Autosomal Dosage Compensation in Drosophila Melanogaster Strains Trisomic for the Left Arm of Chromosome 2 (Enzyme Levels/Gene Modulation/Regulatory Loci) ROBERT H

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Autosomal Dosage Compensation in Drosophila Melanogaster Strains Trisomic for the Left Arm of Chromosome 2 (Enzyme Levels/Gene Modulation/Regulatory Loci) ROBERT H Proc. Natd Acad. Sci. USA Vol. 79, pp. 1200-1204, February 1982 Genetics Autosomal dosage compensation in Drosophila melanogaster strains trisomic for the left arm of chromosome 2 (enzyme levels/gene modulation/regulatory loci) ROBERT H. DEVLIN, DAVID G. HOLM, AND THOMAS A. GIIGLIATTI Department of Zoology, University of British Columbia, Vancouver, British Columbia, Canada V6T 1W5 Communicated by M. M. Green, September 30, 1981 ABSTRACT Drosophila melanogaster individuals trisomic for tural genes are located on the left arm of chromosome 2, have an entire chromosome arm can survive to late' stages of pupal de- been measured in trisomies and in normal diploids. Addition- velopment. We have examined the levels of five enzymes whose ally, we have examined the activity oftwo enzymes whose struc- structural genes are located on the left arm ofchromosome 2 both tural genes are located elsewhere in the genome and, therefore, in trisomy 2L and in diploid strains. In trisomies, three distally remain diploid in all strains used. The result of these prelimi- mappingloci showedcompensated levels ofexpression close to that nary studies affords evidence for a form of autosomal dosage observed in the diploid strains. Analysis ofelectrophoretic variants compensation in Drosophila nelanogaster. of a compensated locus revealed that all three alleles are active in trisomies. Thai-two proximally located loci displayed dose-de- pendent levels of expression. Therefore, at the level of theindi- MATERIALS AND METHODS vidual gene, autosomal compensation appears to bean all-or-nene phenomenon. Furthermore, the compensatory response may be Genetic Strains and Procedures. The following strains of regionally distributed along the chromosome arm. The presence D. melanogaster were used: (i) Oregon R, (ii) C(2L)SHJ +; of both autosomal and sex-linked dosage compensation prompts F(2R)bw/F(2R)bw, (iii) C(2L)VHlit;F(2R)bw/F(2R)bw, (iv) us to speculate that these phenomenon are similar homeostatic C(2L)VD4aiGpdhB Bi/In(2L)Cy,al Cy GpdhA;F(2R)bw/ mechanisms that modulate gene expression both in euploid and F(2R)bw, (v) C(2L)P,b;C(2R)SK1A cn bw, (vi) al GpdhB Bi L/ aneuploid genomes. In(2L+2R)Cy,al Cy GpdhA, (vii) Df(2L)GdhA/In(2LR)SM1,Cy It, (viii) GpdhB0-l-4/In(2LR)SM1 ,Cy it, (ix) b AdhN2 osp pr cn, From individual to individual within a species, the chromosome (x) GpdhA, (xi) GpdhB, (xii) Gpdhc, and (xiii) several strains with complement is remarkably similar with the striking exception translocations between the Y and 2L chromosomes (3), which of the sex chromosomes. In many species, females have twice are listed in Table 2. Characteristics ofthe various mutant alleles as many X chromosomes as males. This imbalance in gene con- and chromosomes have been described previously (2, 5, 6). tent is rectified by dosage compensation, a regulatory mecha- Individuals trisomic for the left arm of chromosome 2 were nism that equalizes gene expression between individuals pos- produced as described (7, 8). Genetic and cytological studies sessing one or two X chromosomes (1). In mammals, equality revealed that whereas monosomic progeny die during embry- of X chromosome-linked gene expression occurs by inactivation ogenesis, a high proportion of the hybrid progeny inheriting ofone X chromosome in females through chromosome conden- three entire left arms of chromosome 2 survive to pharate sation. In contrast, dosage compensation in Drosophila is not adults. In fact, the viability of trisomy 2L- and trisomy X indi- mediated by chromosome condensation; instead, the- transcrip- viduals is comparable (data not shown). tional activity of X chromosome-linked genes is regulated to Five gene-enzyme systems on chromosome 2L, one on the synthesize the same amount ofgene product in both males and X chromosome, and one on chromosome 3L have been analyzed females. Thus, normal males (XY), normal' females (XX), and in this study. Their cytological map positions (2, 9-11) are listed metafemales (XXX) show approximately the same level of X in Table 1. To show that the activity of each enzyme was nor- chromosome-linked gene expression. Dosage compensation of mally proportional to the number ofgene copies, enzyme levels sex-linked genes in Drosophila is one ofthe few well-described were measured in strains with small duplications (three doses) examples of transcriptional modulation in eukaryotes. for each of the five loci studied on chromosome 2L. Segmental Previous studies on autosomal aneuploidy in metazoans have aneuploids were generated by a standard technique (3). not provided evidence for autosomal dosage compensation. For Flies trisomic for chromosome 2L, but carrying either a de- example, the amount of product synthesized by an autosomal ficiency or a null allele for a specific locus were produced by gene appears to be directly proportional to the number ofstruc- crossing C(2L)it;F(2R)bw/F(2R)bw females to males that were tural gene templates (2); individuals heterozygous for either a heterozygous for the inverted chromosome In(2LR)SM1,Cy it deficiency or a duplication of a particular autosomal gene pro- and either GpdhBol4 (a noncomplementing null allele for duce, respectively, 0.5 and 1.5 times the amount ofgene prod- Gpdh) or Df(2L)GdhA (a deficiency for the Gpdh structural uct found in normal diploid individuals. In addition, large al- gene) or to males homozygous for AdhN2 (a noncomplementing terations in the amount of chromosomal material are usually null allele for Adh). Larvae carrying either the null allele or lethal (3, 4). However, the complete absence ofautosomal dos- deficiency were distinguished by the presence of pigment in age compensation has never been critically tested. The purpose the larval Malpighian tubules in contrast to their nonpigmented ofthis investigation was to determine the level of gene expres- (It/l/lt sibs. sion in strains trisomic for the left arm ofchromosome 2 relative to normal diploids. The activity of five enzymes, whose struc- Abbreviations: dopa, dihydroxyphenylalanine; PGK, phosphoglycerate kinase;' aGPDH, a-glycerol-3-phosphate dehydrogenase; cMDH, cy- The publication costs ofthis article were defrayed in part by page charge toplasmic malate dehydrogenase; ADH, alcohol dehydrogenase; DDC, payment. This article must therefore be hereby marked "advertise- dopa decarboxylase; IDH, isocitrate dehydrogenase; 6PGD, 6-phos- ment" in accordance with 18 U. S. C. §1734 solely to indicate this fact. phogluconate dehydrogenase. 1200 Downloaded by guest on October 1, 2021 Genetics: Devlin et aL Proc. Natl. Acad. Sci. USA 79 (1982) 1201 Table 1. Enzyme levels in diploid and trisomic individuals Enzyme and chromosome position Pgk Gpdh cMdh Adh Ddc Idh 6Pgd Genotype 22C-23E 25F-26B 30F-31D 35B2 37B10-37C7 66B-67C 2D3-2D6 Oregon R 0.986 + 0.031 0.212 ± 0.008 3.36 ± 0.056 67.6 ± 2.4 8.61 ± 1.02 110 ± 4.3 36.8 ± 1.2 (10) (14) (10) (14) (16) (10) (10) C(2L)+;F(2R)bw/ 0.831 ± 0.019 0.132 ± 0.008 3.71 ± 0.053 40.9 ± 1.7 10.9 ± 0.784 73.3 ± 2.8 54.0 ± 1.1 F(2R)bw (11) (14) (10) (14) (18) (7) (10) C(2L)+/ 0.973 ± 0.049 0.154 ± 0.005 3.91 ± 0.294 89.0 ± 1.9 16.7 ± 0.714 74.9 ± 1.0 40.2 ± 1.6 +/F(2R)bw(CF Y (10) (10) (4) (10) (20) (10) (10) x OR d) C(2L)+/+/F(2R)bw 0.168 ± 0.019 3.73 ± 0.102 88.1 ± 1.7 81.5 ± 4.0 (ORe x CF d) (3) (11) (3) (3) Noncompensated 1.32 ± 0.016 0.238 ± 0.006 5.39 ± 0.044 74.7 ± 1.80 15.2 ± 0.552 Estimated mean estimate 91.7 ± 1.39 49.7 ± 0.576 Compensated estimate 0.883 ± 0.011 0.159 ± 0.004 3.59 ± 0.029 49.8 ± 1.20 10.1 ± 0.348 Enzyme activities expressed as the mean ± SE in units/mg of protein for Pgk, Gpdh, and cMdh; in units x 103/mg of protein forAdh, Idh, and 6Pgd; and in units x 106/mg of protein for Ddc. Estimates of enzyme activities expected in trisomies for dose-dependent (noncompensated) and compensated gene expression are provided for loci on chromosome 2L, and expected mean values for Idh and 6Pgd are also shown. Numbers in brackets represent the sample sizes. CF = C(2L); F(2R)/F(2R) strain; OR = Oregon R strain. A compound chromosome heterozygous for two Gpdh elec- 1010 becquerels) of [1-'4C]dopa (New England Nuclear; 3 Ci/ trophoretic variants was constructed by mating C(2L)P,b; mmol; isocitrate dehydrogenase (IDH; EC 1.1.1.42), 0.1 M C(2R)SKlA,cn bw males to al GpdhB Bi L/In(2L+2R)Cy, Tris, pH 8/5 mM Mg2+/0.05 mM NADP/0.5 mM isocitrate; al Cy GpdhA females that had been treated with 2500 rads from and 6-phosphogluconate dehydrogenase (6PGD; EC 1.1.1.44), a 'oCo source. A C(2L)VD4al GpdhB Bl/In(2L)Cy,al Cy GpdhA; 0.1 M Tris, pH 7.5/1.3 mM NADP/20 mM MgC12/3.1 mM 6- C(2R) SKlA,cn bw individual was recovered, and a stock was phosphogluconate. Activities are expressed as units per mg of established. From a cross of females bearing this compound protein in the extract, where one unit is defined as the utili- 2L chromosome with C(2L)P,b;F(2R)bw/F(2R)bw males, zation of1 Amol ofsubstrate per min. Protein concentration was C(2L)VD4al GpdhB Bl/In(2L)Cy,al Cy GpdhA;F(2R)bw/ determined (13), with bovine serum albumin as the standard. F(2R)bw nondisjunctional progeny were recovered.
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