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Perspectives Copyright 0 1994 by the Genetics Society of America Perspectives Anecdotal, Historical and Critical Commentaries on Genetics Edited by James F. Crow and William F. Dove Discovery and Genetic Definitionof the Drosophila Antennapedia Complex Rob Denell Division of Biology, Kansas State University, Manhattan, Kansas 66506-4901 NE day in 1976 THOMKAUFMAN called me in great gued fordecades that they must play key regulatory roles 0 excitement. KAUFMANand I shared an interest in in assigning developmental commitments realized Drosophila homeotic genes located near the third chre through theaction of downstream genes. Moreover, the mosome centromere. He hadrecently arrivedat Indiana apparent clustering of genes of similar function in a University, and the resultsof his first set of crosses higher eukaryote was potentially very interesting. convinced him that these genes were part of a complex However, uncertainties as to allelic relationships and important to anterior developmental commitments (KAuF- mapping difficulties due to centromeric inhibition of MAN et aL 1980),just as ED LEWIS’S bithorax complex con- recombination in this region (HANNAH-ALAVA 1969) left trolled fate in more posterior regions. He invited me to thenumber of homeoticgenes and their spatial Bloomington the next summer to join him in a genetic relationships in considerable doubt. study of this Antennapedia complex (ANTC). All known homeotic loci in that region had been rec- In the late 196Os, KAUFMANand I had been graduate ognized by adult transformations, and included Extra students together in BURKEJUDD’S lab at the University of sex combs ( SCX), proboscipedia ( pb),Antennapedia Texas. Althoughmy interest in segregation distortion was (Antp),Polycomb (PC), Multiplesex combs (Msc),and Ear from the focus of the lab, KAUFMANworked at its very Nasobemia (Ns)(Figure 1A). [ThatDeformed (Dfd)and center: a mutational analysis of the restewhi& region. JUDD Humeral (Hu)were homeotic mutations was not then was and remains interested in genome organization, and recognized.] Many Antennapedia mutant alleles shared in this pre-molecularera he wished to ascertain allzygoti- a common dominant antenna +. leg transformation cally active functions in this Xchromosome interval nec- phenotype, rearrangement breakpoint, andrecessive le- essary for normal morphology and/or viability and to ex- thality. WALTERGEHRING (1966) had discovered a muta- amine the distribution of these loci along the polytene tion associated with a similar (albeit more extreme) chromosome map (JUDD et al. 1972). In addition to the transformation that was free of recessive lethality and genetic aspects of this “saturation mutagenesis” effort, gross chromosomal rearrangement. He believed this KAUFMANjoined MARY SHANNONin a study of the develop variant to identify a locus separate from Antennapedia mental consequences of the recessive-lethal variants iso- and named it Nasobemia after MORGENSTERN’Smytho- lated (SHANNONet al. 1972). logical creature that walked on its nose. ELIEZERLIF- I left Austin in 1970 for postdoctoral studies with DAN SCHYTZ, then also in LINDSLEY‘Slab, had recently shown LINDSLEYat UCSD and arrived there ata particularly ex- that the dominant phenotype of a gain-of-function al- citing time. LINDSLEYand long-time collaborator LARRY lele could be “reverted” by loss-of-function mutations SANDERwere also interested in functional aspects of isolated at rates characteristic of forward mutation genetic organization, and I joined their massive effort (LIFSCHWZand FALK1969). LINDSLEYsuggested that I use to systematically generate and study small deficiencies LIFSCHYTZ’Sapproach for the sex-transforming mutation and duplications distributed throughout the genome then known as transformer-dominant (which proved to (LINDSLEYet a,!. 1972).LINDSLEY has served as a repository be doublesex-dominant instead), andI also applied itto and chronicler of Drosophila genetic knowledge and Nasobemia. Most revertants were associated with reces- takes seriously his responsibility to impartthis lore tohis sive lethality that failed to complement the lethality of students. He pointedout to me an apparent enrichment Antennapedia mutations, showing that Nasobemia was of homeotic and sex-transforming genes near the third an Antennapedia allele and that thephenotype that was chromosome centromere. These geneswere fascinating its namesake was neomorphic (DENELL 1973).Extra sex from a developmental standpoint, and it had been ar- combs appeared to be anAntennapedia allele as well. A Genetics 138: 549-552 (November, 1994) 550 R. Denell very similar reversion analysis was done independently BXC. He envisaged the middle thoracic segment as a by KAUFMAN and IAN DUNCAN, then an undergraduateat ground state, such that the loss-of-function phenotype of the University of British Columbia (DUNCANand KAuF- Sex combs reduced caused posteriorlydirected changes ofthe MAN 1975). [In this issue, TALBERTand GARBER(1994) first thoracic leg, and dominant gain-of-function variants discuss the molecular nature of Nasobemia revertants.] Multiple sex mbs and Extra sexcombs caused opposing These results clarified the picture a little, but the ques- changes (KAUFMAN et al. 1980). tion of relationships in the genome and their potential How could the structure and function of this complex significance remained unsolved. be elucidated? KAUFMAN recognized that the available col- At this time ED LEWISwas performing his well known lection of variants, isolatedon the basis of adult homeotic and elegant work at Caltech on other homeotic muta- phenotypes, probablyhad been strongly influenced by as- tions. In this case, alarge number of recessiveand domi- certainment bias. Except for some poboscipedia alleles, all nant variants causing homeotic transformations of the available visible mutations were neomorphs, and null al- adult thorax and abdomen were unambiguously very leles were needed to assess their normal developmental tightly clustered within the bithorax complex (BX-C), significance.Moreover, he anticipated that additional which mapped more distally on the right arm of chro- functionally related genes existed withinthe complex that mosome 3. LEWIS(1978) argued that loss-of-function could be recognized by the embryonic or larval phencl variants caused anteriorly directed transformations, types of recessive lethal alleles. Thus, he proposed that we whereas those associated with gain-of-function variants applyJuDD’s concept of saturation mutagenesis to identify were posteriorly directed. Moreover, themutations and characterize all loci in this regionthat mutate to yield mapped along the chromosome in an order colinear recessive lethal or visible adult phenotypes. WhenI arrived with their mutant effects along the anterior-posterior in Bloomington in the summer of 1976, KAUFMANand body axis. This distribution led Lewis to the hypothesis graduate student RICKILEWIS had set up an experiment to that the numberof genes corresponded to the number isolate X-ray- and EMSinduced mutations that failed of thoracic and abdominal segments. He suggested a to complement Df!3R)Ns’””. Later, graduate student model inwhich the middle thoracic segment was a BARBMWAKIMOTO screened for additionalmutations “ground state”characteristic of no BX-C activity in the using Df(3R)Sm Both sets of variants were subjected to context of an otherwise normal genotype, and the ex- complementation and recombinational analysis, and the pression of a progressively greater number ofBX-C map shownin Figure 1Bwas generated (LEWIS et aZ., genes definedsuccessively more posterior segments. He 1980a,b).As predicted, point mutations associated with a interpreted gain-of-function mutations as being due to dominant adult T1 + T2 transformation were isolated the expression of a gene in an inappropriate domain. at the Sex combs reduced locus. The results also suggested For me at least, this idea provided one satisfymg expla- that the EbRll complementation group included the nation for thedifficult question of howneomorphic mu- Deformed mutation, and preliminary observations showed tations could acquire “a new function” (MULLER1932). that the lethal syndromes associated with the EbRll and Noting that Japanese geneticists studying the silk moth Ep36 complementation groups included larval head equivalent of the BX-C had placed emphasis on larval abnormalities. mutant phenotypes (TAZIMA1964), LEWISalso stressed The description of complementation groups with arbi- theimportance of examining the terminal lethal trary names generated little widespread excitement. The syndromes of genotypes dying at preadult stages. real payoff began when WAKIMOTOand KAUFMAN(1981) KAUFMAN’S first crossesat Indiana used a small deficiency and WAKIMOTOet al. (1984) described the phenotypes of isolated as a revertant of Nasobemia (Df{3R)Ns+R17),and lethal larvae and adult clones homozygous for recessive an overlapping deletion isolated at the University of British lethal alleles (seeUUFMAN etal. 1990). KAUFMAN (1978) had Columbia by DON SINCWR calledDf(3R)Sm The latter was earlier made the unexpected observation that proboscipedia associated with areduction in the size of the sex combsof function is dispensable for normal embryonic develop the male prolegshared by Multiple sex combs, and KAUFMAN ment, so it was satisfying that the null phenotypes of An- postulated that deletion of a hapleiinsufficient Sex combs tennapedia and Sex mbsreduced were associated withlarval reduced gene caused a partial transformationof first to
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