Sex-linked Inheritance in Drosophila

MENDEL'S LAW OF SEGREGATION.

Although the ratio of 3 to 1 in which contrasted characters reappear in the second or F_2 generation is sometimes referred to as Mendel's Law of Heredity, the really significant discovery of Mendel was not the 3 to 1 ratio, but the segregation of the characters (or rather, of the germinal representatives of the characters) which is the underlying cause of the appearance of the ratio. Mendel saw that the characters with which he worked must be represented in the germ-cells by specific producers (which we may call factors), and that in the fertilization of an individual showing one member of a pair of contrasting characters by an individual showing the other member, the factors for the two characters meet in the hybrid, and that when the hybrid forms germ-cells the factors segregate from each other without having been contaminated one by the other. In consequence, half the germ-cells contain one member of the pair and the other half the other member. When two such hybrid individuals are bred together the combinations of the pure germ-cells give three classes of offspring, namely, two hybrids to one of each of the pure forms. Since the hybrids usually can not be distinguished from one of the pure forms, the observed ratio is 3 of one kind (the dominant) to 1 of the other kind (the recessive).

There is another discovery that is generally included as a part of Mendel's Law. We may refer to this as the assortment in the germ-cells of the products of the segregation of two or more pairs of factors. If assortment takes place according to chance, then definite F_2 ratios result, such as 9:3:3:1 (for two pairs) and 27:9:9:9:3:3:3:1 (for three pairs), etc. Mendel obtained such ratios in peas, and until quite recently it has been generally supposed that free assortment is the rule when several pairs of characters are involved. But, as we shall try to show, the emphasis that has been laid on these ratios has obscured the really important part of Mendel's discovery, namely, segregation; for with the discovery in 1906 of the fact of linkage the ratios based on free assortment were seen to hold only for combinations of certain pairs of characters, not for other combinations. But the principle of segregation still holds for each pair of characters. Hence segregation remains the cardinal point of Mendelism. Segregation is to-day Mendel's Law.

LINKAGE AND CHROMOSOMES.

It has been found that when certain characters enter a cross together (i. e., from the same parent) their factors tend to pass into the same gamete of the hybrid, with the result that other ratios than the chance ratios described by Mendel are found in the F_2 generation. {6} Such cases of linkage have been described in several forms, but nowhere on so extensive a scale as in the pomace fly, Drosophila ampelophila. Here, over a hundred characters that have been investigated as to their linkage relations are found to fall into four groups, the members of each group being linked, in the sense that they tend to be transmitted to the gametes in the same combinations in which they entered from the parents. The members of each group give free assortment with the members of any of the other three groups. A most significant fact in regard to the linkage shown by the Drosophila mutants is that the number of linked groups corresponds to the number of pairs of the chromosomes. If the gens for the Mendelian characters are carried by the chromosomes we should expect to find demonstrated in Drosophila that there are as many groups of characters that are inherited together as there are pairs of chromosomes, provided the chromosomes retain their individuality. The evidence that the chromosomes are structural elements of the cell that perpetuate themselves at every division has continually grown stronger. That factors have the same distribution as the chromosomes is clearly seen in the case of sex-linked characters, where it can be shown that any character of this type appears in those individuals which from the known distribution of the X chromosomes must also contain the chromosome in question. For example, in Drosophila, as in many other insects, there are two X chromosomes in the cells of the female and one X chromosome in the cells of the male. There is in the male, in addition to the X, also a Y chromosome, which acts as its mate in synapsis and reduction. After reduction each egg carries an X chromosome. In the male there are two classes of sperm, one carrying the X chromosome and the other carrying the Y chromosome. Any egg fertilized by an X sperm produces a female; any egg fertilized by a Y sperm produces a male. The scheme of inheritance is as follows.

+------------------------------+ | | | Eggs X--X | | Sperm X--Y | +------------------------------+ | Daughter XX | | Son XY | | | +------------------------------+

The sons get their single X chromosome from their mother, and should therefore show any character whose gen is carried by such a chromosome. In sex-linked inheritance all sons show the characters of their mother. A male transmits his sex-linked character to his daughters, who show it if dominant and conceal it if recessive. But any daughter will transmit such a character, whether dominant or recessive, to half of her sons. The path of transmission of the gen is the same as the path followed by the X chromosome, received here {7} from the male. Many other combinations show the same relations. In the case of non-disjunction, to be given later, there is direct experimental evidence of such a nature that there can no longer be any doubt that the X chromosomes are the carriers of certain gens that we speak of as sex-linked. This term (sex-linked) is intended to mean that such characters are carried by the X chromosome. It has been objected that this use of the term implies a knowledge of a factor for sex in the X chromosome to which the other factors in that chromosome are linked; but in fact we have as much knowledge in regard to the occurrence of a sex factor or sex factors in the X chromosome as we have for other factors. It is true we do not know whether there is more than one sex-factor, because there is no crossing-over in the male (the heterozygous sex), and crossing-over in the female does not influence the distribution of sex, since like parts are simply interchanged. It follows from this that we are unable as yet to locate the sex factor or factors in the X chromosome. The fact that we can not detect crossing-over under this condition is not an argument against the occurrence of linkage. We are justified, therefore, in speaking of the factors carried by the X chromosome as sex-linked.

CROSSING-OVER.

When two or more sex-linked factors are present in a male they are always transmitted together to his daughters, as must necessarily be the case if they are carried by the unpaired X chromosome. If such a male carrying, let us say, two sex-linked factors, is mated to a wild female, his daughters will have one X chromosome containing the factors for both characters, derived from the father, and another X chromosome that contains the factors that are normal for these two factors (the normal allelomorphs). The sons of such a female will get one or the other of these two kinds of chromosomes, and should be expected to be like the one or the other grandparent. In fact, most of the sons are of these two kinds. But, in addition, there are sons that show one only of the two original mutant characters. Clearly an interchange has taken place between the two X chromosomes in the female in such a way that a piece of one chromosome has been exchanged for the homologous piece of the other. The same conclusion is reached if the cross is made in such a way that the same two sex-linked characters enter, but, one from the mother and the other from the father. The daughter gets one of her sex chromosomes from her mother and the other from her father. She should produce, then, two kinds of sons, one like her mother and one like her father. In fact, the majority of her sons are of these two kinds, but, in addition, there are two other kinds of sons, one kind showing both mutant characters, the other kind showing normal characters. Here again the results must be due to interchange between the two X's in the hybrid female. The number of {8} the sons due to exchange in the two foregoing crosses is always the same, although they are of contrary classes. Clearly, then, the interchange takes place irrespective of the way in which the factors enter the cross. We call those classes that arise through interchange between the chromosomes "cross-over classes" or merely "cross-overs." The phenomenon of holding together we speak of as linkage.

By taking a number of factors into consideration at the same time it has been shown that crossing-over involves large pieces of the chromosomes. The X chromosomes undergo crossing-over in about 60 per cent of the cases, and the crossing-over may occur at any point along the chromosome. When it occurs once, whole ends (or halves even) go over together and the exchange is always equivalent. If crossing-over occurs twice at the same time a middle piece of one chromosome is intercalated between the ends of the other chromosome. This process is called double crossing-over. It occurs not oftener than in about 10 per cent of cases for the total length of the X chromosome. Triple crossing-over in the X chromosome is extremely rare and has been observed only about a half dozen times.

While the genetic evidence forces one to accept crossing-over between the sex chromosomes in the female, that evidence gives no clue as to how such a process is brought about. There are, however, certain facts familiar to the cytologist that furnish a clue as to how such an interchange might take place. When the homologous chromosomes come together at synapsis it has been demonstrated, in some forms at least, that they twist about each other so that one chromosome comes to lie now on the one side now on the other of its partner. If at some points the chromosomes break and the pieces on the same side unite and pass to the same pole of the karyokinetic spindle, the necessary condition for crossing-over will have been fulfilled.

THE Y CHROMOSOME AND NON-DISJUNCTION.

Following Wilson's nomenclature, we speak of both X and Y as sex chromosomes. Both the cytological and the genetic evidence shows that when two X chromosomes are present a female is produced, when one, a male. This conclusion leaves the Y chromosome without any observed relation to sex-determination, despite the fact that the Y is normally present in every male and is confined to the male line. The question may be asked, and in fact has been asked, why may not the presence of the Y chromosome determine that a male develop and its absence that a female appear? The only answer that has yet been given, outside of the work on Drosophila, is that since in some insects there is no Y chromosome, there is no need to make such an assumption. But in Drosophila direct proof that Y has no such function is furnished by the evidence discovered by Bridges in the case of non-disjunction. (Bridges, 1913, 1914, 1916, and unpublished results.) {9}