E. B. Lewis

The Abdominal Region of the Bithorax Complex

The homeotic mutations in the right half of the bithorax complex of Drosophila cause segmental transformations in the second through the eighth segments of the fly. A chromosomal walk in the bithorax complex has now been extended 215 kb through the right half of the complex, and lesions for over 40 mutations have been located on the DNA map. The mutations can be grouped in a series of phenotypic classes, one for each abdominal segment, although each mutation typically affects more than one segment. The mutant lesions of each class are clustered, and they are aligned on the chromosome in the order of the body segments that they affect. Complementation tests suggest interactions between widely spaced DNA regions; indeed, the right half cannot be split anywhere without some loss of function.

Pseudoallelism and Gene Evolution

It is the purpose of this paper to consider some of the ways in which “pseudoalleles” (McClintock, 1944), or closely linked genes having similar effects, may provide clues to the mode of origin of new kinds of genes.Our underlying thesis will be that in those instances of pseudoallelism in which there is evidence for close functional similarity among the component genes we may come close to seeing the direct results of a process which produces new genes.

Characterization of the intergenic RNA profile at abdominal-A and Abdominal-B in the Drosophila bithorax complex

The correct spatial expression of two Drosophila bithorax complex (BX-C) genes, abdominal-A (abdA) and Abdominal-B (AbdB), is dependent on the 100-kb intergenic infraabdominal (iab) region. The iab region is known to contain a number of different domains (iab2 through iab8) that harbor cis-regulatory elements responsible for directing expression of abdA and AbdB in the second through eighth abdominal segments. Here, we use in situ hybridization to perform high-resolution mapping of the transcriptional activity in the iab control regions. We show that transcription of the control regions themselves is abundant and precedes activation of the abdA and AbdB genes. As with the homeotic genes of the BX-C, the transcription patterns of the RNAs from the iab control regions demonstrate colinearity with the sequence of the iab regions along the chromosome and the domains in the embryo under the control of the specific iab regions. These observations suggest that the intergenic RNAs may play a role in initiating cis regulation at the BX-C early in development.

LEUKEMIA, MULTIPLE MYELOMA, AND APLASTIC ANEMIA IN AMERICAN RADIOLOGISTS.

A survey of 425 death certificates of radiologists dying between the ages of 35 and 74 during the years 1948 to 1961 reveals a statistically highly significant excess of deaths from leukemia, multiple myeloma, and aplastic anemia. That this excess is due to radiation exposure (or to some factor acting in a similar manner), rather than to an artifact of diagnosis is suggested by the absence of deaths ascribed to chronic lymphatic leukemia.

Transcription defines the embryonic domains of cis-regulatory activity at the Drosophila bithorax complex

The extensive infraabdominal (iab) region contains a number of cis-regulatory elements, including enhancers, silencers, and insulators responsible for directing the developmental expression of the abdominal-A and Abdominal-B homeotic genes at the Drosophila bithorax complex. It is unclear how these regulatory elements are primed for activity early in embryogenesis, but the 100-kb intergenic region is subject to a complex transcriptional program. Here, we use molecular and genetic methods to examine the functional activity of the RNAs produced from this region and their role in cis regulation. We show that a subset of these transcripts demonstrates a distinct pattern of cellular localization. Furthermore, the transcripts from each iab region are discrete and the transcripts do not spread across the insulator elements that delineate the iab regions. In embryos carrying a Mcp deletion, the intergenic transcription pattern is disrupted in the iab4 region and the fourth abdominal segment is transformed into the fifth. We propose that intergenic transcription is required early in embryogenesis to initiate the activation of the Drosophila bithorax complex and define the domains of activity for the iab cis-regulatory elements. We also discuss a possible mechanism by which this may occur.

The Relation of Repeats to Position Effect in Drosophila Melanogaster

In Drosophila melanogaster it has been established that the action of at least some genes is affected by their position in the chromosomes. Critical evidence for this phenomenon of position effect has been given by Sturtevant (1925), Dubinin and Sidorow (1935), and Panshin (1935). Position effects have been detected only in cases in which the relative position of a gene with respect to its neighbors has been altered by a chromosomal rearrangement. It is conceivable that the effective position of a gene may also be changed as a result of a substitution in an adjacent gene of one allele by another. Such a possibility was put to experimental test by Sturtevant (1928) for the dominant mutants, Delta (Dl) and Hairless (H), three units apart in the third chromosome; however, no difference could be demonstrated between Dl H/++ and Dl+/+H.

Genetic Control of Body Segment Differentiation in Drosophila

Drosophila, like many other higher organisms, begins development as a tandem array of more or less identical body segments. During later development, these gradually diverge in morphology until the extensive differentiation of body segments seen in the adult is achieved. The genetic control of this divergence is, by now, moderately well understood. The differentiation of the third thoracic and of all abdominal segments appears to be under the control of a cluster of genes known as the bithorax complex (BX-C) [Lewis, 1978]. As reviewed below, the genes of this complex appear to be differentially regulated along the body axis so that each body segment is characterized by a unique subset of active BX-C genes. The activities of these genes are thought to directly determine segmental identity. Recently, it has been proposed that more anteriorly located segments, including those in the head as well as the first and second thoracic segments, are under the control of another gene cluster that has been named the Antennapedia complex (ANT-C) by Kaufman et al [1980]. These authors suggest that the ANT-C genes may function in a manner analogous to that of the BX-C genes.

Some Aspects of Position Pseudoallelism

Contrasting interpretations of position pseudoallelism are discussed, and the types of position effect which characterize this phenomenon are illustrated, with special reference to the case of the bithorax series of five pseudoallelic loci in Drosophila melanogaster. Most of the results in this latter case can be simply interpreted on the basis of a chain of gene-controlled reactions in which each intermediate substance is postulated to act in a dual capacity: as substrate for the succeeding reaction and as a determiner of a specific physiological process. The model also gives a consistent picture of the way in which different levels of developmental determination may be controlled by the different genes of the series.

The Bithorax Complex: The First Fifty Years

Genetics is a discipline that has successfully used abstractions to attack many of the most important problems of biology, including the study of evolution and how animals and plants develop. The power of genetics to benefit mankind was first recognized by the award of the Nobel Prize in physiology or medicine in 1933 to T. H. Morgan. In the 23 years that had intervened between the time Morgan introduced Drosophila as a new organism for the study of genetics and the award of the Prize, he and his students, especially, A. H. Sturtevant, C. B. Bridges and H. J. Muller, had vastly extended the laws of Mendel as the result of a host of discoveries, to mention only a few: that the genes (Mendel’s factors) are arranged in a linear order and can be placed on genetic maps, that they mutate in forward and reverse directions, that they can exist in many forms, or alleles, and that their functioning can depend upon their position. Purely on the basis of breeding experiments, these early workers were able to deduce the existence of inversions and duplications, for example, before it became possible to demonstrate them cytologically. The list of their achievements is a long one and one that has been put into historical perspective by Sturtevant in A History of Genetics (1).

REGULATION OF THE GENES OF THE BITHORAX COMPLEX IN DROSOPHILA

The BX-C is a set of master control genes that trans-regulate other genes and thereby control much of the segmentation pattern of the fly. The BX-C genes are themselves regulated in cis and trans. Three rules governing cis-regulation of BX-C are applicable over a region extending from Ubx to at least iab-7, a distance of nearly 300 kb on the DNA map: The colinearity (COL) rule: genes are colinear with respect to map location and order of expression along the body axis, the only exception thus far being pbx+; the cis-inactivation (CIN) rule: a mutant lesion in one gene tends to cis-inactivate the wild-type gene(s) immediately distally; and the cis-overexpression (COE) rule: certain mutant lesions in a given gene cause the next most proximal gene to overexpress one segment more anterior to the one in which the latter gene normally expresses. A model is proposed that attempts to account for these rules by invoking a special cis-regulatory entity (E) that diffuses more efficiently along the chromosome than between chromosomes.