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A Highly Conserved Sequence in the 3 -Untranslated Region

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A Highly Conserved Sequence in the 3 -Untranslated Region Copyright 1999 by the Genetics Society of America A Highly Conserved Sequence in the 39-Untranslated Region of the Drosophila Adh Gene Plays a Functional Role in Adh Expression John Parsch,*,²,1 Wolfgang Stephan²,1 and Soichi Tanda² *Molecular and Cell Biology Program and ²Department of Biology, University of Maryland, College Park, Maryland 20742 Manuscript received July 15, 1998 Accepted for publication October 19, 1998 ABSTRACT Phylogenetic analysis identi®ed a highly conserved eight-base sequence (AAGGCTGA) within the 39- untranslated region (UTR) of the Drosophila alcohol dehydrogenase gene, Adh. To examine the functional signi®cance of this conserved motif, we performed in vitro deletion mutagenesis on the D. melanogaster Adh gene followed by P-element-mediated germline transformation. Deletion of all or part of the eight- base sequence leads to a twofold increase in in vivo ADH enzymatic activity. The increase in activity is temporally and spatially general and is the result of an underlying increase in Adh transcript. These results indicate that the conserved 39-UTR motif plays a functional role in the negative regulation of Adh gene expression. The evolutionary signi®cance of our results may be understood in the context of the amino acid change that produces the ADH-F allele and also leads to a twofold increase in ADH activity. While there is compelling evidence that the amino acid replacement has been a target of positive selection, the conservation of the 39-UTR sequence suggests that it is under strong purifying selection. The selective difference between these two sequence changes, which have similar effects on ADH activity, may be explained by different metabolic costs associated with the increase in activity. HE Drosophila alcohol dehydrogenase enzyme from the distal promoter) and 1 kb of 39 ¯anking se- T(ADH; EC 1.1.1.1) and the gene that encodes it, quence (Goldberg et al. 1983; Laurie-Ahlberg and Adh, have been used as a model system for many studies Stam 1987). of population genetics, molecular evolution, and molec- Two forms of the ADH protein, designated as Fast ular biology. ADH is responsible for the detoxi®cation (ADH-F) and Slow (ADH-S), which differ by a single of environmental alcohols (David et al. 1976), and ¯ies amino acid (Fletcher et al. 1978), have been found at lacking ADH activity cannot survive in environments high frequency in worldwide populations of D. melano- containing moderate levels of alcohol (Gibson and gaster (Oakeshott et al. 1982). In addition, numerous Oakeshott 1982; Van Delden 1982). ADH also plays polymorphisms have been detected at silent and non- an important role in the metabolism of ethanol into coding sites within the Adh gene (Kreitman 1983; Lau- energy-storage lipids, particularly at the larval stage rie et al. 1991). ADH-F homozygotes have, on average, (Geer et al. 1986, 1991). In D. melanogaster, Adh produces two- to threefold higher levels of enzymatic activity than two developmentally regulated transcripts that differ in ADH-S homozygotes. This difference is due to two fac- their 59-untranslated leaders but are identical in their tors, an increase in catalytic ef®ciency of the ADH en- protein-encoding regions and 39-untranslated regions zyme and an increase in the total amount of enzyme in (UTRs) (Benyajati et al. 1983). Transcripts from a dis- ADH-F ¯ies (Choudhary and Laurie 1991). Experi- tal promoter are found predominantly in adult tissues, ments using site-directed mutagenesis and P-element- while those from a proximal promoter are found pre- mediated germline transformation have shown that the dominantly in larval tissues (Benyajati et al. 1983; Fast/Slow polymorphic site is responsible for the dif- Savakis et al. 1986). Experiments using P-element- ference in ADH catalytic activity between ADH-F and mediated germline transformation have shown that all ADH-S ¯ies (Choudhary and Laurie 1991). This site, cis-acting sequence elements required for proper Adh however, has no effect on in vivo concentration of ADH expression are contained within an 8.6-kb SacI-ClaI frag- protein, which suggests that other, nonreplacement ment, which contains the entire Adh mRNA-encoding sites must also play an important role in determining region and z5kbof59 ¯anking sequence (upstream Adh expression levels. For example, a complex nucleo- tide substitution within the ®rst (adult) Adh intron has been shown to have a signi®cant effect on ADH activity Corresponding author: John Parsch, Department of Biology, University levels (Laurie and Stam 1994). Interestingly, this in- of Rochester, Rochester, NY 14627-0211. tronic sequence has no effect on the concentration of E-mail: [email protected] 1 Present address: Department of Biology, University of Rochester, Adh mRNA, suggesting that there may be an interaction Rochester, NY 14627. between this region of the ®rst intron and other regions Genetics 151: 667±674 (February 1999) 668 J. Parsch, W. Stephan and S. Tanda of the pre-mRNA during polyadenylation or other pro- brook et al. (1989). All Adh constructs were derived from an cessing events that results in a change in the transla- 8.6-kb SacI-ClaI fragment of the D. melanogaster Wa-f allele [originally described by Kreitman (1983)]. A pUC18 plasmid tional ef®ciency of the mature mRNA (Laurie and containing the entire Adh mRNA-encoding region within a Stam 1994). Other nonreplacement sites that affect lev- 3.2-kb SalI-ClaI fragment (Parsch et al. 1997) was used for els of Adh expression have been mapped to the protein- mutagenesis following the QuikChange (Stratagene, La Jolla, encoding region and the 39-UTR, but have not yet been CA) procedure. Following mutagenesis, a BamHI-ClaI restric- tested by mutational analysis (Stam and Laurie 1996). tion fragment containing each mutant 39-UTR was used to replace the corresponding fragment in the original 8.6-kb Phylogenetic analysis has been used to identify non- SacI-ClaI clone. At this point, the entire BamHI-ClaI region coding regions of the Adh gene that may play a func- subjected to mutagenesis was sequenced using a cycle sequenc- tional role in Adh expression. Kirby et al. (1995) used ing method (Life Technologies) to ensure that the desired the phylogenetic-comparative method to predict second- mutation (and no other changes) was present. ary structures of the Adh pre-mRNA and suggest that the P-element-mediated germline transformation: The entire 8.6-kb Adh SacI-ClaI fragment of each mutant construct was patterns of linkage disequilibrium found within the Adh inserted into the polycloning region of the YES transformation gene of D. pseudoobscura (Schaeffer and Miller 1993) vector, which contains the D. melanogaster yellow (y) gene as a are the result of epistatic selection maintaining RNA selectable marker (Patton et al. 1992). Germline transforma- pairing stems within intron sequences. Phylogenetic tion of an ADH-null D. melanogaster y w; Adh fn6D2-3,Sb/TM6 analysis has also identi®ed several short-range RNA pair- stock was achieved by embryo microinjection (Rubin and Spradling 1982; Spradling and Rubin 1982). At least four ing stems within the Adh exon 2, as well as two long- independent insertion lines were generated through embryo range pairings between exon 2 and a highly conserved microinjection for each mutant construct. Additional trans- region of the 39-UTR (Parsch et al. 1997). The func- formed lines were then generated by mobilization of the YES tional signi®cance of one of these long-range pairings vector constructs within the original lines through genetic was tested by mutational analysis in D. melanogaster crosses, using the D2-3 P element as a source of transposase (Robertson et al. 1988; Parsch et al. 1997). Transformants (Parsch et al. 1997). A site-directed mutation at a silent containing the wild-type 8.6-kb Adh Wa-f genomic fragment third-codon position of exon 2, which disrupted a Wat- were used as a control (Parsch et al. 1997). son-Crick base pair in the proposed long-range pairing, Previous experiments indicated that expression levels of resulted in a signi®cant reduction in adult ADH activity Adh insertions on the X chromosome may be increased due level. ADH activity was restored to wild-type levels by a to dosage compensation mechanisms in Drosophila (Laurie- 9 Ahlberg and Stam 1987; Parsch et al. 1997). For this reason, second, ªcompensatoryº mutation in the 3 -UTR. The only autosomal insertion lines were used for analysis. X chro- 39-UTR mutation by itself, however, had no measurable mosome insertion lines were identi®ed as those that produced effect on ADH activity levels. Thus, these observations only y1 female (and only y2 male) offspring when trans- do not ®t a simple model of compensatory evolution formant males were mated to females of a yw, Adh fn6 stock. (Parsch et al. 1997). Furthermore, to ensure that the transformed lines contained To explore the possible cause of this discrepancy and only a single Adh insertion, a Southern blot was performed on genomic DNA prepared from each transformed line. The further examine the role of phylogenetically conserved genomic DNA was digested with three six-cutter restriction sequence elements on Adh expression, we investigated enzymes (BglII, SalI, and StuI) and hybridized with a probe a highly conserved sequence located just downstream derived from the Adh 59 ¯anking region (Parsch et al. 1997). of the nucleotide site where the single 39-UTR mutation The probe hybridizes to a fragment of constant size for the was made. The high level of conservation within this genomic Adh gene and a fragment of unique size for each Adh insertion. A total of 30 independent, autosomal single- region suggests that it may have a function that is distinct insert lines were used for ADH assays, consisting of the wild- from that of the proposed RNA secondary structure.
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