Heredity and Development: Second Edition (1972)

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HEREDITY AND DEVELOPMENT: SECOND EDITION 70 4 The Chromosomes and Inheritance BOVERI AND THE SEA URCHIN CHROMOSOMES In Chapter 2, we learned that in 1900 the hypothesis that ‘chromosomes are the physical basis of inheritance’ seemed to be reasonable. It was far from being established as true and, in fact, there was a real difficulty in knowing how to test such a hypothesis. Until 1902 no one had a clue as to how this might be done. In that year, Theodore Boveri (1862–1915) carried out an ingenious experiment demonstrating that a complete set of chromosomes is necessary for normal development. Since development is one aspect of inheri- tance, the relation between chromosomes and inheritance was established. The significance of Boveri’s experiment will be more apparent if we give something of the background from which he worked. At the time of his exper- iment, most cytologists believed that within any single species one chromo- some was about the same as another. Thus, in the sea urchin each cell of the embryo has 36 chromosomes. They were all very small and looked identical in shape; they reacted alike to fixation and staining; and when things look alike there is a natural tendency to believe that they are alike in other respects as well. Boveri thought otherwise. He believed that chromosomes differed from one another, and that a complete set of 36 was necessary for normal develop- ment in the sea urchin. He believed that not just any 36 would suffice: but the very 36 which were present in each cell of the normal embryo were the neces- sary ones. Double Fertilization of Sea Urchin Ova. Boveri tested this hypothesis in a clever way. Oskar Hertwig and others had observed previously that 

HEREDITY AND DEVELOPMENT: SECOND EDITION 71 if one used a highly concentrated sperm suspension, it was possible to get two sperm to enter one egg of the sea urchin. Mitosis becomes most confused in these double fertilizations, but it is possible by this method to vary the number of chromosomes distributed to the cells. In order to understand the complications we should first review normal fertilization. In the case of an embryo entered by a single sperm, the sperm brings in a centrosome, which is the region containing the centriole. The centrosome divides into two and the spindle forms between the two new centrosomes. The paternal and maternal nuclei fuse, and then their chromosomes appear in the spindle. Each pronucleus of the sea urchin has 18 chromosomes so the fusion nucleus will have 36. Each of these 36 duplicates itself, thus forming a total of 72 chromosomes. These are divided equally at the first cleavage divi- sion, and each daughter cell receives 36. When two sperm enter, not only will there be an additional 18 chromo- somes to make a total of 54 but there will be an extra centrosome as well. Boveri observed that one of two things happened: 1. In some embryos the centrosomes of both sperm divided, giving four centrosomes in the single cell. At the time of first cleavage these embryos divided into four instead of into two cells. 2. In other embryos, the centrosome of one sperm divided but the other remained single, giving three centrosomes for the single cell. At first cleavage this type of embryo divided into three cells. In both classes of double-fertilization embryos, there would be 54 chromo- somes (18 from the maternal nucleus and 18 from each of the two paternal nuclei). These 54 will duplicate themselves during the first mitotic division of the embryo, producing a total of 108 chromosomes. In those embryos with four centrosomes, the chromosomes will be divided among four cells. Boveri found this division very unequal. Some cells would get many chromosomes and others only a few. If the apportionment was strictly equal, each cell would receive 27 chromosomes (108/4=27). This is far from the normal com- plement of 36 per cell, which Boveri believed necessary for regular develop- ment. In fact, there is no way in which each of the four cells could get the normal complement of 36. Abnormal development was to be expected, and this Boveri observed in 1,499 out of 1,500 embryos. The embryos with three centrosomes that divided into three cells at the first division also showed very abnormal distributions of chromosomes. One would expect, however, that they would have a better chance of getting 36 chromosomes in each cell than would the group 

HEREDITY AND DEVELOPMENT: SECOND EDITION 72 that formed four cells. The reason is this: We have seen that there is no way of apportioning 108 chromosomes among four cells so each will receive a normal complement of 36. If the 108 chromosomes are divided equally among three cells, however, the result is 36. The experimental results vali- dated this reasoning. In the group that divided into three cells, 58 in a total of 719 developed normally. We have already seen that only one embryo in 1,500 developed normally among the embryos that divided into four cells at first cleavage. According to Boveri, these data correspond fairly well with the chance expectation that normal larvae will come from embryos that begin develop- ment with a normal set of chromosomes in each of the cells formed at the first division. He interpreted the data to mean that for normal development every cell of the embryo must have the regular set of 36 chromosomes. He believed that each chromosome in the set must be endowed with a specific quality, and that all are necessary for normal development. These experiments emphasized the importance of chromosomes for nor- mal development, which is one aspect of inheritance. It was a direct approach to the study of the role of chromosomes in inheritance. SUTTON AND GRASSHOPPER CHROMOSOMES In the same year that Boveri published the results of his work, a second and much more fruitful approach was made by Walter Stanborough Sutton (1877–1916). At the time, he was a graduate student working at Columbia University with the cytologist Edmund Beecher Wilson (1856–1939). He published two papers on the chromosomal basis of inheritance, the first in 1902 and the second in 1903. Individuality of the Chromosomes. Sutton’s 1902 paper was a study of the chromosomes in the testis of a grasshopper of the genus Brachystola. The chromosomes of this form exhibit a chromosome group, the members of which show distinct differences in size. Accordingly one feature of this study has been a critical examination of large numbers of dividing cells (mainly from the testis) in order to determine whether, as has usually been taken for granted, these differences are merely a matter of chance, or whether in accordance with the view recently expressed by Montgomery,…characteristic size relations are a constant attribute of the chro- mosomes individually considered. With the aid of camera drawings of the chromosome group in the various cell-generations, I will give below a brief account of the evidence which has led me to adopt the latter conclusion. 

HEREDITY AND DEVELOPMENT: SECOND EDITION 73 The cells in the testis undergo a series of mitotic divisions before they begin meiosis. These cells are known as spermatogonia and they have the diploid number of chromosomes. The youngest spermatogonia that Sutton could find possessed 23 chromosomes. One of these, the ‘accessory’ chromosome, had a peculiar behavior and it will be considered separately. The other 22 were of various sizes. When these were measured carefully it was found that there were not 22 different sizes, but only 11. In other words there were two chro- mosomes of each size class (Fig. 4–1). In addition to the minor size variation, the chromosomes could be divided into two groups that differed strikingly in size. Three of the pairs were very small and the other eight were large. Sutton found that these early spermatogonia went through eight mitotic divisions. At each metaphase the same 11 pairs of chromosomes were observed. Of these, eight pairs were large and three small. He concluded that constant size was an attribute of the individual chromosomes. After these eight mitotic divisions, the cells undergo the usual two meiotic divisions. The chromosomes synapse in pairs, each member of the pair being of the same size. As a result, 11 tetrads form; eight are large and three are small. Then the two meiotic divisions occur and each sperm receives one chromosome of each of the 11 sizes. Sutton found that the diploid number in the female was 22. Further, these had the same size relations as were present in the male, consisting of eight large and three small pairs. (Sutton made an error in this count. Later workers found 24 chromosomes.) He postulated that every ovum after meiosis would contain one chromosome of each of the 11 sizes. Fertilization of an ovum containing 11 chromosomes with a sperm contain- ing 11 would restore the diploid number of 22. Some of the sperm will have an accessory chromosome in addition to the regular 11. 4–1 A haploid set of chromosomes of Brachystola. The metaphase chromosomes have been redrawn, showing one of each pair, and arranged in groups. The accessory chromosome is at the left, the eight large chromosomes in the center, and the three small chromosomes at the right. A diploid nucleus in a male would have one accessory, two of each of the eight large chromosomes and two of each of the three small ones to make a total of 23. (Modified from W.S.Sutton. Biolog- ical Bulletin 4:24–39. 1902.) 

HEREDITY AND DEVELOPMENT: SECOND EDITION 74 Fertilization with a sperm of this type will result in a zygote with 22 chromo- somes plus an accessory. (In 1901 McClung suggested that the accessory chromosome is in some way concerned with sex determination. More will be said about this in Chapter 5.) Sutton continues: Taken as a whole, the evidence presented by the cells of Brachystola is such as to lend great weight to the conclusion that a chromosome may exist only by virtue of direct descent by longitudinal division from a pre-existing chromo- some and that the members of the daughter group bear to one another the same respective relations as did those of the mother group—in other words, that the chromosome in Brachystola is a distinct morphological individual. This conclusion inevitably raises the question whether there is also a physiolog- ical individuality, i.e., whether the chromosomes represent respectively differ- ent series or groups of qualities or whether they are merely different-sized aggregations of the same material and, therefore, qualitatively alike. On this question my observations do not furnish direct evidence. But it is a pri- ori improbable that the constant morphological differences we have seen should exist except by virtue of more fundamental differences of which they are an expression; and, further, by the unequal distribution of the accessory chromosome we are enabled to compare the developmental possibilities of cells containing it with those of cells which do not. Granting the normal consti- tution of the female cells examined and the similarity of the reduction process in the two sexes, such a comparison must show that this particular chromosome does possess a power not inherent in any of the others—the power of impress- ing on the containing cell the stamp of maleness, in accordance with McClung’s hypothesis. The evidence advanced in the case of the ordinary chromosomes is obviously more in the nature of suggestion than of proof, but it is offered in this connec- tion as a morphological complement to the beautiful experimental researches of Boveri already referred to. In this paper Boveri shows how he has artificially accomplished for the various chromosomes of the sea-urchin, the same result that nature is constantly giving us in the case of the accessory chromosome of the Orthoptera. He has been able to produce and to study the development of blastomeres lacking certain of the chromosomes of the normal series. If, as the facts in Brachystola so strongly suggest, the chromosomes are persis- tent individuals in the sense that each bears a genetic relation to one only of the previous generation, the probability must be accepted that each represents the same qualities as its parent element. A given relative size may, therefore, be taken as characteristic of the physical basis of a certain definite set of qualities. But each element of the chromosome series of the spermatozoon has a morpho- logical counterpart in that of the mature egg and from this it follows that the two cover the same field in development. When the two copulate, therefore, in synapsis the entire chromatin basis of 

HEREDITY AND DEVELOPMENT: SECOND EDITION 75 a certain set of qualities inherited from the two parents is localized for the first and only time in a single continuous chromatin mass; and when in the second spermatocyte division, the two parts are again separated, one goes entire to each pole contributing to the daughter cells the corresponding group of qualities from the paternal or the maternal stock as the case may be. There is, therefore, in Brachystola no qualitative division of chromosomes but only a separation of the two members of a pair which, while coexisting in a sin- gle nucleus, may be regarded as jointly controlling certain restricted portions of the development of the individual. By the light of this conception we are enabled to see an explanation of that hitherto problematical process, synapsis, in the provision which it makes that the two chromosomes representing the same specific characters shall in no case enter the nucleus of a single spermatid or mature egg. I may finally call attention to the probability that the association of paternal and maternal chromosomes in pairs and their subsequent separation during the reducing division as indicated above may constitute the physical basis of the Mendelian law of heredity. To this subject I hope soon to return in another place. The Chromosomes in Heredity. And soon he did in a paper entitled ‘The Chromosomes in Heredity,’ published in 1903. In this he pointed out that the segregation and recombination of genes as studied by the geneticists showed a striking parallel to the behavior of chromosomes as revealed by the cytolo- gists. The pertinent cytological data, according to Sutton, were as follows: 1. The diploid chromosome group consists of two morphologically similar chromosome sets. Every chromosome type is represented twice. Expressed another way, chromosomes exist in homologous pairs. Strong grounds exist for the belief that one set was derived from the father and one set from the mother at the time of fertilization. 2. Synapsis consists of the pairing of homologous chromosomes. 3. As a result of meiosis every gamete receives only one chromosome of each homologous pair. 4. The chromosomes retain their morphological individuality throughout the various cell divisions. 5. The distribution in meiosis of the members of each homologous pair of chromosomes is independent of that of each other pair. As a result, each gamete receives one of each pair, but which one is a matter of chance. Sutton then made the point that Mendel’s results could be explained on the assumption that genes were parts of the chromosomes. The following exam- ple will show how this is possible: 

HEREDITY AND DEVELOPMENT: SECOND EDITION 76 Let us assume that the round and wrinkled genes in peas are carried on a specific pair of chromosomes (Fig. 4–2). If a chromosome has the round gene, we shall call it R and if it has the wrinkled gene, we shall call it r. Let us further assume that the yellow and green genes are carried by a different pair of chromosomes. If the chromosome has the yellow gene, we shall designate it Y and if it carries the green gene, we shall call it y. A pure-breeding round- yellow plant would be symbolized as RRYY indicating that it has a pair of chromosomes carrying the round gene and another pair with the yellow gene. Similarly, a wrinkled-green plant would be rryy. When the reduction divisions occur, the round-yellow plant would produce haploid gametes with one R and one Y chromosome—or RY. This alone could result, since a gamete receives only one chromosome of every kind. A RR or a YY gamete would be impossible in normal meiosis. The wrinkled- green plant would produce gametes solely of the ry type. A union of gametes of the two plants would result in one type of offspring, namely, RrYy. This F1 individual would be diploid and would have received one member of each chromosome type from the male gamete and one from the female gamete. The gametes of the F1 plant would be of four possible types. The R and the r would go to different cells during meiosis. The Y and y chromosomes would likewise be separated and their separation would not affect the separa- tion of R and r. Thus, all possible combinations, namely, RY, Ry, rY, and ry would be produced, and in approximately equal numbers. If you will re- examine Mendel’s description of this cross (p. 54), you will note the exact parallel between the scheme for Mendel’s breeding experiments and the chromosome movements just described. The F2 chromosomes would be of the type shown in the genetic checkerboard. The sole difference to be noted is that Mendel characterized his pure-breeding peas of the parental generation as RY and ry, while we have used a diploid chromosome designation RRYY and rryy. Mendel could have used RRYY and rryy just as well. Sutton’s Hypothesis. We may conclude, therefore, that genes of a type postulated by Mendel could be 1. parts of the chromosomes, or 2. parts of some other cell structures that behave in the same way as chro- mosomes in mitosis, meiosis, and fertilization. When a scientist is confronted with two hypotheses, one involving known factors and the other invoking unknown factors, the first is usually chosen. In the case under consideration, such a choice would have a great practical advantage: It would be easier to make observa- 

HEREDITY AND DEVELOPMENT: SECOND EDITION 77 4–2 Diagram of chromosome distributions in Mendel’s cross of a round- yellow ×wrinkled-green pea on the basis of Sutton’s hypothesis. 

HEREDITY AND DEVELOPMENT: SECOND EDITION 78 tions and design experiments to test the role of chromosomes in Mendelian heredity than it would be to investigate the role of some unknown cell structures. Sutton’s general hypothesis was not new. As we have already seen, some cytologists believed, at least as early as 1884, that the chromosomes were involved in inheritance. Sutton pointed out additional reasons for so thinking and, even more important, made a definite link between genetic data and cyto- logical data. If we are to use the genes-are-parts-of-chromosomes hypothesis, it will be necessary to find a parallel between all types of genetic behavior and chromo- some behavior. Any variations in chromosomal phenomena from the usual condition must be reflected in the genetic results. Similarly, if genetic ratios are obtained that cannot be explained in Mendelian terms, one must find a chromosomal basis for the deviation. Sutton indicated one type of genetic behavior that could be expected if his hypothesis was correct. We have seen reason, in the foregoing considerations, to believe that there is a definite relation between chromosomes and allelomorphs or unit characters, but we have not before inquired whether an entire chromosome or only a part of one is to be regarded as the basis of a single allelomorph. The answer must unquestionably be in favor of the latter possibility, for otherwise the number of distinct characters possessed by an individual could not exceed the number of chromosomes in the germ-products; which is undoubtedly contrary to fact. We must, therefore, assume that some chromosomes at least are related to a number of different allelomorphs. If then, the chromosomes permanently retain their individuality, it follows that all the allelomorphs represented by any one chro- mosome must be inherited together. If Sutton’s reasoning is correct, the Mendelian principle of independent assortment could apply only to cases where the two pairs of contrasting fac- tors were carried on separate chromosomes. Sutton’s hypothesis demanded that there be exceptions to Mendel’s law of independent assortment. The exceptions would be detected, without fail, when more gene pairs were discovered for an organism than there were pairs of chromosomes. When two pairs of genes were on the same chromosome they would obviously be linked in some manner and tend to be inherited as a unit. Bateson observed such a case (page 66) but he was unable to offer a rea- sonable explanatory hypothesis. The importance of Sutton’s theoretical considerations can scarcely be overemphasized. Two completely different disciplines were found to have an area in common: cytology and genetics became mutually supporting and stimulating fields. Theories of inheritance could be ‘double-checked.’ 

HEREDITY AND DEVELOPMENT: SECOND EDITION 79 Still another line of cytological investigation was to reveal a specific rela- tion of chromosomes to inheritance. SEX CHROMOSOMES The first impression cytologists gained from a study of chromosomes was a feeling that the behavior of these cell structures was similar in all animals. Whether the form studied was a worm, snail, salamander, or mammal, one observed the same duplication of each chromosome to form two chromatids during mitosis. This was followed by the distribution of one of the two chro- matids to each daughter cell. Each chromosome appeared double at the same time, and the movements during metaphase, anaphase, and telophase were synchronous. A similarity of behavior was observed in the events connected with the reduction of chromosome number in meiosis of both male and female gametes. It should be emphasized that this similarity of behavior applied not only to the behavior of the group of chromosomes but to the indi- vidual chromosomes in the group as well. Atypical Chromosomes. It was not long before this concept of uniform behavior was found to have its exceptions. In the last decade of the nine- teenth century and the first years of the twentieth, a few cases were reported of one or two of the chromosomes of a set behaving in a manner quite unlike the rest. The unusual behavior might be a difference in reaction of the chro- mosome to stains, meiotic movements that were not synchronous, or the pres- ence of ‘extra’ or ‘accessory chromosomes.’ The term accessory chromo- some referred to those cases where there was one chromosome without a mate, in contrast to the usual situation of all chromosomes being in morpho- logically similar pairs. The analysis of accessory chromosomes led to important results concern- ing the role of chromosomes in heredity. As is frequently the case in science, these observations were made and recorded before their true significance was understood. Henking’s Description of the X Chromosome. In 1891 H.Henking pub- lished his observations on chromosome behavior during sperm formation in a bug, Pyrrhocoris (Fig. 4–3). This species has 23 chromosomes. Twenty-two of them form 11 pairs, the two members of a pair having the same appear- ance. The extra chromosome was called X. It did not have a mate. During the first meiotic division the 22 chromosomes synapsed to form 11 pairs. Later these formed tetrads. The behavior of the X chromosome was different. Having no mate, it could not synapse and form a tetrad. It did duplicate itself, however, to form a structure like a dyad. At the beginning of meiosis, the cells therefore con- tained 11 tetrads, plus the X in the form of a dyad. At the 

HEREDITY AND DEVELOPMENT: SECOND EDITION 80 4–3 Meiosis in Pyrrhocoris. a shows a cell in the telophase of the second meiotic division. Since this is a lateral view not all of the chromosomes are shown. The peculiar body, indicated as ‘X’ by Henking, goes to one pole of the spindle and will, therefore, be in only half of the cells formed by this division. Consequently two types of cells result from meiosis. One type, b, has 11 chromo- somes and the other type, c, has 11 chromosomes plus the X. These cells develop directly into sperm. Thus, half of the sperm will have an X (e) and the others lack an X (d) (H.Henking, ‘Unter- suchungen über die ersten Entwicklungsvorgänge in den Eiern der Insekten,’ Zeit. für wiss. Zool. 51:685–736. 1891). 

HEREDITY AND DEVELOPMENT: SECOND EDITION 81 first meiotic division the 11 tetrads were separated but the X went entire to one of the daughter cells. At the end of the first division, one of the daughter cells contained 11 dyads of the usual sort, plus the X dyad. The other daugh- ter cell contained only the 11 dyads. At the second meiotic division of the cell with the X, the X dyad and the 11 regular dyads were divided so each of the resulting cells contained an X chromosome plus 11 of the regular chromo- somes. In the cell without the X dyad, the other dyads were divided so each daughter cell contained 11 regular chromosomes. Therefore, the four cells resulting from the two meiotic divisions consisted of two with 11 chromo- somes plus an X, and two with the 11 chromosomes alone. So far as the X was concerned, half of the sperm contained an X and the other half did not. During the next decade, many workers discovered these chromosomes with atypical behavior. They were given a variety of names such as ‘X chro- mosomes’ and ‘accessory chromosomes.’ In every case the accessory was unique in some feature such as stainability, time of movement to the poles of the spindle, enclosure in a separate vesicle instead of the nucleus, lack of a mate during synapsis, or distribution to only half of the sperm. Sex and the Accessory Chromosomes. In 1901 C.E.McClung (1870–1946) suggested that the accessory chromosome was in some way connected with sex determination: Being convinced from the behavior in the spermatogonia and the first sperma- tocytes of the primary importance of the accessory chromosome, and attracted by the unusual method of its participation in the spermatocyte mitoses, I sought an explanation that would be commensurate with the importance of these facts. Upon the assumption that there is a qualitative difference between the various chromosomes of the nucleus, it would necessarily follow that there are formed two kinds of spermatozoa which, by fertilization of the egg, would produce individuals qualitatively different. Since the number of each of these varieties of spermatozoa is the same, it would happen that there would be an approxi- mately equal number of these two kinds of offspring. We know that the only quality which separates the members of a species into these two groups is that of sex. I therefore came to the conclusion that the accessory chromosome is the element which determines that the germ cells of the embryo shall continue their development past the slightly modified egg cell into the highly specialized spermatozoon. It would not be desirable in a preliminary paper of this character to extend it by a detail of the discussion by which the problem was considered. Suffice it to say that by this assumption it is possible to reconcile the results of many empirical theories which have proved measurably true upon the general ground that the egg is placed in a delicate adjustment with its en- 

HEREDITY AND DEVELOPMENT: SECOND EDITION 82 vironment, and in response to this, is able to attract that form of spermatozoon which will produce an individual of the sex most desirable to the welfare of the species. The power of selection which pertains to the female organism is thus logically carried to the female element. Numerous objections to this theory received consideration, but the proof in support of it seemed to overbalance them largely, and I was finally induced to commit myself to its support. I trust that the element here discussed will attract the attention which I am convinced it deserves and can only hope that my inves- tigations will aid in bringing it to the notice of a larger circle of investigators than that now acquainted with it. McClung’s hypothesis was not accepted or even widely believed at first. In part this was due to the type of reasoning displayed in the second paragraph of the quotation. It was difficult to imagine how an unfertilized ovum could select the type of sperm and so produce the ‘sex most desirable to the welfare of the species.’ Were this possible, it would be a most interesting extension of feminine intuition! The question was all the more confusing when somewhat later it was found that the female had not one less chromosome than the male, but one more. Clarification of Chromosomal Sex Determination. In 1905 the situation was clarified by E.B.Wilson and one of his students, Nettie M. Stevens. They studied meiosis in a number of insects and found that X chro- mosomes were the rule, not the exception. Because of the association of X chromosomes with sex they were called sex chromosomes. All other chromo- somes were called autosomes. Thus, Henking’s bug, Pyrrhocoris, would have one X sex chromosome and 22, or 11 pairs, of autosomes. Stevens and Wilson found two types of sex chromosome behavior, the X0- XX type and the XY-XX type (Fig. 4–4). The X0-XX Type. In the species having this type of sex chromosome behavior, the male has a single X chromosome and the female has two X chromosomes. The male can be symbolized as X0, where 0 signifies the absence of a homologue of the X. The female is XX. Both sexes will have the same autosomes. A Pyrrhocoris male would have 11 pairs of autosomes and one X chromosome. In meiosis two types of sperm will be produced: One type will contain 11 autosomes plus the X and the other type will contain 11 autosomes and no X. The ova will all be of one type, containing 11 auto- somes and one X. The union of a sperm of the first type with an ovum will result in a zygote with 22 autosomes and two X chromosomes. This individ- ual will be a female. Fertilization of an ovum with the second type of sperm will result in a zygote with 22 autosomes and a single X (that is, X0). The result will be a male. The XY-XX Type. In this type, both the male and female possess a 

HEREDITY AND DEVELOPMENT: SECOND EDITION 83 4–4 

HEREDITY AND DEVELOPMENT: SECOND EDITION 84 pair of sex chromosomes. Once again, the female has a pair that are identical and she is symbolized as XX. The male has one chromosome that is identical with the X of the female plus another, the Y, that is morphologically differ- ent. The Y might be longer, shorter, or of a different shape. It is similar to the X in some way, since synapsis occurs between X and Y. The results of meiosis would be these: Every ovum would contain auto- somes (the number depending on the species) and one X. The sperm would be of two types. One would contain autosomes and one X, and the other would contain autosomes and one Y. The fertilization of an ovum with an X- bearing sperm would give a zygote with the diploid set of autosomes and XX. This would be a female. The fertilization of an ovum with a Y-bearing sperm would give a zygote with the diploid set of autosomes and XY. This would be a male. (Incidentally, man has the XX-XY type of sex determination and so does Drosophila melanogaster, a small fly much used in genetic work.) These two types of sex chromosome distribution described by Stevens and Wilson are those most frequently encountered in the animal kingdom. With each type, the male produces two classes of sperm, and sex is determined by the kind of sperm entering the ovum. Additional types were discovered later. In birds, for example, it is the female that produces two classes of gametes and the male only one. If these observations on sex chromosomes are correct, we may draw some important conclusions: 1. Sex is determined at the time of fertilization. 2. If sex determination is due only to sex chromosomes, we can regard the sex of an individual as irreversible, unless we can alter the chromosomes. 3. The two sexes should be produced in approximately equal numbers. 4. The relation between sex and chromosomes is additional evidence sup- porting Sutton’s hypothesis that chromosomes are the basis of inheritance. It was becoming even more probable that the physical basis of inheritance was to be sought in the chromosomes. This was a good working hypothesis even before 1900 (page 41) but the observations on the relation of sex to the sex chromosomes, and especially Sutton’s remarkable theoretical analysis, made it a far more useful hypothesis. Inheritance was so poorly understood before 1900 that one could not design specific experiments that might uncover its cellular basis. Mendelism changed all that. It became possible to think in symbolic terms —of organisms having dominant and recessive genes and these 

HEREDITY AND DEVELOPMENT: SECOND EDITION 85 being allocated to the gametes in specific ways. Bateson had emphasized that the essential element of Mendel’s hypothesis was the purity of the gametes formed by a heterozygous individual. Sutton had shown how the observable behavior of chromosomes could account for this otherwise obscure phe- nomenon: the chromosomes of diploid cells exist in pairs and one could carry a dominant gene and the other member of the pair could carry the recessive gene; during meiosis these homologous chromosomes would be separated and half of the gametes would have the dominant gene and the other half the recessive gene; normal meiosis, therefore, could account for the purity of the gametes. Before 1900, one might find the hypothesis ‘the genes are parts of chromo- somes’ to be probable but it was very difficult to see how it might be tested. The great utility of Sutton’s hypothesis was to show how tests could be per- formed. If one assumed that genes are parts of chromosomes, then one could deduce: 1. The distribution of genes from generation to generation, as determined by the animal or plant breeder, must parallel the distribution of the chromosomes. Every specific aspect of the distribution of genes must have a basis in chromosomal movements. 2. Similarly, if the cytologist observes a peculiar chromosomal behavior in mitosis, meiosis, or fertilization, there must be parallel genetic phenomena. The synthesis of the modern theory of genetics was made of this basis. It was completed in the laboratory of Thomas Hunt Morgan, in a decade of research devoted to Drosophila melanogaster. Suggested Readings Chapter 4 of Readings in Heredity and Development includes three items by Edmund B.Wilson: the 1902 paper relating Mendel’s principles to cytology; his famous Croonian Lecture of 1914 in which he summarized the relation of genetics to cytology; and his reminiscences of Sutton. And, as always, there is a more extensive list of references. BOVERI, TH. 1902. ‘Uber mehrpolige Mitosen als Mittel zur Analyse des Zellkerns.’ Verh. der phys. med. Ges. Würzburg. NF 35:67–90. DUNN, L.C. 1965. A Short History of Genetics. New York: McGraw-Hill. Chapter 11. HENKING, H. 1891. ‘Untersuchungen über die ersten Entwicklungsvorgänge in den Eiern der Insekten.’ Zeit. wiss. Zool. 51:685–736. HUGHES, ARTHUR. 1959. A History of Cytology. New York: Abelard-Schuman. MCCLUNG, C.E. 1901. ‘Notes on the accessory chromosome.’ Anat. Anz. 20:220–226. 

HEREDITY AND DEVELOPMENT: SECOND EDITION 86 STURTEVANT, A.H. 1965. A History of Genetics. New York: Harper and Row. Chapter 5. SUTTON, W.S. 1902. ‘On the morphology of the chromosome group in Brachystola magna.’ Biological Bulletin 4:24–39. SUTTON, W.S. 1903. ‘The chromosomes in heredity.’ Biological Bulletin 4:231–51. WILSON, EDMUND B. 1928. The Cell in Development and Heredity. New York: Macmil- lan. Chapters 10 and 12. Questions 1. Evaluate Boveri’s experiment on the relation of chromosomes to normal development in the sea urchin embryo. Do you find it convincing? How does it differ from some of the pre-1900 observations suggesting that the nucleus (and chromosomes) were the basis of inheritance (page 41)? 2. Explain why it is legitimate, on the basis of Mendel’s work, to give the genotype of a pure breeding round pea as R but, on the basis of Sutton’s work, it is necessary to designate it RR? 3. Let us assume that Mendel studied an eighth pair of genes, which we will call Aa. Let us also assume that one of the first seven pairs, Bb, is on the same pair of homologous chromosomes as Aa. Another pair of genes, Cc, is on a different pair of homologous chromosomes. What would you expect to be the F1 and F2 of these crosses? a. AA CC×aa cc b. BB CC×bb cc c. AA BB×aa bb 4. Using Sutton’s hypothesis, can you explain Bateson’s unusual data on coupling of genes (page 66)? 5. In species in which the male has XY sex chromosomes and the female XX, speculate on the relation between the chromosomes and sex. Is the male a male because he has a Y or only one X or an X and a Y? Is the female a female because she has no Y or because she has two X’s. How could you test these various possibilities? 6. Imagine yourself a cytologist, circa 1900. Had you observed a peculiar unpaired chromosome, and discovered that half of the gametes formed by this species had the peculiar chromosome and half did not, what are some of the explanatory hypotheses that you could devise?