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How Y Chromosomes Become Genetically Inert

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How Y Chromosomes Become Genetically Inert Proc. Natl. Acad. Sci. USA Vol. 90, pp. 5737-5741, June 1993 Genetics How Y chromosomes become genetically inert (chromosome structure/Drosophila miranda/sienced Lcp genes/retrotransposons/Y chromosome degeneration) MANFRED STEINEMANN*t, SIGRID STEINEMANN*t, AND FRIEDRICH LOTTSPEICHt *Institut fur Genetik und Mikrobiologie, Universitat Munchen, Maria-Ward-Strasse la, D-8000 Munich 19, Federal Republic of Germany; and tMax-Planck-Institut fur Biochemie, Genzentrum, Am Klopferspitz, D-8033 Martinsried, Federal Republic of Germany Communicated by M. M. Green, February 16, 1993 (receivedfor review January 11, 1993) ABSTRACT We have investigated the mechanistic aspects inally autosomal genes, now present on a degenerating Y of inactivation of the major larval cuticle protein genes chromosome. (Lcpl-4) in Drosophila miranda during Y chromosome evolu- tion. The Lcp genes are located on the X2 and neo-Y chromo- MATERIALS AND METHODS somes in D. miranda but are autosomaily inherited in all other Drosophila species investigated so far. In the neo-Y chromo- Cloning and DNA Sequencing of the Lcp Region of X2 and some all four Lcp loci are embedded within a dense cluster of Y Chromosomes of D. miranda. Cloning and standard DNA transposable elements. The X2Lcpl-4 loci are expressed, while techniques were carried out according to ref. 16. The strategy the Y chromosomal locus shows reduced and for cloning and sequencing the Lcp region from the X2 and Y Lcp3 only activity chromosomes ofD. miranda has been detailed (9, 15). DNA the Lcpl, Lcp2, and Lcp4 are completely inactive. Our results and protein sequence alignments were performed using MAC- suggest that Lcpl and Lcp3 loci on the degenerating Y chro- MOLLY (Soft Gene, Berlin) or DNASIS and PROSIS (Pharmacia) mosome of D. miranda are silenced by neighboring transpos- alignment programs. able elements. These observations support our assumption that Isolation and Separation ofthe LCPs. LCPs from single late the first step in Y chromosome degeneration is the successive third-instar larvae were prepared according to a published silencing of Y chromosomal loci caused by trapping and protocol (17), with modifications. Several cuticles prepared accumulation of transposons. in this way were extracted simultaneously. After centrifuga- tion the supernatants were used for gel electrophoresis. The Regulated and efficient gene expression is based on a struc- gels were overlaid with 0.075 M Tris citrate, pH 8.6. Standard tured chromosome organization. Interactions between chro- nondenaturing 8.5% polyacrylamide slab gels were run in 0.3 mosome structure and gene expression are most obviously M borate buffer, adjusted to pH 8.6. exemplified in genes adapted to a euchromatic or a hetero- Protein Microsequencing of the Electrophoretically Sepa- chromatic environment. Rearrangements that result in trans- rated LCPs. LCPs separated by nondenaturing gel electro- fer of such genes into a novel context-e.g., from a euchro- phoresis were electroblotted onto siliconized glass-fiber matic to a heterochromatic one-can lead to a change in sheets (Glassybond, Biometra, Gottingen, F.R.G.) and expression pattern (1, 2). stained with Coomassie blue (18). Protein-containing bands The Drosophila miranda karyotype is characterized by a were excised and sequenced by using a 477A sequencer pair of heteromorphic sex chromosomes in the male that are equipped with an on-line 120A phenylthiohydantoin analyzer still evolving from a pair of initially homologous autosomes. (Applied Biosystems). This exceptional situation is due to the translocation of one Constructs and P Element-Mediated Germ-Line Transfor- of the autosomes to the Y chromosome, resulting in a neo-Y mation. DNA fragments of interest were inserted into the chromosome and a monosome (neo-X), designated X2 (3-6). polylinker of the pCaSpeR vector (19) by standard cloning Both chromosomes are undergoing an evolutionary process techniques. For the Y chromosomal Lcpl and Lcp3 loci we of chromosome remodeling, each along a different pathway prepared two types offragments, A and B. The Y Lcp3 locus was cloned together with the complete flanking retroelement (7, 8). TRIM and part ofLcp2 (Y3A). In Y3B we removed the TRIM The larval cuticle protein genes (Lcpl-4) are located on the element. The Nsi I fragment (Y1A) encompasses the 5' X2 and Y chromosomes in D. miranda (9, 10), while they are flanking ISY1-3 insertion sequences (see Fig. 3). For the Y1B autosomally inherited in the two sibling species Drosophila fragment we deleted the ISY1-3 sequences. pseudoobscura and Drosophila persimilis (here we follow the As an internal control for expression we designed hybrid locus designation Lcp of ref. 11). They are expressed in the constructs in which Lcpl genes were fused to the LX2/3 epidermal cells of late third-instar larvae (12, 13) and repre- construct. The Hl(YlA;X2/3) construct contains the Y1A sent a set of genes which encode the larval cuticle proteins, fragment cloned into the Pst I site ofthe LX2/3 construct. In LCP1-LCP4 (in the original literature CP1-CP4; for consist- the H2(YlB;X2/3) construct we cloned the Pst I and Bgl II ency, we suggest LCPs). On comparing the DNA structure of sites of the Y1B fragment into the Pst I and BamHI sites of the Lcp region from the two chromosomes ofD. miranda we the LX2/3 construct. As an autosomal reference gene we observed insertions, deletions, and a large duplication asso- used the BamHI fragment (P1) containing Lcpl from D. ciated with the loci on the Y chromosome (14, 15). The pseudoobscura. The P1 fragment was cloned in the BamHI densely clustered insertions were identified as retrotrans- site of the LX2/3 construct to give H3(P1;X2/3). The inte- posons and transposon-like DNA elements (10, 15). grated fragments are indicated in Fig. 3. Constructs were We have used Lcpl-4 as test genes to address the question injected into homozygous Drosophila melanogaster Ore- of the impact of these DNA insertions and heterochromati- gon-R w snw embryos, together with a helper plasmid, A2-3 nization processes on the regulation and expression of orig- (20). The constructs were integrated into the Drosophila The publication costs ofthis article were defrayed in part by page charge Abbreviation: LCP, larval cuticle protein. payment. This article must therefore be hereby marked "advertisement" tPresent address: Institut fur Molekulare Genetik, Grisebachstrasse in accordance with 18 U.S.C. §1734 solely to indicate this fact. 8, D-3400 Gottingen, F.R.G. 5737 Downloaded by guest on October 3, 2021 5738 Gehetics: Steinemaiin et al. Proc. Natl. Acad. Sci. USA 90 (1993) SPECIES N-TERMINAL SPECIES N-TERMNAL SPECIES N-TERhlvNAL SPECIES N-TERMNAL MEL(OR) SEQUENCE MIR (f) SEQUENCE MIR (m) SEQUENCE PSEU SEQUENCE LCP 1 NPPVP.. LCP2 'we PVSLCP........1 4 GVAHV. LCP 1 GVAHV... LCP 1 _' GVAHV.. LCP 3 NANVE.. VAPVS... LCP2 _U~ VAPVS... LCP 2 _gp0 VAPVS.. LCP 2 '4mM' LCP 4 iI*- NENPE... NENAE.. LOP 3/4 LCP 5 " LCP 3/4 _ NENAE... LCP 3/4 _wNENAE... NENAE... NENAE NENAE.. LCP 5 41 LCP 5 qupi LCP 5 4p LCP 6 -.P LCP66 LCP 6 , FIG. 1. Identification ofthe LCPs encoded by Lcpl-4. The proteins were isolated and separated in nondenaturing 8.5% polyacrylamide gels. For illustration the photograph ofa Coomassie blue-stained gel was scanned with a laser scanner and processed for the application ofdesignations without changing the positions ofthe bands. The faint band corresponding to the LCP3 encoded by the Y chromosomal Lcp3 locus is not visible (cf. Fig. 4B). Protein designations and the sequences of the first five N-terminal amino acids (single-letter symbols) are indicated for the corresponding bands. LCP3 (X2 chromosomal) and LCP4 show the same mobility. MEL(OR), D. melanogaster Otegon-R; MIR, D. miranda; PSEU, D. pseudoobscura; f, female; m, male. genome by P element-mediated germ-line transformation suggesting that they originate from a duplication that oc- (21). Localization of the constructs was performed geneti- curred after the separation of the obscura and melanogaster cally. Balancer chromosomes, FM7c, CyO, and TM3 Sb Ser, groups. It is of interest that the strong D. miranda LCP band used to balance the established lines are described in ref. 11. with highest mobility, LCP6, must also be encoded on the X2/Y chromosome pair, as we consistently have observed RESULTS two LCP6 bands in males. This is obviously due to a polymorphism in the Y chromosomal Lcp6 locus. The poly- Correlation of Individual LCPs with Lcpl-4 Genes. We morphic band shows the same mobility as the D. pseudoob- isolated the LCPs from single cuticles ofthird-instar male and scura LCP6 (Fig. 1; see also Fig. 4). The position ofthe locus female larvae ofD. melanogaster Oregon-R (w snw, the strain is unknown. Interestingly, the Y chromosomal Lcp6 locus is used for germ-line injections), D. pseudoobscura, and D. expressed normally (see below). miranda. The electrophoretically separated LCPs were elec- Are X2 and Y Loci Both Expressed? We sequenced the X2 troblotted onto a hydrophobic membrane and the N-terminal and Y loci of Lcpl-4. Alignment of the allelic DNA se- amino acids from each of the bands (Fig. 1) were determined quences revealed several point mutations, some of which by microsequencing (18). Based on their sequence relation- lead to amino acid exchanges in the signal peptides and ships with the corresponding proteins from D. melanogaster mature proteins. We used the amino acid substitutions which (details of sequence comparisons will be published else- are closest to the N-terminal ends (Fig. 2) as genetic markers. where), we identified LCP1-4 from D. pseudoobscura and D. Thus, we were able to address the question of whether each miranda (male and female). The X2 chromosomal LCP3/4 of ofthe Lcpl-4 loci on the X2 and Y chromosomes is active or D.
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