Zoology

Chromosomal Basis of Mendelian Inheritance

Walter S. SUTTON. From The chromosomes in heredity, in Biological Bulletin, vol. 4, 1902–1903; by permission of the editor.

In a recent announcement of some results of a critical study of the chromosomes in the various cell-generations of Brachystola the author briefly called attention to a possible relation between the phenomena there described and certain conclusions first drawn from observations on plant hybrids by Gregor Mendel in 1865, and recently confirmed by a number of able investigators. Further attention has already been called to the theoretical aspects of the subject in a brief communication by Professor E. B. Wilson. The present paper is devoted to a more detailed discussion of these aspects, the speculative character of which may be justified by the attempt to indicate certain lines of work calculated to test the validity of the conclusions drawn. The general conceptions here advanced were evolved purely from cytological data, before the author had knowledge of the Mendelian principles, and are now presented as the contribution of a cytologist who can make no pretensions to complete familiarity with the results of experimental studies on heredity. As will appear hereafter, they completely satisfy the conditions in typical Mendelian cases, and it seems that many of the known deviations from the Mendelian type may be explained by easily conceivable variations from the normal chromosomic processes.

It has long been admitted that we must look to the organization of the germ-cells for the ultimate determination of hereditary phenomena. Mendel fully appreciated this fact and even instituted special experiments to determine the nature of that organization. From them he drew the brilliant conclusion that, while, in the organism, maternal and paternal potentialities are present in the field of each character, the germ-cells in respect to each character are pure. Little was then known of the nature of cell-division, and Mendel attempted no comparisons in that direction; but to those who in recent years have revived and extended his results the probability of a relation between cell-organization and cell-division has repeatedly occurred. Bateson clearly states his impression in this regard in the following words: "It is impossible to be presented with the fact that in Mendelian cases the cross-bred produces on an average equal numbers of gametes of each kind, that is to say, a symmetrical result, without suspecting that this fact must correspond with some symmetrical figure of distribution of the gametes in the cell divisions by which they are produced."

Nearly a year ago it became apparent to the author that the high degree of organization in the chromosome-group of the germ-cells as shown in Brachystola could scarcely be without definite significance in inheritance, for, as shown in the paper already referred to, it had appeared that:

1. The chromosome group of the presynaptic germ-cells is made up of two equivalent chromosome-series, and that strong ground exists for the conclusion that one of these is paternal and the other maternal.

2. The process of synapsis (pseudo-reduction) consists in the union in pairs of the homologous members (i.e., those that correspond in size) of the two series.

3. The first post-synaptic or maturation mitosis is equational and hence results in no chromosomic differentiation.

4. The second post-synaptic division is a reducing division, resulting in the separation of the chromosomes which have conjugated in synapsis, and their relegation to different germ-cells.

5. The chromosomes retain a morphological individuality throughout the various cell divisions.

It is well known that in the eggs of many forms the maternal and paternal chromosome groups remain distinctly independent of each other for a considerable number of cleavage-mitoses, and with this fact in mind the author was at first inclined to conclude that in the reducing divisions all the maternal chromosomes must pass to one pole and all the paternal ones to the other, and that the germ-cells are thus divided into two categories which might be described as maternal and paternal respectively. But this conception, which is identical with that recently brought forward by Cannon, was soon seen to be at variance with many well-known facts of breeding; thus:

1. If the germ-cells of hybrids are of pure descent, no amount of crossbreeding could accomplish more than the condition of a first-cross.

2. If any animal or plant has but two categories of germ-cells, there can be only four different combinations in the offspring of a single pair.

3. If either maternal or paternal chromosomes are entirely excluded from every ripe germ-cell, an individual cannot receive chromosomes (qualities) from more than one ancestor in each generation of each of the parental lines of descent, e.g., could not inherit chromosomes (qualities) from both paternal or maternal grandparents.

Moved by these considerations a more careful study was made of the whole division-process, including the positions of the chromosomes in the nucleus before division, the origin and formation of the spindle, the relative positions of the chromosomes and the diverging centrosomes, and the point of attachment of the spindle fibers to the chromosomes. The results gave no evidence in favor of parental purity of the gametic chromatin as a whole. On the contrary, many points were discovered Which strongly indicate that the position of the bivalent chromosomes in the equatorial plate of the reducing division is purely a matter of chance—that is, that any chromosome pair may lie with maternal or paternal chromatid indifferently toward either pole irrespective of the positions of the other pairs—and hence that a large number of different combinations of maternal and paternal chromosomes are possible in the mature germ-products of an individual. To illustrate this, we may consider a form having eight chromosomes in the somatic and presynaptic germ-cells and consequently four in the ripe germ-products.

The germ-cell series of the species in general may be designated by the letters A, B, C, D, and any cleavage nucleus may be considered as containing the chromosomes A, B, C, D from the father and a, b, c, d, from the mother. Synapsis being the union of homologues would result in the formation of the bivalent chromosomes Aa, Bb, Cc, Dd, which would again be resolved into their components by the reducing division. Each of the ripe germ-cells arising from the reduction divisions must receive one member from each of the synaptic pairs, but there are sixteen possible combinations of maternal and paternal chromosomes that will form a complete series, to wit: a, B, C, D; A, b, C, D; A, B, c, D; A, B, C, d; a, b, C, D; a, B, c, D; a, B, C, d; a, b, c, d; and their conjugates A, b, c, d; a, B, c, d; a, b, C, d; a, b, c, D; A, B, c, d; A, b, C, d; A, b, c, D; A, B, C, D. Hence instead of two kinds of gametes an organism with four chromosomes in its reduced series may give rise to 16 different kinds; and the offspring of two unrelated individuals may present

or 256 combinations, instead of the four to which it would be limited by a hypothesis of parental purity of gametes. Few organisms, moreover, have so few as 8 chromosomes, and since each additional pair doubles the number of possible combinations in the germ-products and quadruples that of the zygotes it is plain that in the ordinary form having from 24 to 36 chromosomes, the possibilities are immense. The table below shows the number of possible combinations in forms having from 2 to 36 chromosomes in the presynaptic cells.

Thus if Bardeleben’s estimate of sixteen chromosomes for man (the lowest estimate that has been made) be correct, each individual is capable of producing 256 different kinds of germ-products with reference to their chromosome combinations, and the numbers of combinations possible in the offspring of a single pair is

or 65,536; while Toxopneustes, with 36 chromosomes, has a possibility of 262,144 and 68,719, 476,736 different combinations in the gametes of a single individual and the zygotes of a pair respectively. It is this possibility of so great a number of combinations of maternal and paternal chromosomes in the gametes which serves to bring the chromosome-theory into final relation with the known facts of heredity; for Mendel himself followed out the actual combinations of two and three distinctive characters and found them to be inherited independently of one another and to present a great variety of combinations in the second generation.

The constant size-differences observed in the chromosomes of Brachystola early led me to the suspicion, which, however, a study of spermatogenesis could not confirm, that the individual chromosomes of the reduced series play different rôles in development. The confirmation of this surmise appeared later in the results obtained by Boveri in a study of larvae actually lacking in certain chromosomes of the normal series, which seem to leave no alternative to the conclusion that the chromosomes differ qualitatively and as individuals represent distinct potentialities. Accepting this conclusion we should be able to find an exact correspondence between the behavior in inheritance of any chromosome and that of the characters associated with it in the organism.

In regard to the characters, Mendel found that, if a hybrid produced by crossing two individuals differing in a particular character be self-fertilized, the offspring, in most cases, conform to a perfectly definite rule as regards the differential character. Representing the character as seen in one of the original parents by the letter A and that of the other by a, then all the offspring arising by self-fertilization of the hybrid are represented from the standpoint of the given character by the formula AA: 2Aa: aa—that is, one fourth receive only the character of one of the original pure-bred parents, one fourth only that of the other; while one half of the number receive the characters of both original parents and hence present the condition of the hybrid from which they sprang.

We have not heretofore possessed graphic formulae to express the combinations of chromosomes in similar breeding experiments, but it is clear from the data already given that such formulae may now be constructed. The reduced chromosome series in Brachystola is made up of eleven members, no two of which are exactly of the same size. These I distinguished in my previous paper by the letters A, B, C . . . K. In the unreduced series there are twenty-two elements which can be seen to make up two series like that of the mature germ-cells, and hence may be designated as A, B, C . . . K plus A, B, C . . . K. Synapsis results in the union of homologues and the production of a single series of double-elements thus: AA, BB, CC . . . KK, and the reducing division affects the separation of these pairs so that one member of each passes to each of the resulting germ-products.

There is reason to believe that the division-products of a given chromosome in Brachystola maintain in their respective series the same size relation as did the parent element; and this, taken together with the evidence that the various chromosomes of the series represent distinctive potentialities, make it probable that a given size-relation is characteristic of the physical basis of a definite set of characters. But each chromosome of any reduced series in the species has a homologue in any other series, and from the above consideration it should follow that these homologues cover the same field in development. If this be the case chromosome A from the father and its homologue, chromosome a, from the mother in the presynaptic cells of the offspring may be regarded as the physical bases of the antagonistic unit-characters A and a of father and mother respectively. In synapsis, copulation of the homologues gives rise to the bivalent chromosome, Aa, which as is indicated above would, in the reducing division, be separated into the components A and a. These would in all cases pass to different germ-products and hence in a monoecious form we should have four sorts of gametes,

A male     A female

a male     a female

which would yield four combinations,

A male plus A female equal AA

A male plus a female equal Aa

a male plus A female equal aA

a male plus a female equal aa

Since the second and third of these are alike the result would be expressed by the formula AA: 2Aa: aa which is the same as that given for any character in a Mendelian case. Thus the phenomena of germ-cell division and of heredity are seen to have the same essential features, viz., purity of units (chromosomes, characters) and the independent transmission of the same; while as a corollary, it follows in each case that each of the two antagonistic units (chromosomes, characters) is contained by exactly half the gametes produced.

The observations which deal with characters have been made chiefly upon hybrids, while the cytological data are the result of a study of a pure-bred form; but the correlation of the two is justified by the observation of Cannon that the maturation mitoses of fertile hybrids are normal. This being the case it is necessary to conclude, as Cannon has already pointed out, that the course of variations in hybrids either is a result of normal maturation processes or is entirely independent of the nature of those divisions. If we conclude from the evidence already given that the double basis of hybrid characters is to be found in the pairs of homologous chromosomes of the presynaptic germ-cells, then we must also conclude that in pure-bred forms likewise, the paired arrangement of the chromosomes indicates a dual basis for each character. In a hypothetical species breeding absolutely true, therefore, all the chromosomes or subdivisions of chromosomes representing any given character would have to be exactly alike, since the combination of any two of them would produce a uniform result. As a matter of fact, however, specific characters are not found to be constant quantities but vary within certain limits; and many of the variations are known to be inheritable. Hence it seems highly probable that homologous chromatin-entities are not usually of strictly uniform constitution, but present minor variations corresponding to the various expressions of the character they represent. In other words, it is probable that specific differences and individual variations are alike traceable to a common source, which is a difference in the constitution of homologous chromatin-entities. Slight differences in homologues would mean corresponding, slight variations in the character concerned—a correspondence which is actually seen in cases of inbreeding, where variation is well known to be minimized and where obviously in the case of many of the chromosome pairs both members must he derived from the same chromosome of a recent common ancestor and hence be practically identical. . . .

[In the omitted portion of the paper, Sutton develops two principal themes. First he predicts genetical consequences to be expected in certain instances of anomalous chromosome behavior, especially that occurring in parthenogenesis. Second he shows how both Mendelian inheritance and apparent exceptions to it could be explained on the chromosome theory by assuming details of chromosome behavior as yet unobserved. Although not all of Sutton’s detailed assumptions and predictions have been validated by subsequent observation and research, his central ideas proved sound.—Ed.]

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 chromosome must be inherited together. On the other hand, it is not necessary to assume that all must be apparent in the organism, for here the question of dominance enters and it is not yet known that dominance is a function of an entire chromosome. It is conceivable that the chromosome may be divisible into smaller entities (somewhat as Weismann assumes), which represent the allelomorphs and may be dominant or recessive independently. In this way, the same chromosome might at one time represent both dominant and recessive allelomorphs.

Such a conception infinitely increases the number of possible combinations of characters as actually seen in the individuals and unfortunately at the same time increases the difficulty of determining what characters are inherited together, since usually recessive chromatin entities (allelomorphs?) constantly associated in the same chromosome with usually dominant ones would evade detection for generations and then becoming dominant might appear as reversions in a very confusing manner.

In their experiments on Matthiola, Bateson and Saunders mention two cases of correlated qualities which may be explained by the association of their physical bases in the same chromosome. "In certain combinations there was close correlation between (a) green color of seed and hoariness, (b) brown color of seed and glabrousness. In other combinations such correlation was entirely wanting." Such results may be due to the association in the same chromosomes of the physical bases of the two characters. When close correlation was observed, both may be supposed to have dominated their homologues; when correlation was wanting, one may have been dominant and the other recessive. In the next paragraph to that quoted is the statement:

"The rule that plants with flowers either purple or claret arose from green seeds was universal." Here may be a case of constant dominance of two associated chromatin-entities.