Homeotic Genes Determine Segment Identity

Bithorax mutant

Bithorax mutant

There are 11 homeotic genes that determine the identities of different body segments along the A/P axis and 2 additional related genes that provide the same type of positional information in the head. The groundbreaking analysis of a homeotic mutant called Bithorax by Ed Lewis provided the first example of a gene functioning to define a specific region of an organism. In recognition of this discovery, he was awarded the 1996 Nobel Prize for medicine, along with Wieschaus and Nusslein-Volhard. In Bithorax mutants, the third thoracic segment (T3) is transformed into the second thoracic segment (T2), which normally makes wings (Fig. 3.3H). Such mutants have four wings instead of two, since the two adjacent T2-like segments in these flies both make wings. Because primitive insects such as dragonflies have four wings, it is thought that an important function of the fruit fly Bithorax gene is to suppress the activity of genes required for wing formation in the second thoracic segment. Another homeotic gene, called Antennapedia, is expressed and functions in the second thoracic segment (T2), which has wings and legs. Mutants deficient for Antennapedia function lack wings due to the transformation of the T2 segment into the non-wing-bearing T1 segment (Fig. 3.3I). It is important that expression of homeotic genes is confined to the segments in which they normally function. For example, mutants in which the Antennapedia gene is inappropriately expressed in head segments have their antennae transformed into legs (legs are appendages produced in thoracic segments where the Antennapedia gene normally is active).

In 1933, the primary founder of the field of fly genetics, Thomas Hunt Morgan, received the Nobel Prize in Medicine "for his discoveries concerning the role played by the chromosome in heredity." Morgan was unable to attend the Nobel ceremony in Stockholm, Sweden. In his place, F. Henschen from the Royal Caroline Institute wrote an eloquent presentation speech in which he said of Morgan's work, "Who could dream some ten years ago that science would be able to J fc ' i . V penetrate the problems of heredity in that way, and find the mechanism that lies behind the crossing results of ^^^ plants and animals; that it would be possible to localize ^^^^^^^^^^^ in these chromosomes, which are so small that they Edward B. Lewis (1918- ) must be measured by the millesimal millimetre, hun dreds of hereditary factors, which we must imagine as corresponding to infinitesimal corpuscular elements (e.g., genes). And this localization Morgan had found in a statistic way! A German scientist has appropriately compared this to the astronomical calculation of celestial bodies still unseen but later on found by the tubeā€”but he adds: Morgan's predictions exceed this by far, because they mean something principally new, something that has not been observed before." These same words of praise could be equally well applied to the scientific grandson of Morgan, Ed Lewis, for his brilliant analysis of homeotic mutants and his remarkable prediction that homeotic genes would be members of a gene family that arose through a series of gene-duplication events during the course of evolution.

Ed Lewis was born in Wilkes-Barre, Pennsylvania. He graduated from the University of Minnesota with a B.A. in biostatistics and entered graduate school at Caltech in 1939 just as World War II broke out. He quickly made important genetic observations known as the cistrans effect, which he wrote up for his Ph.D. thesis in 1942, just in time to enlist in the armed forces. Following the war, Lewis accepted a position at Caltech as an instructor. He then went to Cambridge University as a Rockefeller Foundation Fellow for a year and returned to Caltech as a faculty member, where he has remained ever since.

As a graduate student with one of the founding pioneers of fly genetics, Allan H. Sturtevant, Lewis had complete freedom to explore a novel genetic phenomenon in fruit flies called the cis-trans effect. Lewis's primary observation was that two mutations, a and b, had no effect when combined onto a single chromosome (i.e., mutations carried in the form a b/++ resulted in normal flies), but caused very severe defects when the mutations were present on opposite chromosomes (i.e., the mutations were carried in the form a+/+ b). From today's vantage point, the most likely explanation for this unusual genetic phenomenon is that the a and b mutations disrupted the same gene, but in different positions (see Chapter 2). Although very difficult, it was possible for Lewis to put these two distinct mutations together so that the same gene was simultaneously disrupted in two different places. Animals carrying this doubly disrupted gene and one good copy of the gene on the other chromosome (i.e., a b/+ individuals) were normal, as is typical for a mutant carrier (see Chapter 3), whereas flies having one of the mutations (a) on one chromosome and the second mutation (b) on the other chromosome had no good copies of the gene and therefore exhibited mutant defects. Lewis remembers this discovery as the most exciting in his career: "It required looking at tens of thousands of flies to get a and b on the same chromosome and predicting that it would be different from a +/+ b, and ran contrary to all genetic theory at the time."

In describing his most famous work analyzing homeotic genes, Lewis recalls, "I was testing the idea that new genes arise by tandem duplication of a gene followed by one of the duplicates diverging to carry out a new BUT RELATED function. And that ultimately is what the HOX complex turns out to be, but it took molecular genetics to establish that they must have come from a common ancestor by repeated tandem duplication." We now know, in addition, based on the subsequent molecular analyses of these genes (see bioboxes on McGinnis, Levine, and Scott), that this duplication of homeotic genes occurred before the split of vertebrate and invertebrate lineages and thus that segment identities are defined by the same fundamental mechanisms in all segmented animals.

Lewis isolated and studied many mutations in the Bithorax gene and closely related homeotic genes. He, much like a contemporary Charles Darwin, devoted incredible undis-tracted focus to his work over many years before publishing in 1978 (at the age of 60!) his most important paper where he put forth his ideas on how different homeotic genes acted in a spatially restricted fashion (e.g., only in particular segments) to define segment identity. Because Lewis has not strayed from his singular passion to understand the function of homeotic genes, it is not surprising that he sees focus as a key ingredient to his scientific success in commenting "INTENSE depth of focus is the only way in my opinion, but one can then turn to other problems and use that approach." Regarding the general elements for discovery he continues that what is most important is "having a testable hypothesis even if wrong; usually persistence is required; usually it has to be the right time, and one has to be in the right place where there is an atmosphere or freedom to pursue new ideas and methods. Of course, sometimes it is simply serendipity, but that obviously is not what a scientist should count on."

Ed Lewis is still performing experiments at Caltech. In addition to receiving the 1995 Nobel Prize in medicine for his pioneering work on homeotic genes, Lewis has won many other awards and distinctions, including the National Medal of Science (USA, 1990) and the Albert Lasker Basic Medical Research Award (1991).

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