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Genetic Analysis of "Transvection" Effects Involving Contrabithorax

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Genetic Analysis of Proc. Nati. Acad. Sci. USA Vol. 85, pp. 1146-1150, February 1988 Genetics Genetic analysis of "transvection" effects involving Contrabithorax mutations in Drosophila melanogaster (transcription/cis control of gene expression/bithorax complex/somatic chromosome pairing) Jost L. MICOL AND ANTONIO GARCIA-BELLIDO Centro de Biologia Molecular, Consejo Superior de Investigaciones Cientfficas, Universidad Aut6noma de Madrid, 28049, Madrid, Spain Contributed by Antonio Garcia-Bellido, October 12, 1987 ABSTRACT Contrabithorax (Cbx) alleles are dominant 17, 18) as if transvection could only occur in the presence of mutations in the Ultrabithorax (Ubx) gene of Drosophia that an active zeste gene. Recently, it has been shown that the cause its ectopic expression in the mesothorax. We have zeste protein binds to a regulatory region of the gene white studied the role of the homologous chromosome in the meso- and to the 5' region of the Ubx transcription unit in the thoracic phenotype in several Cbx beterozygotes. None of the Ultrabithorax (Ubx) gene (19). Cbx alleles studied shows variations in phenotype with extra Genetic studies of the BX-C indicated that the Ubx gene is doses of the Ubx gene. Only Cbx9 and CbxIRM (a revertant of not normally expressed in the mesothorax of wild-type flies Cbx') show synapsis-dependent gene expression ("trans- but it is in flies carrying Contrabithorax (Cbx) alleles (20). vection"). The mesothoracic phenotypes of CbXlRM and Cbx2 This was confirmed by using antibodies against Ubx proteins heterozygotes are strongly modified when the homologous (Ubx-P) in the corresponding imaginal discs (21-23). Thus, chromosome carries breakpoints proximal to or at the Ubx in Cbx/+ heterozygotes the wild-type allele of Ubx is locus or nuli alleles of this gene. These lesions in the homolo- expected to be inactive in the mesothorax. However, Lewis gous chromosome enhance the Cbx9 mutant phenotype and (16) and the present results show that the mesothoracic reduce that of CbXJRM one. The genetic analysis of these phenotype of some Cbx alleles is affected by the genetic transvection effects suggests that the transcription of the nature of the homologous chromosome in heterozygotes. CbXIRM and Cbx2 alleles depends on RNAs of short radius of In this work we analyze the phenotypes of different Cbx action from the homologous Ubx gene. alleles in heterozygotes carrying chromosome breakpoints close to or at the Ubx locus, deficiencies, and point muta- tions to determine the nature of the putative elements The mutant phenotypes of certain heterozygotes are en- involved in synapsis-dependent expression of the Ubx gene. hanced by chromosomal rearrangements. This phenomenon, The phenotypes of some Cbx alleles when heterozygous called "transvection" by Lewis (1), is thought to be due to a suggest that they are affected by transvection and that this is perturbation of somatic pairing, presumably necessary for possibly mediated by Ubx RNAs of short radius of action. the normal expression of genes. Synapsis-dependent com- plementation was first found modifying the expression of MATERIALS AND METHODS some alleles of the bithorax complex (BX-C), but similar With the exception of CbXIRM, UbXMNI, and UbxMXJ7, all cases have also been observed for the phenotypes of muta- genetic variants and chromosomes used in this work have tions at other loci-e.g., white (2-6), decapentaplegic (7, 8), been described (ref. 24 and other references indicated in Sgs4 (9, 10), and cubitus interruptus (11) of Drosophila. text). CbXIRM (Contrabithorax 1 revertant of Madrid) arose These genetic inferences are supported by cytological obser- spontaneously in a y su-Cbx vf3sa/FM7a;Cbx'e/T(2;3)apxa vations in polytene chromosomes showing puffing depen- stock. UbxmXl7 is a weak, homozygous viable, Ubx allele dent on synapsis of homologues (9, 12) and by mitotic (A. Busturia, personal communication). UbxMN' is an ex- recombination data indicating tight pairing of homologous tremely weak Ubx allele, induced by ethylnitrosourea (J. sequences in interphase nuclei of somatic cells (13). Botas and J.L.M., unpublished). Both are cytologically To account for transvection effects, Ashburner (14) pro- normal. The Za alleles used were Za69-2 and Za69-3. posed that asynapsis would prevent the normal transfer of Variations in expressivity of the mesothoracic phenotype activator signals from an intact regulatory region of one of CbXIRM are defined in five phenotypic classes (see Fig. 2). chromosome to the structural one of its homologue. Three The Cbxi mesothoracic phenotype varies in expressivity and different hypotheses have since been advanced for the penetrance. Penetrance is measured as the percentage of nature of the elements involved in the synapsis-dependent wings showing any transformation to haltere. At least 50 interactions between homologues. (i) Jack and Judd (6, 15) individuals of each genotype were scored, except in some proposed that these interactions are mediated by diffusion of poorly viable genotypes, such as Cbx2/Ubx heterozygotes unstable RNAs produced at the interacting sites. Lewis (16) (minimum of 5). We have used the FP3.38 monoclonal invoked a cis-regulatory entity with a limited effective radius antibody to monitor the expression of Ubx-P in imaginal of action in the nucleus. (ii) Bingham and Zachar (3) sug- discs as described (21-23). gested that synapsed alleles are positioned at specific com- partments of the nucleus, whose local properties are respon- RESULTS sible for transvection effects. (iii) Zachar et al. (5) suggested The CbXlRM Mutation. Cbx)RM arose in a Cbx' chromo- that cis-acting DNA enhancer-like sequences may also trans- some. Cbx' is an x-ray-induced mutation in the Ubx gene activate transcription in synapsed chromosomes. associated with the transposition of a 17-kilobase (kb) frag- Several authors have reported that loci exhibiting trans- ment from the bxd unit of transcription to the 5' region of the vection effects also interact with certain zeste alleles (5, 8, Ubx unit (Fig. 1) (20, 25). Cbx' causes a dominant partial transformation of wing tissue into haltere in the mesothorax. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" Abbreviations: BX-C, bithorax complex; Ubx-P, Ultrabithorax pro- in accordance with 18 U.S.C. §1734 solely to indicate this fact. teins. 1146 Downloaded by guest on September 26, 2021 Genetics: Micol and Garcfa-Bellido Proc. Natl. Acad. Sci. USA 85 (1988) 1147 -100 -80 -60 -40 -20 0 20 Kb W- tk.- ...-- r: D Hm bxdlOO bxdl A 3' Ubx unit 5' 3 bxd unit 5' .... Er- Ubx922 Ubx195 Ubxl FIG. 1. Molecular map of the Ubx domain of the BX-C showing B mutations used in this study. Deletions appear as rectangles and insertions appear as triangles. Primary transcripts and exons are represented by heavy lines. Arrows indicate breakpoints. Horizon- tal bars indicate extents of uncertainty in map positions. Ubx'95 is --.S.... I. associated with a single nucleotide substitution (from data in refs. 25-28). .. vs ( :s~.~ This phenotype is correlated with the ectopic presence of Ubx-P in the corresponding territories of the wing imaginal FIG. 2. Wing phenotypes for genotypes representative of phe- disc (22, 23). Cbx' is homozygous viable and viable in notypic classes of Cbx'RM and Cbx. (A) Class A; Dp(3;J)P15; heterozygotes with Ubx recessive lethal alleles. It has, in CbxIRM/Df(3R)P9; wild-type wing. (B) Class B; CbxIRM/TM1; very weak Cbx transformation, with reduced alula and wing surface, and addition, weak recessive metathoracic and first abdominal spread wings. (C) Class C; CbxIRM/TM6B; weak Cbx transforma- transformation phenotypes, which are detected when it is tion, with alula absent, wing surface moderately reduced, and heterozygous with some lack of function mutations in the spread wings. (D) Class D; Cbx'RM/Dp(3R)P5; moderate Cbx Ubx gene (29, 30). For Cbx' there is only a weak transvec- transformation, slightly weaker than that of class E. (E) Class E; tion effect reported: Cbx'Ubx'/+ + individuals have a very CbxJRM/+; strong Cbx transformation, with posterior compartment slight Cbx transformation, whereas Cbx'Ubx'/R(+ +) flies of wing almost completely transformed into haltere. This latter have wild-type wings (16, 29). The mesothoracic transfor- phenotype is slightly weaker than that observed in Cbx'/+ flies. (F) Example of Cbx2/Jn(3R)Ubx'30 wing-to-haltere transformation mations of Cbx' and Cbx'Ubx' remain unaffected by the (x20). presence of extra doses of the Ubx gene, suggesting that only paired homologues affect the Cbx' expression. breakpoints in the homologue and the degree of CbxJRM Analysis of the CbXIRM mutation shows it to differ from transformation was observed. Interestingly, CbxJRM/Dp- the Cbx' mutation. Like Cbx', the CbXIRM chromosome (3;3)P5 individuals [Dp(3;3)P5 is a small tandem duplication does not show cytologically visible aberrations. It is lethal of the BX-C] show a mesothoracic transformation (class D when or when reces- homozygous heterozygous with Ubx phenotype; see Fig. 2D) weaker than CbXlRM/+, consistent sive lethal alleles. This lethality is due to Ubx insufficiency [it can be rescued with an extra dose of BX-C; Dp(3;1)P115]. Table 1. Variations of the mesothoracic phenotypes of CbXIRM It may result from a second-site Ubx mutation, judging from and Cbx2 depending on the presence of breakpoints in the the metathoracic phenotypes of heterozygotes over reces- homologous chromosome sive mutations of the Ubx gene (see below). This second Mesothoracic mutation may be the cause of the reversion of the Cbx' Cytological positions phenotype. Unlike Cbx', the Cbx phenotypes of CbXJRM Homologous phenotype of breakpoints in the heterozygotes largely depend on the nature of the homolo- chromosome CbXIRM* Cbx2t homologous chromosome: gous chromosome (Fig. 2; see Tables 1 and 2). CbXJRM/+ +§ E 2-11 individuals have a mesothoracic phenotype (Fig.
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