In 1915, Calvin Bridges, one of the first Drosophila (fruitfly) workers to join Thomas Hunt Morgan in the fabled fly room, discovered bithorax1 , a mutation that transformed part of the haltere (organ that controls balance) into wing. This mutation was called “homoeotic”- William Bateson’s terminology (a Greek word) for the malformation that substituted the pattern of one region; not that there has been just a change but “something changes into the likeness of something else”. This thinking was mainly in the terms of reiterated elements, such as segments in arthropods, petals and sepals in a flower or teeth in a vertebrate. It is particularly encouraging that the homeotic mutations raised the clarifying prospect of a class of genes responsible for large chunks of body pattern. Little progress was made until Ed Lewis started his pioneer work on the locus in 1946, and later was awarded the noble prize for genetics of development (1995) after 50 years of his work. In an early piece of his research, it was determined by Dr. Lewis that an extra pair of wings seen in a natural mutation of Drosophila was due to a duplication of the entire body segment. Studies on a homeotic gene cluster, containing a minimum of eight genes; the Bithorax-Complex (BX-C), were summarized in this review (1978). It mainly describes the molecular locus of this complex cluster and its functional significance in being responsible for this phenomenon. A separate regulatory locus; the Polycomb , was described to play as a repressor of this HOM-complex.
Embryonic phenotypes of a range of mutations in the various regions of BX-C were illustrated in this review to show that the genes in this complex code for differential controlling levels of thoracic and abdominal development in the fly, right from early embryogenesis to adulthood. The flies carrying Ultrabithorax (Ubx) mutations as surviving adults show a classic "four-winged" phenotype implying a transformation of the third thoracic segment into second thoracic segment. The haltere, in these flies is transformed to a pair of wings and therefore the phenotype clearly represents a characteristic feature of four-winged ancient ancestor. The phenotype also presents a unique feature in the sense that in these individual animals, the genes suppressing the haltere development are active as an evolutionary step forward. Basically, in a fly, two groups of genes evolved; as leg-suppressing genes which helped elimination of legs from abdominal segments of millipede-like ancestors; followed by the haltere-promoting genes which suppressed the second pair of wings of four-winged ancestors. Remarkably, in a fly, both types of mutations are observed following the loss of both types of genes and the phenotypes, consequently resulting in more number of legs or extra pair of wings with the loss of these genes respectively. Thus, a varied number of genes diversified during evolution to finally give rise to this complex. It is a stepwise process by which the phenotypes are achieved, whereby various components of this complex are added.
Utilizing various deficiencies (representing loss-of-function), gain-of-function mutations and allelic combinations of the member genes lying in BX-C and those (like Polycomb; Pc ) lying in the vicinity on the same chromosome ( cis -condition), genetic interactions were monitored by Lewis to determine and deduce the BX-C gene action.
Some mutations suggested that the whole system of bithorax genes was integrated while others pointed to individual and separable elements of function. As the range of mutant phenotypes expanded, his models inevitably became more complex and trendy with time. He believed that thoracic and abdominal segments are basically defined by producing certain substances (gradients), which in turn, regulate a battery of other genes that govern the basic elements of body design,, i.e., the structure and function. Lewis put forward important formulations and theories with regard to the control of BX-C (for details, see the review). Whether acting in concert or sequentially or in hierarchical fashion, the final patterning of the fly is laid out by major members of selector gene complexes, such as, BX-C and fine tuned by directed “gradients” to establish the intricate pattern in the elegant fly.
Lewis, through his work, also realized that the wild type function of bithorax genes was in specifying developmental pathways i.e. the routes followed in building the characteristic pattern of the different parts of the body and that the genes worked locally to regulate this. This was again a crucial step forward in his understanding of the function of homeotic genes. Further studies by Lewis on mosaic analysis in the fly, and studies by other workers like Gines Morata and Antonio Garcia-Bellido, who utilized better marker systems later, proved that bithorax- complex genes indeed work in specific groups of cells and the differentiation of each cell depends on the gene/s expressed in them. In other words, the requirement of genes is cell autonomous. The corresponding order of genes and parts of the body has reached a mystical status in present times and the conservation of gene order has a functional significance. Indeed, Lewis believed that genes are subtly interdependent; and that the correspondence between the order of body parts and sites of mutations affecting them is no accident. His pioneering work on homeotic genes induced other scientists to examine families of analogous genes in higher organisms and earned him the noble prize in Medicine (Genetics and Development), which he shared with other two of the eminent Drosophila geneticists; Christiane Nuesslein-Volhard and Eric Weischaus.