Genetica 107: 261–269, 1999. © 2000 Kluwer Academic Publishers. Printed in the Netherlands.
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Transposable DNA elements and life history traits: II. Transposition of P DNA elements in somatic cells reduces fitness, mating activity, and locomotion of Drosophila melanogaster R.C. Woodruff1 , J.N. Thompson, Jr.2 , J.S.F. Barker3 & H. Huai4 1 Department
of Biological Sciences, Bowling Green State University, Bowling Green, OH 43403, USA (Phone: 419-372-0376; Fax: 419-372-2024; E-mail:
[email protected]); 2 Department of Zoology, University of Oklahoma, Norman, Oklahoma 73019, USA; 3 Department of Animal Science, University of New England, Armidale, NSW 2351, Australia; 4 University of Texas-Houston, School Public Health, Human Genetics, Houston, TX 77225, USA Accepted 31 January 2000
Key words: fitness, Drosophila melanogaster, locomotion, mating activity, P DNA elements
Abstract Some transposable DNA elements in higher organisms are active in somatic cells, as well as in germinal cells. What effect does the movement of DNA elements in somatic cells have on life history traits? It has previously been reported that somatically active P and mariner elements in Drosophila induce genetic damage and significantly reduce lifespan. In this study, we report that the movement of P elements in somatic cells also significantly reduces fitness, mating activity, and locomotion of Drosophila melanogaster. If other elements cause similar changes in life history traits, it is doubtful if transposable DNA elements remain active for long in somatic cells in natural populations.
Introduction Although the activity of many transposable DNA elements (TE) in higher organisms is limited to germ cells (Thompson, Woodruff & Schaefer, 1978; McElwain, 1986; Berg & Howe, 1989; McDonald, 1993; Engels, 1996), somatically active transposable elements have been identified in D. melanogaster, Caenorhabditis elegans, mice and humans (Emmons & Yesner, 1984; Jacobson, Medhora & Hartla, 1986; Herman & Shaw, 1987; Morse et al., 1988; Seperack et al., 1988; Blackman & Gelbart, 1989; Hartl, 1989; Moerman & Waterston, 1989; Georgiev et al., 1990; Getz & van Schaik, 1991; Ilyin, Lyubomirskaya & Kim, 1991; Kim & Belyaeva, 1991; Bratthauer & Fanning, 1992; Branciforte & Martin, 1994; Giraud & Capy, 1996; Jouan-Dufournel et al., 1996; Wu et al., 1997; Kazazian, 1998; Miki, 1998). Somatic recombination events between DNA elements in somatic cells and
cell culture can also lead to rearranged DNA (Rothberg et al., 1997; Nass et al., 1998; Slebos, Resnick & Taylor, 1998; Moran DeBerardinis & Kazazian, 1999). What effect does the movement of these and other DNA elements in somatic cells have on life history traits? It has previously been observed that the somatic movement of P DNA elements in D. melanogaster and mariner elements in D. simulans significantly reduces the lifespan of males (Woodruff, 1992; Woodruff & Nitikin, 1995). In D. melanogaster there is a log-linear decrease in lifespan as the number of active P elements increases (Woodruff, 1992), and a significant reduction in lifespan can be caused by the movement of a single P element (Woodruff & Nitikin, 1995); a single mariner element can also significantly reduce lifespan in D. simulans (Nitikin & Woodruff, 1995). Since the movement of P elements was also associated with somatic (and germinal) genetic damage
262 (Woodruff, 1992; Woodruff & Nitikin, 1995), and since DNA elements only cause damage to DNA and not to other cell structures, these results clearly show that increased genetic damage in somatic cells can decrease lifespan. This conclusion gives strong support to the somatic mutation and genetic damage theories of aging Kirkwood, 1988; Finch, 1990; Bernstein & Bernstein, 1991; Rose, 1991; Martin, Austad & Johnson, 1996; Barnett, 1997; Osiewacz, 1997; Beckman & Ames, 1998). What is the impact of DNA-element-induced genetic damage in somatic cells on other life history traits? In this study, we report that P element transpositions significantly reduce fitness, mating activity, and locomotion in D. melanogaster. Taken together with the previously observed decrease in lifespan, if these results are true for other DNA elements, it is doubtful if TE remain active for long in somatic cells in natural populations.
Materials and methods Drosophila stocks See Lindsley and Zimm (1992) and FlyBase (http://flybase.bio.indiana.edu:82) for detailed descriptions of mutants and special chromosomes. Canton-S A standard wild-type strain that contains no complete or defective P elements (Woodruff, unpublished results from Southern blot analysis). Defective P elements have DNA deleted sequences and usually do not produce transposase. Yet, defective P elements can move under the direction of transposase from other intact P elements or P[ry+ 12-3](99B), unless these defective P elements have altered or missing bases in their inverted repeat regions or in regions that bind transposase (Engels, 1989, 1996; Rio, 1990). Birm-2; ry506 Birm-2 = a second chromosome that contains 17 defective P elements that produce no transposase (Robertson et al., 1988). The defective P elements in the Birm-2 stock respond to transposase from other intact P elements and from P[ry+ 12-3](99B) (Engels et al., 1987; Robertson et al., 1988); ry 506 = rosy eye color, 3-52.0.
Homozygous ry 506 P[ry+ 12-3](99B) and ry506 P[ry+ 12-3](99B)/Sb The P[ry+ 12-3](99B) element is an insert that contains the wild-type rosy gene and an in vitro modified P sequence with a deletion of the third intron (Laski, Rio & Rubin, 1986). The P[ry+ 12-3](99B) element has inserted into the third chromosome at cytological position 99B and is stable (Robertson et al., 1988). Structurally normal P elements only move in germinal cells (Thompson, Woodruff & Schaefer, 1978) because of a lack of splicing of the third intron in somatic cells (Laski, Rio & Rubin, 1986). Yet, the P[ry+ 12-3](99B) element, which does not contain the third intron, produces transposase in somatic and germinal cells (Laski, Rio & Rubin, 1986). See Engels (1989, 1996) and Rio (1990) for detailed reviews of the genetics and molecular biology of P elements. CyO/+; ry 506 Sb P [ry + 12-3](99B)/+ CyO = I n(2LR), Cy dp1V I pr cn2 and is a balancer chromosome that contains the Cy (Curly wings, 26.1) dominant mutation. This stock was derived from a cross of CyO/Sp; ry 506 SbP[ry+ 12-3](99B)/TM6, Ubx with Canton-S (Sb = Stubble bristles, 358.2; Sp = Sternopleural bristles, 2-22.0; TM6 = In(3LR)TM6, H nP ss p88 bx 34e U bx P 15 e and is a balancer chromosome). y; C(3L)RM, ri; C(3R)RM, ry2 y = X-linked, yellow body; ri = radius incompletus, wing vein; ry 2 = rosy eye color; C(3L)RM; C(3R)RM = compound-autosome stock in which the two 3L arms and the two 3R arms each are attached to a centromere (Holm, 1976; Ashburner, 1989); the normal chromosome configuration is 3L-centromere3R. C(2L)RM, dpov1; F(2R), bw dpov1 = dumpy wings, 2-13.0; bw = brown eyes, 2-104.5; and C(2L)RM; F (2R) = two 2L chromosomes attached to a single centromere and two free 2R chromosomes each with a centromere (Grell, 1970; Ashburner, 1989). Cross set I The following cross was initially performed to synthesize sibling male progeny with 17 defective P elements that were inactive (lacked the 12-3 element) or active (contained the 12-3 element) in somatic cells. In this and following crosses, P[ry+ 12-3](99B) will
263 be given the symbol 12-3, and ry 506 will be given the symbol ry.
G1
Birm-2; ry females
X .&
G2A Birm-2/+; Sb/ry (Sb females and males with 17 inactive P elements from the Birm-2 chromosome) Movement of P elements in somatic cells It was essential to verify that the Birm-2 P elements in cross set I were unstable in somatic cells in the presence of 12-3. It has previously been reported that many Birm-2; 12-3 flies reared at 25◦C, but not 18◦ C, die as pupae, presumably due to P-element induced genetic damage in somatic cells of larvae (Engels et al., 1987; Woodruff, 1992). To confirm that this was true in this study, the above G1 cross was performed at 25◦C and 18◦C. At 25◦ C 1,558 Birm-2/+; Sb/ry flies and 74 Birm-2/+; ry/ry 12-3 flies survived (5% Birm-2; 12-3 flies), whereas at 18◦C, 1,124 Birm2/+; Sb/ry flies and 909 Birm-2/+; ry/ry 12-3 flies survived (45% Birm-2; 12-3 flies). Clearly, the P elements in the Birm-2 chromosome are unstable in the presence of 12-3. In the test for fitness, the G1 cross was performed at 18◦ C. Fitness To measure fitness of the G2A and G2B flies from the above cross set I, twenty virgin females and twenty males (3–4 days old) were placed into half-pint milk bottles with the same number of y; C(3L)RM, ri; C(3R)RM, ry 2 virgin females and males (3–4 days old) for 7–9 days at 18◦ C. The adults were then subcultured to new bottles for 7–9 more days, parents discarded, and progeny counted for 34 days from the day each bottle was initiated. Any matings between the compound-autosome stock and the Birm2 G2A or G2B stocks lead to embryonic lethality of hybrid progeny because of aneuploidy (extra or missing arms of the third chromosome); hence, only matings among the Birm-2 G2A or G2B flies or among the compound-autosome flies gave rise to viable adult progeny. The two stocks therefore are in direct competition in the milk bottles for all resources, and the ratio of progeny types (non-y; ri ry 2 flies/total flies)
gives a measure of the fitness (competitive index) of the two stocks (see Hartl & Jungen, 1979; Jungen
+/+; ry 12-3/Sb males G2B Birm-2/+; ry/ry 12-3 (Sb+ females and males with 17 active P elements from the Birm-2 chromosome) & Hartl, 1979; Hartl & Haymer, 1983; Haymer & Hartl, 1982, 1983; Sved, 1989 for discussions of this fitness technique). The compound-autosome technique is a simple, one-generation, straightforward test of overall fitness, including mating ability, fecundity, fertility and viability (Belyaeva et al., 1982; Minkoff & Wilson, 1992; Borlase et al., 1993; Gilligan et al., 1997). Cross set II In subsequent experiments, the following two crosses were performed to remove the possible role of Sb versus Sb+ markers on measures of fitness, mating activity, and locomotion. Note that in cross A the active P elements are in the G2 Sb+ progeny, whereas in cross B the active P elements are in the G2 Sb progeny.
Movement of P elements in somatic cells cross set II was also tested to make sure that the Birm2 P elements were unstable in the presence of 12-3 in somatic cells. At 25◦C, the results from cross A were: 7 Birm-2/+; ry 12-3/ry and 1,618 Birm-2/+; ry/Sb flies (0.4% Birm-2; 12-3 flies), whereas from cross B: 5 Birm-2/+; Sb ry 12-3/ry and 1,594 Birm-2/+; ry/+ flies survived (0.03% Birm-2; 12-3 flies). On the other hand, at 18◦C, the results from Cross A were: 909 Birm-2/+; ry 12-3/ry and 1,124 Birm-2/+; ry/Sb flies survived (45% Birm-2; 12-3 flies; as reported above), and from Cross B: 631 Birm-2/+; Sb ry 12-3/ ry and 989 Birm-2/+; ry/+ flies survived (39% Birm2; 12-3 flies). Again, the P elements were unstable in the presence of 12-3 at 25◦ C and there seems to be some instability at 18◦ C. The subsequent G1 cross A and cross B from cross set II were performed at 18◦C.
264 Cross A G1
Birm-2; ry X +/+; ry 12-3/Sb females males y
G2
Birm-2/+; ry 12-3/ry (Sb+ ; active P elements) and Birm-2/+; ry/Sb (Sb; inactive P elements)
Cross B G1
G2
Birm-2; ry females
X CyO/+; ry Sb 12-3/+ males y
Birm-2/+; ry Sb 12-3/ry (Sb; active P elements) and Birm-2/+; ry/+ (Sb+ ; inactive P elements)
Fitness Fitness was measured as in cross set I, except the freearm stock C(2L)RM, dpov1; F (2R), bw was used in place of the compound-autosome stock. As with the compound-autosome stock, any matings between the G2 progeny of cross A or cross B and the freearm stock give embryonic lethality of hybrid progeny because of aneuploidy (see discussion in Ashburner, 1989). Mating activity Mating activity was measured for males with and without somatically active P elements from cross set II by two assays. First, Sb and Sb + males from cross A and cross B were aged for five days, individual males were placed into a glass vial with a single five-dayold, virgin Canton-S female, and it was recorded if the males mated in 10 min. Second, as a measure of mating competition between males with and without somatically active P elements, Sb+ and Sb males from cross A and cross B were aged for five days, one male of each genotype was placed together in a glass vial with a single five-day-old Canton-S female for 30 min, and progeny were recorded as Sb + or Sb. Flies were not etherized at any stage of these assays.
Locomotion Locomotion activity was measured for males from cross set II with and without somatically active P elements by use of the Connolly (1966; see his Figure 5) circular runway apparatus. In this apparatus, flies are introduced into a 3 mm diameter channel in a 15.7 cm round runway that is marked with radial lines. Single, unetherized, males were placed into the runway for 90 s to recover from the transfer process and then the number of radial lines crossed by the fly in one minute was recorded (distance between lines is 2 cm).
Results Fitness The fitness results from cross set I are shown in Table 1 and Figure 1 and those from cross set II are shown in Table 2. In both sets of crosses, P-element movement in somatic cells significantly reduces fitness. The reason for the low fitness of Birm-2/+; ry Sb 12-3 flies in cross B of cross set II is not known, but is probably not due to an interaction between P-element movement and Sb, because the fitness of Birm-2/+; Table 1. Results from fitness test of Birm-2/+ males that do or do not have somatically active P elements from cross set I Genotypes Birm-2/+; Sb/ry Birm-2/+; ry/ry12-3 (inactive P elements) (active P elements) Run 1 Bottle 1 Bottle 2 Bottle 3 Run 2 Bottle 1 Bottle 2 Bottle 3 Run 3 Bottle 1 Bottle 2 Bottle 3 Run 4 Bottle 1 Bottle 2 Bottle 3
1990/1996 = 0.99a 2140/2172 = 0.99 1693/1732 = 0.98
625/727 = 0.86∗ 167/322 = 0.52∗ 643/939 = 0.69∗
2017/2023 = 0.99 1968/1977 = 0.99 1832/1846 = 0.99
592/731 = 0.81∗ 642/709 = 0.91∗ 721/769 = 0.94∗
1353/1362 = 0.99 1368/1375 = 0.99 1182/1190 = 0.99
626/700 = 0.88∗ 615/759 = 0.81∗ 565/733 = 0.77∗
1133/1171 = 0.97 1329/1429 = 0.93 1491/1525 = 0.98
567/673 = 0.84∗ 451/663 = 0.68∗ 182/657 = 0.28∗
a Competitive index = number of non-y; ri ry2 flies/total number of flies. A value of 0.99 means that 1% of the flies that eclosed were y; C(3L)RM, ri; C(3R)RM, ry 2 . ∗ P< 0.001.
265 Table 2. Results from fitness test of Birm-2/+ males that do or do not have somatically active P elements from cross set II Cross A Birm-2/+; ry 12-3/ry Birm-2/+; ry/Sb (Sb+ , active P) (Sb, inactive P)
Cross B Birm-2/+; ry Sb 12-3/ry Birm-2/+; ry/+ (Sb, active P) (Sb+ , inactive P)
1,767/2,921 = 0.61a
314/1,268 = 0.25a
6,280/6,916 = 0.91a
5,851/5,898 = 0.99a
Results are from seven bottles in cross A and five bottles in cross B. a P< 0.001.
lower than males with inactive P elements. As with the test of fitness, the Birm-2/+; Sb ry 12-3/ry males had the lowest locomotion activity, which was caused by the P-12-3 interaction and not by Sb, since Birm2/+; ry/Sb and Birm-2/+; ry/+ males had similar locomotion activity values (14.77 and 14.19; Table 4).
Discussion
Figure 1.
ry/Sb flies in cross A is similar to that of the Birm-2/+; ry/+ flies in cross B (0.91 vs 0.99). Mating activity The mating activity of males with somatically active P elements was significantly reduced in both mating assays. The number of males that mated in the single female with single male assay and in the single female with two male assay is shown in Tables 3a and 3b. In the first assay, a significantly higher percentage of males with inactive P elements mated in 10 min than did males with active P elements (P< 0.001). In the second assay, a significantly higher proportion of males with inactive P elements mated in competition with a male carrying active P elements (P< 0.001). Locomotion As shown in Table 4, the locomotion activity of male flies with somatically active P elements is significantly
The results from this study indicate that the movement of P elements in somatic cells significantly reduces fitness, mating ability and locomotion of D. melanogaster males. Previously, it had been reported that P movement in somatic cells also causes genetic damage and reduces the lifespans of D. melanogaster and D. simulans males (Woodruff, 1992; Woodruff & Nikitin, 1995; Nikitin & Woodruff, 1995). When one adds to these results the reports that P-element transpositions in germ cells of D. melanogaster also reduce the fitness of offspring and can cause sterility due to excessive chromosome breakage (Henderson, Woodruff & Thompson, 1978; Fitzpatrick & Sved, 1986; Eanes et al., 1988; Ajioka & Hartl, 1989; Mackay, 1989), that TE insertions into coding regions of Drosophila genes are usually selected against in natural populations (Charlesworth & Langley, 1989; Eanes, Labate & Ajioka, 1989, and references therein; Charlesworth, Sniegowski & Stephan, 1994; Nitasaka, Yamazaki & Green, 1995; ten Have, Green & Howells, 1995), that Ty insertions in yeast are, on average, deleterious (Boeke, Eichinger & Natsoulis, 1991; Wilke & Adams, 1992; Wilke, Maimer & Adams, 1993), that TE events in germ cells cause human diseases (Sassaman et al., 1997; Kazazian, 1998; Levran, Doggett & Auerbach, 1998; Miki, 1998; Huie et al., 1999), and that TE mediated insertions and rearrangements can cause cancer (Miki et al., 1992; Petrij-Bosch et al., 1997; Swensen et al., 1997; Morse et al., 1988; Montagna et al., 1999), these results taken together highlight the negative impact of active transposable
266 Table 3a. Mating activity of males with and without somatically active P elements from cross set II: Single Canton-S female
Active P elements Inactive P elements
X ↓ Determine if mate in 10 min Mated Did not mate
Single male % mated
13 73
10 38
121 120
P < 0.001 Table 3b. Mating activity of males with and without somatically active P elements from cross set II: Single Canton-S female
P-active male P-inactive male
X ↓ Determine which male mates in 30 min Mated Did not mate
Single Sb male and single Sb+ male
10 93
10 90
93 10
% mated
P < 0.001
elements on their hosts (see discussions in Ajioka & Hartl, 1989; Charlesworth, Sniegowski & Stephan, 1994). Yet, transposable elements are also known to be used for positive, adaptive changes in genomes. For example, TE, partial TE sequences, and TE coded proteins have been used in antibody segment joining (Agrawal, Eastman & Schatz, 1998; Hiom, Melek & Gellert, 1998), as modifiers of gene regulation (see references in McDonald, 1990, 1993), in formation of new introns (Nouaud et al., 1999), in repair of chromosome breaks (Moore & Haber, 1996; Teng et al., 1996), and in telomere formation (Mason & Biessmann, 1995; Pardue et al., 1997) (for reviews of this topic see Britten, 1997; Fedoroff, 1999). In addition, TE induce genomic changes that could be beneficial to their hosts, including exon shuffling (Moran, DeBerardinis & Kazazian, 1999), formation of novel splice junctions (Nurminsky et al., 1998), induction of inversions by ectopic recombination between TE (Montgomery et al., 1991; Lyttle & Haymer, 1992; Mathiopoulos et al., 1998; Andolfatto, Wall & Kreitman, 1999; Caceres et al., 1999), and induction of quantitative trait mutations (Mackay, Lyman & Jackson, 1992). It has even been proposed that TE may play a role in reproductive isolation and speciation (Bingham, Kidwell & Rubin, 1982; Rose & Doolittle, 1983; Bregliano & Kidwell, 1983; Ginzburg, Bing-
ham & Yoo, 1984; McDonald, 1989; Fontdeveil, 1992; Evgen’ev et al., 1998; Hurst & Schilthuizen, 1998; Graur & Li, 2000, and references therein). Which is true? Are TE beneficial or deleterious to their hosts (Brookfield, 1995)? The answer may depend upon whether one is considering the short term or long term consequences of a host containing active, or potentially active, TE. It may be suggested that TE are important to their hosts because TE can be used to generate new genetic variation in the future when needed by the host. However, this would imply that evolution can look ahead, and even more importantly, that any future advantage of TE movement outweighs the short-term consequence of the common detrimental genetic changes caused by the somatic and germinal movement of TE. Hence, should we think of TE as simply selfish DNA that cannot be eliminated by the host? Are active TE maintained in a genome because they undergo replicative transpositions to counter their loss by selection against their hosts that carry TE-induced deleterious mutations? Even if this is true, it is also true that TE and the gene and chromosomal variation they induce can occasionally be used by the host in a positive, adaptive way. Maybe TE should be thought of as more often acting as indirect agents of evolution, instead of frequently playing a direct role in adaptive evolution.
267 Table 4. Locomotion activity of males with and without somatically active P elements from cross set IIa Cross A Birm-2/+; ry 12-3/ry Birm-2/+; ry/Sb (Sb+ , active P) (Sb, inactive P)
Cross B Birm-2/+; ry Sb 12-3/ry Birm-2/+; ry/+ (Sb, active P) (Sb+ , inactive P)
9.65 + 0.46b (145)c
7.27 ± 0.79b (130)
14.77 ± 0.39b (167)
14.19 + 0.38b 42
a Mating activity measured in number of times 2 cm is crossed in 1 min in a Connolly (1966) circular runway apparatus. b P< 0.001. c Number of males tested.
Acknowledgements This work was partly supported by a Public Health Service grant (RO1 GM49362) to Dr. Ian A. Boussy and R.C.W. R.C.W. was partially funded by a University of New England Visiting Research Fellowship. We thank Annette Edmonds, Phyllis Oster, Linda Treeger and Donna Tampurages for technical assistance.
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