., if the heterozygotes show the recessive phenotype. Recessive mutants are non-allelic, represent changes in different genes if they are complementary to each other, and the double heterozygotes have the "normal" dominant phenotype. Now, mutations in adjacent mutational sites or recombination units may act as so-called position pseudoalleles. Pseudoallelic recessive mutants complement each other when they lie in the same chromosome (in the "cis" arrangement, i.e., rir2 in one chromosome and +1+2 in the other chromosome), but are only partially Downloaded from symposium.cshlp.org on September 12, 2016 - Published by Cold Spring Harbor Laboratory Press 20 DOBZHANSKY complementary, or not complementary at all, when they are in the "trans" arrangement (i.e., r1+2 in one chromosome and +1r2 in the other). To quote Pontecorvo (1958): "Thus in the cis-trans test we have an additional criterion to that of non-complementarity for concluding that the degree of functional integration between the sites of one gene is more intimate than that between the sites of two genes. We have, in fact, an objective test, purely genetical and not requiring any biochemical analysis, for defining a unit of function in heredity. . . . The difference between allelism and non-allelism arises at the transition between complementarity only in the cis arrangement, and complementarity irrespective of arrangement. This transition defines the 'cistron' in the case of recessive mutants." The possibility that the cistrons may sometimes be overlapping is not excluded, and everything points to the conclusion that every cistron contains more than one, possibly as many as a thousand or more, mutational sites, and perhaps several to many recombinational units. EVOLUTION OF THE G E N E STRUCTURE The units of heredity have suffered the same fate as the units of chemistry. The "indivisible" atoms proved to be like miniature solar systems; fixed numbers of planet-like electrons whirl around a sun-like nucleus, which is in turn composed of other subatomic particles. The "bead-on-string" gene has resolved itself into a section of a string of nucleotide pairs. This is, however, not an undifferentiated string, for its sections are functional units; they are different genes or cistrons. If the nucleotide pairs be likened to letters, then a gene is like a word, or even a sentence. It is an open question whether the words and sentences in the genetic "message" are separated by spaces and punctuation marks, or whether they follow one after the other without interruptions, like words in ancient inscriptions. It may even be that the letters in the adjacent genetic "words" are sometimes jumbled together. It seems to me necessary to point out that, contrary to what is sometimes alleged, the recent developments in genetics have in no sense vindicated Goldschmidt's famous disallowance of the existence of genes. Goldschmidt was a great geneticist and a great mind; he performed well and with dignity the important function assigned by Goethe to Mephistopheles: to keep people, in this case geneticists, intellectually on their toes. This function is all too easily pre-empted by failures in original scientific research, or even by mountebanks, whose only qualification is their intellectual sterility. However, Goldschmidt's ideas that the genetic material in the chromosome is functionally a continuum, and that rearangements of this continuum would result in so-called systemic mutations, have at best a coincidental resemblance to the new findings. This is not a proper place to discuss Goldsehmidt's unconventional ideas about evolution, but there is no escape from the conclusion that they have found no confirmation eitherY On the assumption that all life on earth is ultimately monophyletic, the genes of a virus particle and human genes are the products of equally long evolutionary histories. (This assumption may be difficult to reconcile with the fact that the genetic information in some plant viruses is coded in ribonucleic acids, RNA, rather than in DNA). In a sense, these histories may be recorded in the gene structure. Some attenuated version of the old-fashioned biogenetic law may apply to gene structures as well as to embryonic structures. However that may be, the gene structure has certainly evolved, and the question what this evolution was must sooner or later be raised. The origin of life is ground which angels, or at least geneticists, fear to tread. Yet the splendid work of Kornberg and his school (see Bessman et al., 1958, and Lehman et al., 1958, for further references) seems to contain a real promise that the Riddle of the Sphinx may be answered in a not too distant future. These authors have obtained synthesis of DNA from four deoxynucleoside triphosphates (adenosine-, guanosine-, cytidine-, and thymidinc-triphosphates), in the presence of an enzyme isolated from the cells of colon bacteria, of magnesium ions, and of a small amount of a DNA "primer". The DNA synthesized has apparently the double-helical structure demanded by the Watson-Crick model. But the most remarkable fact is that the DNA synthesized resembles in composition the DNA used as the primer. Primers obtained from different organisms cause the synthesis of their own copies. It looks as if the primer DNA reproduces itself from the raw materials (the four deoxynucleoside triphosphates) supplied by the experimenter. This comes closer to realization of the homunculus dream then anything claimed since Paracelsus. We do not know what the primordial genes were like. They certainly synthesised their own copies from materials drawn from their environment; they probably had a chemical constitution related to the nucleic acids--DNA or RNA; and just possibly they acted like Kornberg's primers. Speculations concerning the origin of life on earth assume that some organic compounds (such as amino acids, and perhaps purines and pyrimidines) were formed in the primeval seas by nonliving agencies. The primodial life supposedly 2 Digressing for a m o m e n t from the sublime to the ridiculous, one should take note of t h e efforts of Lysenkoists to find a way of r e t r e a t from t h e i r indefensible positions. T h e y now claim t h a t the recent discoveries in genetics merely confirm w h a t M i c h u r i n was saying long ago, a n d even w h a t Lysenko was saying more recently. This line has been t a k e n in m a n y recent Russian publications (for example, N u j d i n 1958), a n d at least one w r i t t e n in E n g l i s h (Michie 1958). Downloaded from symposium.cshlp.org on September 12, 2016 - Published by Cold Spring Harbor Laboratory Press EVOLUTION OF GENES AND GENES IN EVOLUTION utilized these organic compounds for "food" and as building blocks for self-reproduction. Since, however, such compounds existed in only low concentrations and were soon exhausted, natural selection put a high premium on the ability of genes, and eventually of organisms, to build themselves from simpler substances. An important achievement of the evolution of life was the appearance of fully autotrophic organisms, such as green plants, able to build their bodies from inorganic salts, water, CO2, and to utilize the energy of the solar radiations. It seems plausible, although there is obviously no direct evidence for this view, that the genes had to evolve more complex structures as the complexity of the metabolic activities became more and more advanced. A single virus-like gene was no longer sufficient, and symbiotic groups of them had to be formed to cope with greater synthetic demands. Such groups of genes had to form something like chromosomes, to insure accuracy in reproduction. Gene recombination and sexual reproduction were the next capital achievements of the evolutionary process. The advent of gene recombination and of sex made heavy demands on the gene structure. This matter was discussed by Sewall Wright in his Presidential Address at the Genetic Congress in Montreal (thanks are due to Professor Wright for his permission to quote his work before publication). The basic considerations are simple enough. Where the reproduction is exclusively or at least predominantly asexual, the chromosome may really be nothing other than a succession of different functional sections of the Watson-Crick double helix, following each other without interruptions. The occurrence of meiosis, parasexuality, or transduction may initially be compatible with recombination taking place between any two nucleotide pairs. Suppose, however, that, in an organism like maize, Drosophila, or man, the genes (cistrons) are sections of the helix containing some 1000 nucleotide pairs, and that the populations carry many variable genes, each represented by several or many alleles. Recombination within a cistron would then cause changes resembling mutations, and natural selection would be expected to act to promote a reasonable stability of the adaptively successful gene alleles. This will lead to a functional integration of the genes (cistrons), and a restriction of the recombination to the intergenic connecting links. Several possible solutions of the above biological problem can easily be visualized. One of them is that the genes, the physiologically significant sections of the DNA helix, may be separated by physiologically relatively inert stretches of the same material. Crossing over would then occur predominantly or exclusively, in these intergenic connecting links of the helix. The genetic materials in the simplest forms of life, such as viruses and bacteria, may be little differentiated continua, but this is quite unlikely in higher organisms. In 21 fact, we have conclusive evidence that the chromosomes in higher organisms consist of more or less discrete segments, and this evidence is no less conclusive because it is old and is, or at least should be, well known. I mean, of course, the chromomeric structure of the chromosomes in meiotic prophases and in the giant chromosomes of the salivary glands in Diptera. One of the polemical footballs of cytology used to be whether the chromomeres are actual thickenings of the chromonema, or merely localized tighter coils of that chromonema. This we may well leave to the cytologists to settle; either way, the chromomeres visibly and clearly testify that the chromosomes of a Drosophila, maize, or a grasshopper contain a succession of qualitatively different and discrete segments linearly arranged. It is nature's fault, not that of geneticists, that the microscopicMly observable pictures do suggest the "bead-onstring" analogy. We do not, of course, know whether the "string" as well as the "beads" may carry some genetic information, but the discontinuity in the chromosome's components is evident enough. GENE HOMOLOGY The evidence presently available seems to show that the DNA nucleic acids extracted from quite dissimilar organisms are built of the same components, the two purine and two pyrimidine bases, pentose sugars, and phosphoric acid. In this sense, all genes in all organisms are alike in composition. At least ignoring the RNA viruses, it might appear that there has been no evolution at all in the chemical components of the genes. All this may well be true; nevertheless, it is more correct to say that, as far as we know, no new "letters" have been added to the genetic "alphabet" in the course of evolution. The genetic "language" has evolved entirely on the level of "words" and "sentences", not on the level of the "letters". The fact that the genetic "messages" transmitted from generation to generation in amoeba and in man are composed of the same "letters" is, however, not stranger than that the same alphabet can be used for languages as heterogeneous as English, Finnish, Turkish, and even Japanese. I have hitherto, and quite deliberately, refrained from asking the obvious question, how many and how profound are the gene changes in evolution? There is no unanimity concerning the answer among evolutionary geneticists. Two fairly distinct views have emerged. The first is that rather few mutations suffice to account for evolution; the second proposes that most genes must have changed many times, and, at least in the aggregate, radically. The first, and the older of the two views, goes back to Morgan and to De Vries. De Vries believed that new species arose through single mutations, but to him a mutation did not mean a change in a single gene. Later on, new races and species were supposed to incorpo- Downloaded from symposium.cshlp.org on September 12, 2016 - Published by Cold Spring Harbor Laboratory Press 22 DOBZHANSKY rate one or several lucky mutant genes or chromosomal changes, which happened to be favorable in some environments. A great majority of the genes composing a genotype were, however, assumed to be alike in at least closely related species, and even in not so closely related ones. Perhaps the most explicit recent statement of this view is that of Sturtevant (1948). A not illogical corollary was that similar genes may be found in quite remote forms of life, and that, in fact, some genes may have never changed in the evolution at all. Evidence of this was seen in the presence of similar or homologous organs, and particularly of similar chemical constituents, in organisms remote in the biological system. Yeast cells and human cells have a number of similar enzymes; why not also similar genes? According to the second view, evolution involves far-reaching reconstructions of integrated gene systems. Evidence of this comes, before all else, from genetic analyses of differences between related species, and also between subspecies or races. At least in higher organisms, such differences, whenever adequate analysis is possible, are shown to be compounded of not easily countable, but certainly numerous, polygene differences. The gene pool of a Mendelian population usually contains a multitude of unfixed genes. As a consequence, most individuals in such populations are complex heterozygotes; different individuals differ in many genes; and no two individuals, excepting identical twins, are likely to have the same genotype. Everyday experience shows that every person is recognizably different from all other persons, owing to numerous small differences in many bodily features. These differences are conditioned by genetic variations, mostly of polygenic nature. I do not wish to be understood as suggesting that gene differences with phenotypically discontinuous effects are of no significance in evolution. Polygenes are certainly not a class of genes separable from the so-called major genes. Some mutations yield isoalleles which enter in the genetic causation of polygenic variability; other mutations of the same genes give phenotypically discrete alterations. All intermediates also occur, and some specific and racial differences include relatively major genetic components. But the evidence is clear that polygenic (isoallelic) variations are predominant among the raw materials of evolution. The statement that two or more organisms have one or several identical or homologous genes should have only one meaning: that the organisms in question have inherited these genes from a common ancestor. Suppose that we observe vestigial wings in about one-quarter of a secondgeneration progeny from a cross of vestigial x normal Drosophila flies. It is fairly certain that the vestigial-winged flies have inherited copies of the vestigial m u t a n t gene which the parent of the cross had carried. Even here there is a possible pitfall, since an occasional vestigial-winged fly may contain a freshly arisen mutant gene at the same or at a different locus. Human albinos may be seen in New York and among the San Blas Indians in the wilds of Panama. It is quite improbable that these New Yorkers and Panamanians have inherited their albino alleles from common ancestors. But their common ancestors, probably very remote ones, did carry an allele a t the albino locus, which produced normal pigmentation but which from time to time mutated to the albino allele. The New Yorkers and the Panamanians have inherited normal or albino alleles of the same gene. Now suppose that different species of Drosophila are observed, in nature or in the laboratory, to produce phenotypically similar mutants. We conclude that they have inherited from a common ancestor a gene locus capable of undergoing similar changes by mutation. This conclusion can be verified for species which are able to cross and to produce viable hybrids. If the mutants are recessive and they fail to complement each other in the hybrids, it is reasonably safe to regard them as allelic variants of the same gene; if they are complementary they are changes of different genes. Evidence of this sort is, however, difficult or impossible to adduce for dominant mutants, and for any mutants in species which cannot be hybridized. The inference of gene homology must then rest on more tenuous indications. Altogether about a dozen Drosophila species have produced sex-linked mutants which look more or less similar, and also produced some parallel autosomal mutants. In the absence of the complementarity tests, it is still reasonable to iudge that species of Drosophila have many gene loci in common, and that the process of mutation yields similar mutants. Genetic maps of chromosomes have been worked out for several Drosophilae, and their comparisons have produced some quite interesting conclusions and speculations. But here is a caveat--phenotypically similar, or mimetic, mutants are produced also at different, fully complementary and not even linked genes within a species. Among the classic mutants in Drosophila melanogaster there are several nonallelic but visibly similar changes of the eye color, the eye surface, bristle shape, etc. A few of these mimetic genes may conceivably have arisen in evolution through reduplication of the same ancestral genes. But for a majority such a supposition is quite gratuitous. Our powers of observation are limited, and what to our eyes are phenotypically similar changes may actually be due to different genes. These were, indeed, found in number of instances, as in eye-color mutants when these were studied physiologically and biochemically. Morphological mimics m a y often be distinguished physiologically. However, the difficulty is exacerbated when mutants in different species are compared. The more distinct the species, the less the phenotypic similarity of even truly Downloaded from symposium.cshlp.org on September 12, 2016 - Published by Cold Spring Harbor Laboratory Press EVOLUTION OF GENES AND GENES IN EVOLUTION homologous mutants, and the greater the chance of error. The difficulty is still further aggravated for polygenes, within or between species. Traits like the numbers of bristles on certain parts of the body of Drosophila are modified by presumably scores of genes, each producing only a small effect, and not distinguishable from the effects of other genes. H u m a n traits, like height, head shape, intelligence, and even skin color have genetic architectures presumably like the bristle numbers in Drosophila. Whether or not size variations in, for example, Drosophila melanogaster and D. pseudoobscura are due to the same or to different genes remains outside the framework of our analysis, and no conceivable improvements of biochemical or physiological methods are likely to change this situation. The MendelianMorganian method of analysis is simply not practicable where polygenes are concerned, and other methods, chiefly statistical, have to take their place. This has even led Darlington (1956) to entitle an essay, "Natural populations and the breakdown of classical genetics", which certainly does not err on the side of understatement. In choosing to consider the polygenes (isoalleles) in connection with the problem of gene homology we are not being arbitrary. The raw materials from which evolutionary changes are compounded are in the main polygenic variants. This has a consequence which was pointed out first apparently by Harland (1936). The eyes of all vertebrates, from fish to man, are homologous organs. Despite their manifold differences they have the same basic plan. In a sense, all vertebrates have inherited their eyes from common ancestors. But it does not follow that the eyes of a fish, a frog, a lizard, a bird, and a mammal are formed by the same genes. In the first place, the genes do not form eyes or parts of eyes. Genes so canalize the physiological processes that the egg, the embryo, and the adult body develop in certain speciesspecific and genotype-specific ways. The presence of homologous organs is, then, not necessarily good evidence of persistence of identical, similar, or even homologous genes. The genetic system which brings about the development of the eye in a fish is probably quite different from that in a bird or in man. What has been said above concerning organs applies as well to their chemical constituents and to enzymes. To an evolutionist, the fact that certain enzymes are widely distributed in most diverse organisms is very impressive. But to conclude that these chemical constituents arc produced everywhere by the same genes is going far beyond what is justified by the evidence. In the first place, what is really known is merely that some enzymes extracted from different organisms facilitate the same chemical reactions. These enzymes are not necessarily identical in their protein moieties. Secondly, the functional similarity of the enzymes is not necessarily conferred 23 upon them by identical genes in different organisms. The retention in the phylogeny of an enzyme has the same meaning as retention of an organ or a structure. Eyes are useful or essential for survival in most vertebrates. Excepting in cave animals, moles, and in a few others, natural selection opposes disruption of the eye function. The enzymes of the Krebs cycle of the cellular respiration are perhaps even more indispensable than eyes. The functional parts of these enzymes must be preserved intact if life is to endure. This does not make an evolution of enzymes any less likely than an evolution of the organs of vision. On the assumption that evolution was monophyletic, all organisms have inherited their genes from the primordial life. Man and fish received their genes from common ancestors of a more recent vintage; the common ancestor of man and chimpanzee is even less remote. In this, but only in this sense, all genes everywhere are homologous. But the genes have changed so many times and so much during evolution that they differ in kind they are different genes. Their residual similarity may be solely that of D N A strands with four and only four different kinds of nucleotides. To use again the language analogy--the "letters" of the genetic alphabet have not changed in biological evolution, but the words and the syntax have changed, perhaps beyond recognition. SEX AND CONTROL OF RECOMBINATION Sex is perhaps the grandest of all inventions achieved in the evolution of life. Above the level of simplest viruses, any organism is a product of symbiosis of many, in the higher forms probably of tens of thousands, qualitatively different genes. Gene recombination, which is a corollary to sexual reproduction, permits gradual compounding of organic forms of superior adaptive value from mutational building-blocks having arisen in different places, times, and lines of descent. As pointed out above, transduction, parasexuality, and some other methods serve the same biological function as sex does. All these methods are trial experiments, among which sexual reproduction, with syngamy regularly followed by meiosis, has evidently proven the most successful one. As a broad generalization, it may perhaps be said that among the lower forms of life the different genes, which an organism has, are relatively autonomous in their action (which is, of course, not to deny the existence even in the lower organisms of chains of sequential physiological reactions). Progressive evolution has, on the whole, led to a greater and greater complexity of the developmental processes, and accordingly to more and more interdependence and integration of the gene-induced reactions. On the other hand, microorganisms often multiply to enormous numbers of individuals, and they can afford to rely on the occurrence of the right mutation at the right Downloaded from symposium.cshlp.org on September 12, 2016 - Published by Cold Spring Harbor Laboratory Press 24 DOBZHANSKY time to become adapted to changing environments. Where an individual does not count for much, the destruction of masses of them does not expose the species to a risk of extinction, provided only that a variant adjusted to the new environment appears in time to start building up a new population. Among higher organisms individuals cannot be sacrificed with such impunity. The challenges of the environment are then met in two ways. On the individual level, the adaptedness lies in a homeostatic buffering of the developmental pattern. On the populations level, a great array of genotypes is built to exploit the different spatial and temporal facies of the environment. Furthermore, sexual reproduction goes on eontinuously generating new genotypes. Some of these may prove to be more homeostatic in the old environments, or capable of holding forth in new ones. It is virtually certain that the different evolutionary patterns in lower and in higher organisms are reflected in the architecture of their germinal materials. At present we are, however, only beginning to grope for understanding in this field. It is, for example, certain that polygenic variation exists among the lower as well as among the higher organisms but it begins to look as though it is less prevalent among the former than among the latter. How much the recombination of polygenic variants can do in an organism like Drosophila can be gleaned from recent experiments of Spassky, Spiess, Levene, and the writer (reviewed at the 1958 Symposium; see Spiess 1958). In each of 3 different species of Drosophila, we selected from natural populations 20 chromosomes which gave, in homozygous condition, normally or near-normally viable flies. These chromosomes were, thus, nearly alike as judged from their phenotypie effects. We then obtained, from each pair of the original chromosomes, ten recombination products (i.e., 1900 "new" chromosomes per species). Homozygotes for these recombination chromosomes varied in viability all the way from normality to complete lethality (synthetic lethals). The amount of the genetic variance released by recombination can fairly be compared with the total variance in viability found among the chromosomes of the natural Mendelian population from which the experimental chromosomes were picked out. Such a comparison gives very impressive results. The variance among the recombination chromosomes amounts to between 25 % in Drosophila persimilis and D. prosaltans to 43 % in D. pseudoobscura of the total variance. In other words, the recombination, in iust one generation, of the gene contents of chromosomes selected for ostensible uniformity, re-creates from onequarter to four-tenths of the total variance present in nature. It would seem that, in Mendelian populations of this sort, a temporary suspension of the mutation pressure would not appreciably diminish the genetic variance for quite some time to come. Recombination, like mutation, is a two-edged weapon. It produces novel adaptive genotypes. On the other hand, it also breaks up the genotypes, old or new, with a fine impartiality as to their adaptive values. A compromise must then be struck between too much rigidity and too much fluidity of the gene patterns. Reaching such a compromise is especially difficult in higher organisms with their highly interactive genotypes. Such genotypes can be arrived at only by a trialand-error mechanism operating on a grand scale. But natural selection often produces genetic death. The loss of individuals must be minimized, for their supply is limited. Favorable gene patterns, once found, must be protected from disintegration. SUPERGENES The problem of the control of the amount of gene recombination in evolution has too many aspects to be considered here in its entirety. Some of its aspects were discussed at the 1958 Symposium, particularly by Levitan, Carson, White, Grant, and Stebbins. The remarks that follow are restricted to recombination on the gene-chromosome level only. Suppose that a group of genes lying in the same chromosome is adaptively favorable when present together, but less favorable or unfavorable separately or in other combinations. Tying together the successful gene patterns is advantageous. The bond must be strong enough to minimize losses through break-up by recombination, but loose enough to permit further improvement. A group of genes "acting as a mechanical unit" has been called a supergene by Darlington and Mather (1949). Some of the sex-determining X- and Y-chromosomes are good examples of supergenes. Bisexuality arose independently, and in different groups of organisms, both animals and plants, from hermaphroditism. The original method of the determination of sex in individuals, as female or male, was probably monogenic. With monogenic sex-determination, a pair of alleles of a gene acts as a sex-differentiator, AA being a female and Aa a male, or vice versa. However, when bisexuality becomes firmly established in a phylogenetic line, the sex-determination by a single gene is replaced by that of an integrated gene complex. As pointed out particularly by Schmalhausen (1949), trends from single gene determination to polygenic determination of phylogenetically old and adaptively important traits are rather general, at least among higher organisms. The situation in Drosophila may serve as an example. Excepting the heteroehromatin, all parts of the X-chromosome of D. melanogaster contain genes for femaleness. No short section of the chromosome is by itself sufficient to transform one sex into another, as would be expected Downloaded from symposium.cshlp.org on September 12, 2016 - Published by Cold Spring Harbor Laboratory Press EVOLUTION OF GENES AND GENES IN EVOLUTION with a single sex-differentiating locus. Since crossing-over between the X- and Y-chromosomes would generate sex-intergrades, polygenic sexdetermination can operate efficiently only if recombination of the genes in the X- and Ychromosomes is excluded. Furthermore, a mechanism of the so-called dosage compensation has developed, whereby the presence of two X-chromosomes in the female, and of only one in the male, gives, apart from the sexual differences, about similar developmental patterns (Muller 1950, Dobzhansky 1957). Duplications or deficiencies for parts of the X-chromosome may cause, however, gross phenotypic disturbances or even lethality. Chromosomal polymorphism, observed in many Mendelian populations of both animals and plants, includes a variety of examples of the formation of supergenes. It is well known that the populations of many, though not all, species of Drosophila are polymorphic for inversions of sections of chromosomes. Thus, in D. willistoni as many as 50 different inversions have been found in nature, and in certain populations in central Brazil an individual is heterozygous for, on the average, nine inversions. Several convergent lines of evidence have shown that the inversion polymorphism is maintained, at least as a rule, by adaptive advantages of the inversion heterozygotes. It is a balanced polymorphism maintained by heterosis. We are, however, interested in a different aspect of the situation. Why should inversion heterozygores be heterotie? Some inversions may cause position effects favorable in heterozygous condition. But for a maiority of them the answer lies probably elsewhere. Heterozygosis for an inversion causes suppression of the recombination in a chromosome, or a part of the chromosome, which contains the inversion. Suppose that the chromosomes differing by the inversion carry the genes NtB1C~DL and D2C~B~A~ respectively, and that the heterozygote A1B~CtD~/D2C2B2A2 is heterotie. The inversion preserves, then, the gene complexes A1B1CxD1 and D~C2B2A2 from being broken up by recombination. Inversion polymorphs are supergene polymorphs. It will suffice here to mention a single experiment (Dobzhansky and Pavlovsky 1958), in which a dissolution of heterosis was obtained by breaking up the supergenes normally bound together by an inversion. Two geographic populations of Drosophila pautistorum from the eastern slope of the Peruvian Andes are both polymorphic for a certain inversion. Experimental populations in laboratory population cages were made separately from population samples from the two localities. The potymorphism was conserved for a series of generations; it is evidently balanced owing to hybrid vigor in the heterozygotes. Experimental populations were then made, using as the foundation stocks hybrids between strains coming from the two geographic localities. This 25 time, the inversion heterozygotes became rare, and within a year from the start of the experiment were close to elimination. How shall we interpret these results? Suppose that one geographic population has chromosomes A1B1C1D1 and D~C2B2A~, and that the heterozygotes AtB1C~D1/D~C2B~A2 are heterotic; the other population has chromosomes AaBaCaDa and D~C~B~A4, and the heterozygotes AaBaCaDs/ D4C4B4A4 are also heterotie. When the populations are crossed, the genotypes AIBICIDI/ AaBaC3Da and D2C2B~A~/D4C4B4A4 will be formed among the hybrids. Crossing over is not suppressed in these genotypes, and recombination of the constituent parts of the supergenes yields chromosomes which produce no hybrid vigor in heterozygotes. The formation of supergenes guarded by the inversions may be visualized as follows. Disregarding the possible position effects, an inversion may arise in a chromosome carrying the alleles AxB~, which happen to interact favorably with the combination ByA~ which is reasonably common in the same population. Balanced polymorphism is established owing to the heterosis in the heterozygote AxB=/ByAy. The supergenes are built up further by addition, either by mutation or by recombination, of further gene differences, such that A~B~C~D~/DyCyByAy has a net adaptive advantage (Haldane 1957). The assumption that the inversion happens to arise in a chromosome with a heterotic complex of polygenes makes no undue demands on chance. We have seen above that recombination of genes present in "normal" chromosomes in a Mendelian population may generate an amazing amount of genetic variance. New polygene complexes are, then, constantly formed and broken down, and some of them are heterotic in combination with other complexes present in the gene pool of the same population. Chromosomal inversions also arise from time to time; most of them confer no advantage on their possessors, because they do not contain a polygene complex of any particular merit in heterozygotes. Such inversions are lost, or remain rare and local. Only a minority of the inversions persist and spread. After all, the 50 inversions in Drosophila willistoni, which is the record number thus far for any species, are doubtless a small fraction of the total assortment of inversion which arose in the species, at different times and places, in its evolution. The properties of supergenes merit more attention than they have received. The simplest form of gene interaction is, unquestionably, additivity of gene effects. But it should be kept in mind that epistatic and other interactions are by no means unknown. Reference has been made above to the experiments of Spassky, Spiess, Levene, and the writer on the release of the genetic variance by recombination in three species of Drosophila. Crossing over between chromosomes giving normally viable homozygotes, yields Downloaded from symposium.cshlp.org on September 12, 2016 - Published by Cold Spring Harbor Laboratory Press 26 DOBZHANSKY recombination chromosomes, the average viability of which in homozygous condition, is decidedly below that of the parental chromosomes. Moreover, a chromosome A may give only normally viable recombinants with B, and B with C, while A and C may give many lethal or scmilethal recombinants. In short, a substantial part of the variance released by recombination between "normal" chomosomes is due to epistatic interactions between the polygenes which they contain. Levitan (1958) found an even more unexpected kind of interaction in Drosophila robusta. Suppose that a population is polymorphic for two inversions in the same chromosome, A1-A2 and BI-B2. The double heterozygotes may, evidently, be of two kinds: A1B1/A2B2 and A1B2/A2B1 (i.e., the inverted sequences in the same chromosome or in the opposite chromosomes). One would suppose that these two kinds of heterozygotes should be exactly alike, hut Levitan finds that they are sometimes different. At first sight, this appears to be like a case of position effect, with the "cis" and "trans" combinations being different. But if so, it is a very special case; the inversions A and B are, in Levitan's material, far apart in the chromosome, and the two chromosomal configurations, A1B1/A~B2 and A1B2/ A2BI, are cytologically indistinguishable. Perhaps one should refer to the phenomenon discovered by Levitan as "organization effect"; it consists in allelic variants of different genes interacting differently when they lie in the same chromosome and in homologous chromosomes. Perhaps some of you will find the following suggestion not too audacious or far-fetched. In determining the fitness of their carriers, the chromosomes, or certain sections of them, may act, especially in higher organisms, not as mechanical aggregations of independently functioning genes, but as supergenes. A gone combination which a chromosome or chromosome section may carry, should, as far as its effects on fitness are concerned, be considered as a supergene allele of classical genetics. A population, the gone pool of which contains a great variety of gene patterns in its ehromosomes, carries in effect a very large number of allelie variants of a relatively small number of supergenes. The formation by recombination of ever-new gene patterns in the chromosomes amounts to emergence of new altelie variants of the supergenes. Supergenes are, then, units of integration of hereditary materials, which are greater than genes (eistrons), and equal to or smaller than chromosomes. SUMMARY Both the ontogenetic and the phylogenetic development of living organisms is epigenetic. Neither organs, nor body parts, nor characters, nor biochemical constituents of the adult organism are preformed in the gametes. The heredity is coded in the gametes by means of the "genetic alphabet" consisting of only four "letters", which are the four kinds of nucleotide pairs of the deoxyribose nucleic acids. Evolution may be viewed as a result of these "letters" combining into new "words". The genetic code has become perfected in the course of organic evolution. The genes, which may be compared with "words" in the genetic message, have probably become better integrated when gene recombination and sexual reproduction became firmly established. The prevalence of polygenic (isoallelic) mutations and of heterotic heterozygotes created the need for further integration of the genes into supergenes. The supergenes in a chromosome may perhaps be treated as being in some ways similar to multiple alleles. ACKNOWLEDGEMENTS The author is deeply grateful to several colleagues, particularly to Betty Moore, J. A. Moore, M. Demerec, R. Lewontin, George Streisinger, and Monroe Strickberger, for most valuable suggestions and criticisms which have helped to eliminate several errors. Needless to say, the author alone is responsible for the errors which still remain in the article. REFERENCES BENZER, S., 1955. Fine structure of a genetic region in bacteriophage. Proc. Nat. Acad. Sci. 51: 344-354. 1957. The elementary units of heredity. In : The Chemical Basis of Heredity (W. D. McElroy and B. Glass, Eds.) : 7(~93. BESSMAN, M. J., I. R. LEHMAN, E. S. SIMMS, and A. KORNBERG, 1958. Enzymatic synthesis of deoxyribonucleic acid. II. General properties of the reaction. Jour. Biol. Chem. 233: 171-177. CARSON, H. L., 1958. Response to selection under different conditions of recombination in Drosophila. Cold Spring Harbor Symp. Quant. Biol. 23: 291-306. CHETVERIKOV, S. S., (Tschetwerikoff), 1926. On certain features of the evolutionary process from the viewpoint of modern genetics. Jour. Exp. Biol. (Russian), 2: 3-54. CRICk, F. H. C., 1954. The structure of the hereditary materials. Sci. American 191: 56-61. 1957. The structure of DNA. In: The Chemical Basis of Heredity. (W. D. McElroy and B. Glass, Eds.): 532-539. DARLINGTON, C. D. 1956. Natural populations and the breakdown of classical genetics. Proc. Roy. Soc. B, 155:350 364. DARLINGTON, C. [)., and K. MATHER, 1949. The elements of Genetics. New York: Macmillan. DEMEREC, M., Z. HARTMAN,P. E. HARTMAN,T. YURA, J. S. GOWN, H. OZEKI, and S. W. GLOWER, 1956. Genetic studies with bacteria. Carnegie Inst. Washington, Publ. 612. DOBZHANSKY, Th., 1936. Position effects on genes. Biol. Reviews 11: 364-384. 1957. The X-chromosome in the larval salivary glands of hybrids Drosophila insularis x Drosophila tropicalls. Chromosoma 8: 691-698. DOBZHANSKY,Th., and O. PAVLOVSKY,1958. Interracial hybridization and breakdown of coadapted gene complexes in Drosophila paulistorum and Drosophila willistoni. Proc. Nat. Acad. Sci. 54: 622-629. DUBININ, N. P., and B. N. SIDOROV, 1934. Relation between the effect of a g e n e and its position in the system. Biol. Zhurnal 3: 307-331. DUNN, D. B., and J. D. SMITH,1958. The occurrence of Downloaded from symposium.cshlp.org on September 12, 2016 - Published by Cold Spring Harbor Laboratory Press EVOLUTION OF GENES AND GENES IN EVOLUTION 6-methylaminopurine in deoxyribonucleic acids. Biochem. Jour. 68: 627-636. FISHER, R. A., 1930. The Genetical Theory of Natural Selection. Oxford. GOLDSCHMIDT, R., 1935. Gen und Ausseneigenschaft. Zeits. ind. Abst. Vererbungsl. 69: 38-131. 1938. Physiological Genetics. New York: McGraw Hill. GRANT,VERNE,1958. The regulation of recombination in plants. Cold Spring Harbor Symp. Quant. Biol., 28: 337-363. HALDANE,J. B. S., 1957. The conditions for coadaptation in polymorphism for inversions. Jour. Genetics, 55: 218-225. HARLAND, S. C., 1936. The genetical conception of species. Biol. Reviews 11: 83-112. LEHMAN, I. R., S. B. ZIMMERMAN, J. ADLER, M. J. BESSMAN, E. S. SIMMS, and A. KORNBERG, 1958. Enzymatic synthesis of deoxyribonucleic acid. V. Chemical composition of enzylnatically synthesized deoxyribonucleic acid. Proc. Nat. Acad. Sci., 44: 1191-1196. LEVITAN, M., 1958. Non-random associations of inversions. Cold Spring Harbor Symp. Quant. Biol. 23: 251-268. LEWIS, E. g., 1945. The relation of repeats to position effect in Drosophila melanogaster. Genetics 30: 137-166. 1950. The phenomenon of position effect. Advances in Genetics 3: 73-115. MICHIE, D., 1958. The third stage of genetics. In: A Century of Darwin (S. A. Barnett, Ed.), London: Heinemann. MIRSKY, A. E., and H. Ris, 1951. The deoxyribonucleic acid content of animal cells and its evolutionary significance. Jour. Gen. Physiol. 34: 451-462. MORGAN, T. H., 1919. The Physical Basis of Heredity. Philadelphia : Lippincott. MULLER,H. J., 1950. Evidence of the precision of genetic adaptation. Harvey Lectures 43: 165--229. 1958. Evolution by mutation. Bull. Amer. Math. Soc. 64: 137-160. MULLER,H. J., and A. PROKOFIEVA,1935. The individual gene in relation to the chromomere and chromosome. Proc. Nat. Acad. Sci. 21: 16-26. NUJDIN, N. I., 1958. Concerning some methodological problems of modern genetics. (Russian). Voprosy Filosofii 8: 82-97. PONTECORVO, G., 1958. Trends in Genetic Analysis New York: Columbia Univ. Press. SCHMALHAUSEN,I. I., 1949. Factors of Evolution. Philadelphia : Blakiston. SPASSKY, B., SPASSKY, N., H. LEVENE, and Th. DOBZHANSKY., 1958. Release of genetic variability through recombination. I. Drosophila pseudoobscura. Genetics 43: 844-867. SPIESS, E. B., 1958. Effects of recombination on viability in Drosophila. Cold Spring Harbor Syrup. Quant. Biol. 23: 239-250. STEBBINS, G. L., 1958. Longevity, habitat, and release of variability in higher plants. Cold Spring Harbor Symp. Quant. Biol. 23: 365-378. STURTEVANT,A. H., 1948. The evolution and function of genes. Amer. Scientist 36: 223-236. TAYLOR, J. H., P. S. WOODS,and W. L. HUGHES 1957. The organization and duplication of chromosomes as revealed by autoradiographic studies using tritium-labeled thymidine. Proc. Nat. Acad. Sci. 43: 122-128. VENI)RELY, R., 1958. La notion d'~spSce a travers quelques donnfies biochimiques recentes et le cycle L. Ann. Inst. Pasteur 94: 142-166. WATSON,J. D., and F. H. C. CRICK, 1953. The structure of DNA. Cold Spring Harbor Syrup. Quant. Biol. 18: 123-131. WHITE, M. J. D., 1958. Restrictions on recombination in grasshopper populations. Cold Spring Harbor Symp. Quant. Biol. 23: 307-317. 27 WILLIAMS, C. B., Possible frequency distributions for all insects. (Unpublished manuscript) WRIGHT, S., 1931. Evolution in Mendelian populations. Genetics 16: 97-159. DISCUSSION EMERSON: Instead of an example of a "homologous" organ (eye), with strong selection pressure resulting in nearly complete genetic change during phylogeny, does not the long retention of vestigial organs with weak selection pressure depend upon molecular identity of portions of the genetic complex with many other pleiotropic effects? DOBZHANSKY: Let us keep in mind that genes do not determine "organs" or "traits" or "characters"; they determine the development pattern of the organism, of which traits or characters are manifestations. Vestigial organs need not be determined by vestigial genes. They are rather by-products of developmental processes which bring about the appearance of vestigial as well as of non-vestigial organs and characters. The retention in the phylogeny of vestigial traits is, accordingly, no different from that of fully functional ones. Neither means necessarily that a certain gene, or genes, has remained unchanged. The same developmental pattern may be brought about in ancestral and in descendant forms, as well as in different contemporaneous forms, by different genetic systems. Suppose we find a vestigial organ, such as the vermiform appendix, retained in the phylogeny long after it has presumably lost its function. One asks the question: W h y has this organ not disappeared? One m a y as well ask this: W h a t advantage would the organism get from so modifying its development that the vestigial organ will be gone but the rest of the development will remain unchanged? If there existed a one-to-one relation between a gene and a trait (as classical geneticists liked to assume), then a vestigial organ would make a gene unnecessary and it would disappear. But the situation is really different: evolution does not consist of independent changes of organs or traits; what changes is the genetic system and the developmental system which rests on it. APPENDIX The work of Chetverikov (S. S. Tsehetwerikoff), entitled "Concerning certain aspects of the evolutionary process from the standpoint of modern genetics", was published in the Zhurnal Experimentalnoi Biologii, Vol. 2, pp. 1-54, in 1926. The translation printed below covers parts of Chetverikov's Chapter II, "Mutation under the conditions of free crossing" (parts of pages 1522 of the original), and the "Conclusions" (parts of pages 48-51). The places in which some paragraphs of the original are omitted in the translation are marked by . . . . The obsolete word "genovariation" employed by Chetverikov has been translated as "mutation". His use of the expression "free crossing" is however rather wider Downloaded from symposium.cshlp.org on September 12, 2016 - Published by Cold Spring Harbor Laboratory Press 28 DOBZHANSKY t h a n w h a t is u s u a l l y m e a n t b y " r a n d o m m a t i n g " , and it has been preserved in the translation. MUTATION UNDER THE CONDITIONS OF FREE CROSSING . . . . Free crossing is the normal condition found in a great m a j o r i t y of n a t u r a l species of animals as well as of plants, a n d the i m p o r t a n c e of this factor in evolution m u s t be appreciated. Indeed, w h a t an i m p o r t a n t role was ascribed to this factor b y the greatest evolutionists can be seen from the fact t h a t D a r w i n considered till t h e end of his life, t h a t the most i m p o r t a n t objection against his theory was raised n o t b y a n y of the great biologists, b u t by an engineer, Jenkins, who in 1867 showed b y a simple calculation t h a t , as a result of free crossing, a n y accidentally arising genetic v a r i a n t will very soon be dissolved in a mass of normal individuals. Free crossing has a dissolving, swamping according to Darwin, effect on a n y newly arising single genetic variant, even a strongly m a r k e d one. These considerations p r o m p t e d Darwin, in the successive revisions of his theory, to deviate more and more from the m o d e r n genetic views on the role of single changes, m u t a t i o n s (sports, according to D a r w i n ' s terminology), in the process of the development of t h e living world, a n d forced him to ascribe greater and greater roles to the small b u t widespread individual v a r i a t i o n s , now referred to as " f l u c t u a t i o n s " . As we shall see below, the considerations which have so m u c h impressed Darwin do n o t appear valid according to the modern conceptions of the role of crossing. I t is, nevertheless, i m p o r t a n t to point out t h a t they have deflected D a r w i n ' s t h i n k i n g from his earlier and more valid ideas towards acceptance of views akin to the m o d e r n neoLamarckism . . . . Among all the works referred to above, the greatest i n t e r e s t and i m p o r t a n c e for us are the studies of K. Pearson a n d G. H. H a r d y . T h e l a t t e r a u t h o r has, in a s h o r t paper only two pages long, established a most imp o r t a n t law, governing t h e equilibrium s t a t e u n d e r the conditions of Mendelian i n h e r i t a n c e a n d of free crossing. I t m a y be referred to as the law of equilibrium with free crossing, or H a r d y ' s law. This law can be s t a t e d as follows : T h e relative frequencies of homozygous ( d o m i n a n t as well as recessive), and of heterozygous individuals, with free crossing and in the absence of any selection, remain c o n s t a n t if the p r o d u c t of the frequencies of the homozygotes ( d o m i n a n t s times recessives) equals t h e square of the half-frequency of the heterozygotes. To express this law in a genetic formula, the composition of the population if represented as p A A 42qAa -4- ran, where p, 2q, a n d r are the frequencies of the respective homozygotes a n d heterozygotes. T h e equilibrium condition u n d e r conditions of free crossing is t h e n : pr = q~ A conclusion of great i m p o r t a n c e to us follows from this law: since for any values of p a n d r there is always a value of 2q such t h a t pr =q~, therefore a population u n d e r free crossing m a y be at equilibrium with any frequencies of the d o m i n a n t and recessive forms. In a free-crossing population m a y be preserved from gene r a t i o n to generation not only t h e classical Mendelian r a t i o 1:2:1 (phenotypically 3:1), b u t the frequency of either homozygote (the d o m i n a n t or the recessive one) m a y equal, or be greater t h a n , t h a t of the other, and yet, t h e p o p u l a t i o n will remain a t equilibrium, provided only t h a t the basic condition pr =q2 is satisfied. Closely connected with the law s t a t e d above stands a n o t h e r i m p o r t a n t law, h a v i n g to do with the equilibrium s t a t e in a free-crossing population, which m a y be called t h e law of stabilizing crossing. I t was established b y K. Pearson in 1904, b u t remained unnoticed because of its a b s t r a c t form inaccessible to a great maj o r i t y of biologists who received it initially. This law was again d e m o n s t r a t e d b y H a r d y in the article re- ferred to (1908), a n d s u b s e q u e n t l y s t a t e d again in different m a t h e m a t i c a l a n d biological formulations (Jennings 1916, W e n t w o r t h a n d Remick 1916, Tietze 1923). This second law of free crossing, which we shall refer to as t h e law of stabilizing crossing or P e a r s o n ' s law, m a y be s t a t e d briefly as follows: In a population with a n y initial frequencies of homozygous or heterozygous p a r e n t a l forms, the equilibrium condition is a t t a i n e d after a single generation of free crossing. T h e r e fore, no m a t t e r how m u c h an external factor m a y modify the equilibrium in a free-crossing population, t h e first generation of free crossing establishes in the p o p u l a t i o n a new equilibrium, which will t h e n be m a i n t a i n e d u n t i l again d i s t u r b e d by some external force. Using genetic formulae again, we m a y s t a t e t h e above thus : Given a free-crossing p o p u l a t i o n x A A A- 2yAa + zaa, in which t h e equilibrium condition has been so disturbed that xz ~= y2, t h e n the very first generation of stabilizing crossing will lead to the relation xl 2 A A + 2XLZlAa -4- zl~aa, such t h a t xl2zl 2 = (XlZl) 2 a n d t h e population wilt be a t a stable equilibrium (according to H a r d y ' s law). T h u s , in the very m e c h a n i s m of free crossing t h e r e is c o n t a i n e d an a r r a n g e m e n t which stabilizes the frequencies of t h e components of this population. Any a l t e r a t i o n of these frequencies is possible only because of some external influence, a n d remains possible only as long as t h a t external influence is acting. Among these external influences, we shall consider in the present article only two: selection in the b r o a d e s t sense of this word, a n d the appearance of genotypic changes, m u t a t i o n s . We shall take up the m u t a t i o n s first. In the foregoing paper, I tried to show t h a t t h e r e is no reason to deny t h a t new m u t a t i o n s arise c o n t i n u o u s l y in n a t u r e . T h e d a t a concerning the best s t u d i e d Drosophila show t h a t the n u m b e r of m u t a t i o n s k n o w n is growing w i t h o u t limit; some m u t a t i o n s h a v e arisen repeatedly and more or less f r e q u e n t l y (e.g., white, N o t c h , etc.), while in other cases the same gene changes in various ways, giving rise to a series o[ alleles (e.g., t h e same gene white, also T r u n c a t e , d u m p y , etc.). However, a m a j o r i t y of m u t a n t s have arisen only once, a n d the n u m b e r of possible kinds a n d v a r i a n t s of m u t a n t s seems thus far to be unlimited. What, then, is the fate of these single m u t a n t s , these " s p o r t s " according to D a r w i n ' s terminology? Are t h e y really disappearing w i t h o u t trace, dissolved in a sea of normal individuals, h a v i n g no influence on the fate of t h e species a n d on its evolution? Let us consider first the appearance in n a t u r e of a recessive homozygous m u t a n t , aa. W h a t shall be t h e fate of this gene? T h e appearance of t h e m u t a n t dist u r b s the equilibrium s t a t e of t h e free-crossing population. If t h e m u t a n t is not destroyed by n a t u r a l selection because of its defective v i a b i l i t y or poor adaptedness, it will m a t e with a normal form, A A . F r o m t h e law of stabilizing crossing we deduce t h a t in the next generation the equilibrium is reestablished, and the recessived gene passes in a hetero~ygous condition, Aa. Assuming t h a t a pair of p a r e n t s aa x A a will, in a numerically c o n s t a n t population, produce a progeny of two, t h e p o p u l a t i o n will contain two p h e n o t y p i e a l l y normal individuals heterozygous for a pair of alleles, Aa. This equilibrium s t a t e of t h e populations, or of the species, will t h e n continue u n c h a n g e d generation a f t e r generation. Downloaded from symposium.cshlp.org on September 12, 2016 - Published by Cold Spring Harbor Laboratory Press E V O L U T I O N OF G E N E S A N D G E N E S I N E V O L U T I O N 29 A simple reckoning shows t h a t the p r o b a b i l i t y of such two heterozygous individuals meeting t o g e t h e r is equal to u n i t y , divided b y the n u m b e r of individuals in t h e p o p u l a t i o n minus one. Assuming, t h e n , t h a t the p o p u l a t i o n c o n s i s t s of N + 1 individuals, the p r o b a b i l i t y of the meeting of t h e heterozygotes is: where m , which is the n u m b e r of the concealed m u t a n t s , m a y e v i d e n t l y grow w i t h o u t limit. I t is evident t h a t as t h e n u m b e r m increases, this p r o b a b i l i t y m a y become very large, a n d the species will manifest here one and t h e r e a n o t h e r of the m u t a n t s which it c o n t a i n s . . . . . p = 1/N Let us summarize: 1. The process of m u t a t i o n is going on in n a t u r e as it does in the l a b o r a t o r y and among domesticated animals a n d c u l t i v a t e d plants. Observing it in n a t u r e is, however, difficult because of several reasons. 2. Most m u t a n t s are less viable t h a n the normal forms. This is, however, not a general rule, since there are some m u t a n t s the v i a b i l i t y of which is not reduced. 3. A freely-crossing species p o p u l a t i o n is a stable system which includes a m e c h a n i s m which stabilizes t h e frequencies of the c o m p o n e n t pairs of alleles (the laws of H a r d y a n d of Pearson). 4. E v e r y m u t a t i o n which arises is absorbed b y the species in a heterozygous condition, and, provided t h a t selection is absent, remains indefinitely conserving its frequency. 5. New m u t a n t s arise year a f t e r year, generation a f t e r generation. T h e y are either like the m u t a n t s which arose previously or new ones. The m u t a n t s are absorbed into the species population, which conserves its external uniformity. T h e heterozygosity for m u t a n t s gradually s a t u r a t e s the species, combining a n d spreading as random (in so far as t h e separate genes are not linked), and e v e n t u a l l y " i n f e c t s " most individuals. 6. When a large enough n u m b e r of m u t a n t s have arisen, and this depends upon the " a g e " of the species, almost all individuals will be " i n f e c t e d " by different recessive and heterozygous m u t a n t s . 7. A l t h o u g h the p r o b a b i l i t y of m a n i f e s t a t i o n of a n y given m u t a n t is extremely low, the probabilities are additive, a n d c o n s e q u e n t l y the p r o b a b i l i t y of manifestation of some m u t a n t s is proportional to the n u m b e r of the m u t a n t s absorbed by t h e species. When enough of t h e m are absorbed, t h e y will become manifested more a n d more often, the species becoming u n s t a b l e a n d "old". 8. T h e most favorable conditions for m a n i f e s t a t i o n of the genotypic v a r i a t i o n are found in large species s u b d i v i d e d in m a n y medium-sized isolated colonies (island forms of land snails). 9. Isolation i n t e r a c t i n g with the continuous m u t a tion process is the basic factor bringing a b o u t the i n t r a specific, a n d consequently also the inter-specific, differentiation. The isolation is mostly spatial, b u t sometimes it is temporal, or else e n v i r o n m e n t a l (ecological). 10. N a t u r a l selection is an a n t a g o n i s t of the free crossing. It is a dynamic factor. 11. T h e t a b l e of N o r t o n shows t h a t a n y e v o l u t i o n a r y process caused by selection, either with d o m i n a n t or w i t h recessive v a r i a n t s , always leads to complete replacement of the less well a d a p t e d b y the b e t t e r a d a p t e d form. I t shows also t h a t selection utilizes and e v e n t u a l l y fixes every i m p r o v e m e n t , no m a t t e r how small. 12. A d a p t i v e evolution w i t h o u t isolation leads to a t r a n s f o r m a t i o n of the species (Waagen's m u t a t i o n s ) , b u t can never split t h e species in two and thus lead to speciation. 13. D i s c o n t i n u a t i o n of selection leads to f o r m a t i o n of stable polymorphic species. 14. Selection, like free crossing, leads to accumulation in the p o p u l a t i o n of recessive, and less viable, genes in heterozygous condition. 15. T h e great p r e d o m i n a n c e in some of the forms studied of the recessive, compared to d o m i n a n t , mut a n t s is a c c o u n t e d for by this a c c u m u l a t i o n u n d e r nat u r a l conditions of recessive r a t h e r t h a n d o m i n a n t genes, b r o u g h t a b o u t b y the specific action of b o t h t h e free crossing a n d selection. 16. W i t h respect to newly arising m u t a t i o n s , t h e role of selection and of the free crossing differs greatly from t h e above. T h e free crossing conduces to differentiation This means t h a t one such meeting is liable to occur in N consecutive series of meetings (generations). To illustrate b y a concrete example: let us assume t h a t in the whole n o r t h e r n E u r a s i a are living 1,000,000 + 1 grey crows. Suppose t h a t t h e r e appears among t h e m one homozygous recessive albino m u t a n t . If the m u t a n t is not lost a n d m a t e s with a normal individual, the popul a t i o n in the next generation, a n d in generation after generation, will c o n t a i n two individuals, normal in appearance b u t heterozygous for the albinism. T h e probability of t h e two heterozygotes meeting and m a t i n g (assuming ideal r a n d o m mating) is 1 / N = 1/1,000,000. T h e chance t h a t a white, homozygous, individual will appear is only one among 1,000,000 consecutive matings. I n practice this is negligible, and therefore the albino m u t a n t is concealed, " a b s o r b e d " , b y the free crossing. And yet, the fate of the m u t a n t will be quite different from w h a t was imagined b y old evolutionists. T h e m u t a n t does not perish, is not dissolved in the mass of normal individuals. I t will continue to exist in heterozygous condition generation after generation, being concealed from view, b u t representing a certain genotype. T h e above considerations p e r m i t us to see more clearly and more profoundly the g.enetic s t r u c t u r e of a freely-crossing population, a specms. Is a species population genotypically uniform? And assuming some heterogeneity, how to explain the constancy, the "monot y p i s m " , which is so characteristic of n a t u r a l , wild, species, c o n t r a s t i n g with domestic breeds? . . . . Assume a freely-crossing population of N + 1 individuals. T h e p r o b a b i l i t y of a new appearance, owing to a m a t i n g of heterozygous individuals, of a previously arisen m u t a n t , a a , is, as we have seen 1 / N , which is, with large N's, negligibly small. B u t imagine t h a t in some population t h e r e has arisen a n o t h e r single m u t a n t , bb, which has also passed in a heterozygous state. The p r o b a b i l i t y of a reappearance of this m u t a n t will also be 1 / N , a n d the same will be for a t h i r d m u t a n t , ce, for a fourth, dd, a fifth, ee, etc. All these m u t a n t s arising among normal representatives of the species, pass into the heterozygous state, a n d are t h u s concealed, absorbed into the species, existing in it as isolated individuals. T h e species acts like a sponge, absorbing heterozygous m u t a n t s , a n d yet remaining p h e n o t y p i c a l l y uniform. T h a t this conception of the genotypic s t r u c t u r e of the species is realistic, is confirmed b y the as yet unfinished analysis of n a t u r a l populations of species of D r o s o p h i l a u n d e r t a k e n b y the L a b o r a t o r y of Genetics of the I n s t i t u t e of E x p e r i m e n t a l Biology last sulnmer (1925). T h e p r o b a b i l i t y , 1 / N , of the meeting of two like heterozygotes is so small in more or less large species as to be practically negligible. B u t w i t h repeated origin of the m u t a n t , the p r o b a b i l i t y of m a n i f e s t a t i o n of some of t h e m will be growing more and more, according to the law of s u m m a t i o n of i n d e p e n d e n t probabilities. Thus, with two concealed m u t a n t s , the p r o b a b i l i t y of a m a n ifestation will be almost twice as great: p = 2/N - 1 / N ~, and with t h r e e m u t a n t s will be 3 / N - ( 3 / N 2 - 1/NS). In general, with m m u t a n t s concealed in a population, t h e p r o b a b i l i t y , p, of t h e m a n i f e s t a t i o n of a n y one of t h e m t h r o u g h r e c o m b i n a t i o n with a free crossing will be: p=l-- CONCLUSIONS Downloaded from symposium.cshlp.org on September 12, 2016 - Published by Cold Spring Harbor Laboratory Press 30 DOBZHANSKY of forms, while selection, destroying the harmful mutants, purges the species of excessive variability, and generally tends towards a uniformity of the species. 17. There is no reason to deny the possibility of unadaptive evolution. In many cases one may suppose that the existing adaptive differences of closely related forms were not the reasons of the divergence of the latter, but, on the contrary, the specific character of these adaptive traits is a consequence of an earlier separation of these forms. The more ancient the separation, the greater will be the number of adaptive traits in which the forms will differ. 18. The concept of pleiotropic action of genes, introduced by Morgan, is very important for understanding the action of selection. This concept leads us to the idea of the genotypic milieu, which acts from the in- side on the manifestation of every gene in its character. An individual is indivisible not only in its soma but also in the manifestation of every gene it has. 19. The concept of the pleiotropic action of genes helps to clarify some difficult and confused problems in genetics--intensifiers, modifiers, and the invariably polymeric nature of quantitative traits. 20. The selection selects not only a gene which determines the character under selection, but it affects the whole genotype (the genotypic milieu), leads to an intensification of the trait selected, and in this participates actively in the evolutionary process. 21. The concept of pleiotropic action of genes gives a new theoretical basis of the phenomena of relative variability and of genotypie correlation of traits. Downloaded from symposium.cshlp.org on September 12, 2016 - Published by Cold Spring Harbor Laboratory Press Evolution of Genes and Genes in Evolution Theodosius Dobzhansky Cold Spring Harb Symp Quant Biol 1959 24: 15-30 Access the most recent version at doi:10.1101/SQB.1959.024.01.004 References Email alerting service This article cites 33 articles, 15 of which can be accessed free at: http://symposium.cshlp.org/content/24/15.refs.html Receive free email alerts when new articles cite this article sign up in the box at the top right corner of the article or click here To subscribe to Cold Spring Harbor Symposia on Quantitative Biology go to: http://symposium.cshlp.org/subscriptions Copyright © 1959 Cold Spring Harbor Laboratory Press