Genetic Mapping

The several scientists who rediscovered Gregor Mendel's experiments on plant hybridization around 1900 believed that he had established the independence of the various traits of plants. “[The] behavior of any two of the differentiating marks in hybrid combination is independent of the other distinguishing marks of the two strains of the plant.” Breeding experiments on other organisms than those Mendel studied soon showed, however, that not all pairs of distinguishing characters segregated completely independently of other pairs. In some cases combinations represented in the first hybrid generation remained together in subsequent generations; in other cases they did not always stay together, but did so more frequently than would occur by chance. Moreover, when Walter Stanborough Sutton and Theodor Boveri independently drew attention to the parallelism in the behavior of chromosomes observed in cell division and the Mendelian factors in breeding experiments, each noticed that there were far fewer chromosomes to assort independently than factors assumed to segregate independently.

In 1911 Thomas Hunt Morgan, who had recently organized a small group of students at Columbia University to conduct genetic experiments on the fruit fly Drosophila, suggested that these discrepancies could be reconciled if the Mendelian factors lined up along the chromosomes. Drawing on a hypothesis proposed two years earlier by F. A. Janssens, that homologous chromosomes twist around each other during the reduction divisions of meiosis and may thus exchange material, Morgan proposed that the different degrees of “coupling” observed between the factors could be explained by their relative separations on the same chromosome.Morgan showed that two factors known to be on the same Drosophila chromosome could be recombined by crossing flies containing one or the other of each of the character pairs.

In a conversation with Morgan late in 1911, one of his young assistants, Alfred Henry Sturtevant, realized that the proportion of “cross-overs” between any two factors could serve as an index of the distance between them. Working through the night, Sturtevant calculated the proportions of cross-overs between six sex-linked factors previously identified in the laboratory and showed that they could be represented on a linear diagram. For three factors relatively close together, the proportion of cross-overs between the outer two equaled the sum of the proportions between each of these and the intermediate factor. For greater distances, the proportion of cross-overs for the more distant two fell under the sum. Sturtevant explained the shortfall as a consequence of “double cross-overs” in which the middle factor was exchanged, but the outer two remained on the same chromosome.

During the next two years Morgan, Sturtevant, and Calvin Blackman Bridges produced similar linear diagrams of the factors on two more of the four Drosophila chromosomes, and another member of the “fly-room” group, Hermann Joseph Muller, did the fourth. Morgan and Sturtevant believed that the linear character of these diagrams indicated that the Mendelian factors are physically located along the chromosomes, although they stressed that the linear “linkage” distances might not be proportional to their physical spacing. The more theoretically oriented Muller set out to provide stronger demonstrations. In 1916 he showed that the total linkage distances of each of the four groups in Drosophila that segregated independently from the other groups were proportional to the lengths of the four chromosomes. In an elaborate set of experiments for which he constructed a Drosophila strain in which the female contained twenty-two different recessive mutations located on two different chromosomes, he determined that all factors on either side of the cross-over segregated together, as would be expected if they constituted segments of the chromosomes exchanged intact. By then the Morgan group was confident of their interpretation of the factors as a “series of beads” of which “whole sections will come to lie, now on one side, now on the other side, in the double chromosome.” When the chromosomes separate, the series may break apart “between the beads at the crossing point.” Although not all geneticists accepted this conception at first, it soon prevailed.

In The Mechanism of Mendelian Heredity (1915) Morgan, Sturtevant, Muller, and Bridges presented the first comprehensive summary of “classical genetics.” They placed the linear diagrams or maps showing the spatial locations of the factors of all four of the linkage groups of Drosophila side-by-side as a frontispiece to the book. The renaming of what Sturtevant in his original paper had merely called a “diagram” as a “chromosome map” has had long-lasting consequences for the language of genetics. Calling linear representations of the cross-over frequencies of Mendelian factors “maps” not only shaped the relationship perceived between the linkage diagram and the physical chromosome by analogy to the relation of an ordinary map with a portion of the surface of the earth. Although both the methods of mapping and the conception of the factors mapped (soon renamed “genes”) have changed substantially since the early days of classical genetics, the phrase “genetic mapping” has remained firmly in place.