The next major step in genetic research was accomplished by Thomas Hunt Morgan, who spent most of his career at Columbia University, New York City, USA (see Box 2.1).
In the early part of the twentieth century, Morgan began working with fruit flies, Drosophila melanogaster. This was an even better choice than Mendel’s peas because the flies breed very rapidly and could be raised in large numbers in very little space. This was important because Morgan was dependent, for much of his work, on the occurrence of rare, spontaneous mutations. These were the source of the changes in the genes that produced modified alleles and hence phenotypes. Thus the discovery, by Hermann Joseph Muller in Morgan’s lab, that mutations could be induced by X-rays or other damaging radiation was very helpful. Muller was awarded the 1946 Nobel Prize in Physiology or Medicine “for the discovery of the production of mutations by means of X-ray irradiation.”
Contrary to Mendel’s observations, Morgan found that a number of traits of the flies appeared to be genetically linked. The difference from Mendel’s conclusion may have lain in the fact that many of the pea traits studied by Mendel corresponded to genes on different chromosomes, which would be expected to segregate independently, whereas Morgan was initially concentrating on genes on the same chromosome, the X sex chromosome. In any event, Morgan observed linked transmission of a number of genes. He hypothesized that the lack of linkage in some cases must result from recombination of alleles (Figure 1). Furthermore, he noted that the probability of such recombination must increase with the distance between the two genes in the chromosome. Thus, the degree of linkage must measure gene separation. Then something wonderful happened. Alfred Sturtevant, a student working in Morgan’s laboratory, realized that this fact allowed mapping of genes on chromosomes. He skipped his assigned homework one night to produce the first genetic map. Soon this was extended to many Drosophila genes, and a new paradigm emerged: genes are arranged linearly on chromosomes. A sample genetic map is presented in Figure 2. In 1933, Morgan was awarded the Nobel Prize in Physiology or Medicine “for his discoveries concerning the role played by the chromosome in heredity.”
Fig1. Recombination between the two X chromosomes of the female Drosophila fly. Chromosome X1 carries two wild-type alleles: m+ codes for normal wings and w+ determines red eyes. Chromosome X2 carries two mutant alleles, m coding for miniature wings and w coding for white eyes. During egg formation, a crossing-over or recombination event occurs somewhere between these two genes on the two chromosomes, resulting in two recombinant chromosomes, each of which carries a mixture of the parental alleles. This process creates a new combination of alleles, hence the name “recombination.”
Fig2. Genetic and physical maps of S. cerevisiae chromosome III. The genetic map was constructed by determining the frequency of recombination in genetic crosses; the physical map was determined by DNA sequencing. Despite some discrepancies between the two maps, their overall similarity is impressive. Note that the order of the upper two markers or identifiable genes has been incorrectly assigned on the genetic map; the relative positions of some markers are also somewhat different on the two maps. [Adapted from Oliver SG, van der Aart QJM, Agostoni Carbone ML et al. (1992) Nature 357: 38–46. With permission from Macmillan Publishers, Ltd.]
