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The Drosophila melanogaster Hybrid male rescue Gene Causes Inviability in Male and Female Species Hybrids
Daniel A. Barbasha, John Rootea, and Michael Ashburneraa Department of Genetics, University of Cambridge, Cambridge CB2 3EH, United Kingdom
Corresponding author: Daniel A. Barbash, Department of Genetics, University of Cambridge, Downing St., Cambridge CB2 3EH, United Kingdom., d.barbash{at}gen.cam.ac.uk (E-mail)
 | ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The Drosophila melanogaster mutation Hmr rescues inviable hybrid sons from the cross of D. melanogaster females to males of its sibling species D. mauritiana, D. simulans, and D. sechellia. We have extended previous observations that hybrid daughters from this cross are poorly viable at high temperatures and have shown that this female lethality is suppressed by Hmr and the rescue mutations In(1)AB and D. simulans Lhr. Deficiencies defined here as Hmr- also suppressed lethality, demonstrating that reducing Hmr+ activity can rescue otherwise inviable hybrids. An Hmr+ duplication had the opposite effect of reducing the viability of female and sibling X-male hybrid progeny. Similar dose-dependent viability effects of Hmr were observed in the reciprocal cross of D. simulans females to D. melanogaster males. Finally, Lhr and Hmr+ were shown to have mutually antagonistic effects on hybrid viability. These data suggest a model where the interaction of sibling species Lhr+ and D. melanogaster Hmr+ causes lethality in both sexes of species hybrids and in both directions of crossing. Our results further suggest that a twofold difference in Hmr+ dosage accounts in part for the differential viability of male and female hybrid progeny, but also that additional, unidentified genes must be invoked to account for the invariant lethality of hybrid sons of D. melanogaster mothers. Implications of our findings for understanding Haldane's rule—the observation that hybrid breakdown is often specific to the heterogametic sex—are also discussed.
THE sterility and lethality of species hybrids is a defining characteristic of species (
Lack of progress cannot be attributed to the lack of a model for explaining hybrid breakdown.
When
The complete sterility of D. melanogaster hybrids has been the primary obstacle to identifying the genes that distinguish D. melanogaster from its siblings. The recent discovery of D. simulans strains that produce fertile F1 female hybrids with D. melanogaster provides reason for optimism (
It is not unreasonable to suppose that these rescue mutations are alleles of genes that actually cause hybrid lethality, but it is also possible that they are mutations that suppress lethal interactions between other unknown genes (
We have looked, therefore, for possible phenotypes of Hmr in hybrid females. It has long been known that D. melanogaster/D. simulans hybrid females are fully viable only at low temperatures (
| MATERIALS AND METHODS |
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| TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Culture conditions:
All crosses were done at 25°. Progeny were collected for 1 or 2 days; after removing the parents, cultures were immediately shifted to the temperatures indicated in each table, with the following two exceptions. Crosses with D. simulans mhr mothers (see Table 9 and Table 10) were kept at 25° for ~24 hr after removing the parents and then shifted to the appropriate temperature. Progeny for the temperature-shift experiments shown in Fig 4 were collected at 25° for 6–9 hr (29° to 18° shifts) or 12–14 hr (18° to 29° shifts); shorter collections were used for the 29 to 18° shifts because we found the viability of these cultures to be particularly sensitive to overcrowding. After removing the parents, cultures were placed immediately at the appropriate starting temperature and then shifted at the times indicated in Fig 4.
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For some experiments it was informative to count and score dead pharate and eclosed adults. We defined pharate adults as those stages where sex and eye color (w or wa vs. w+) could be scored easily; this corresponds approximately to stage P10 of
Stocks:
Sibling species marker stocks were from the Drosophila Species Center (DSC, Bowling Green, OH, or Cambridge, United Kingdom) stock collections, with the exception of D. sechellia f, which was obtained from J. Coyne. Wild-type stocks were as follows:
- D. mauritiana: C164.1 was collected in Riviere Noire, Mauritius, and is identical to stock S7 used in
HUTTER et al. 1990 ; Iso 152 and Iso 197 are iso-female stocks obtained from the DSC. - D. simulans: Tsimbazaza (Gif 247.1) and Ethiopia (Gif 225.1) are described in
LACHAISE et al. 1986 ; C167.4 was collected in Kenya and reported inDAVIS et al. 1996 . - D. sechellia: Gif 228.1 is described in
LACHAISE et al. 1986 ; Iso 4 and Iso 24 are isofemales lines from the DSC. - D. melanogaster: Nguruman-4 was obtained from the Umeå (Sweden) stock center; Oregon-R was originally obtained from the National Institute of Genetics (Mishima, Japan).
D. melanogaster deficiency and duplication stocks were obtained from the Bloomington or Umeå stock centers. Their breakpoints are shown in Fig 3; we verified the published cytologies (with the exception of Df(1)ras-v17) by analyzing orcein-stained squashes of polytene chromosomes. All D. melanogaster marker mutations and aberrations are described in
Nomenclature:
Chromosomes from the melanogaster complex species D. melanogaster, D. mauritiana, D. sechellia, and D. simulans are indicated by the subscripts mel, mau, sec, or sim, respectively. The latter three species are referred to collectively as siblings, abbreviated as sib. For clarity we use the designation Hmr1 to refer explicitly to the rescue allele described in
Experimental design:
Most of the experimental crosses involved comparisons of sibling hybrids of different genotypes with respect to Hmr. A summary diagram is shown in Fig 1.
| RESULTS |
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| TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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High-temperature lethality in female hybrids:
D. simulans hybrid daughters from D. melanogaster mothers vary in their viability at 25°, depending on the stocks used (
Our results with D. simulans hybrids were consistent with previous studies: all female hybrids were at least 78% viable at 18° but varied from fully viable to fully lethal at 25°. Viable escapers at 25° often displayed morphological defects including crinkled wings, rough eyes, and multiple necrotic patches similar to those shown in Fig 2B.
To investigate the genetic basis of the variation among D. simulans stocks, we made reciprocal crosses between a stock that produced fully viable female hybrids with Oregon-R at 25° (v f2) and a second stock (ryi83) that produced lethal female hybrids at 25° and crossed the resulting F1 males to Oregon-R (Table 1B). Female hybrids from both crosses had ~50% viability, suggesting that the difference in hybrid viability between the D. simulans ryi83 and v f2 stocks is caused by an autosomal gene (or genes). This result contrasts with the report of
All D. simulans hybrids were essentially lethal at 29°, with rare escapers being quite sickly (Table 1B). Intriguingly, the one exception occurred in hybrids between Oregon-R and a stock homozygous for the mutation Lhr (
D. mauritiana hybrid females had significantly higher viabilities than D. simulans hybrids. Of four stocks tested, three produced female hybrids with Oregon-R at both 25° and 29° that were 
89% viable (Table 1A). Hybrids from the fourth stock, Iso 197, however, were only 23 and 20% viable at 29° with Oregon-R and Nguruman-4, respectively. Escapers from these crosses had morphological defects similar to those seen in D. simulans hybrid escapers, albeit at a reduced frequency and intensity. At 18° a small number of pharate males were found in some crosses (see Table 1, footnote a). These animals typically had extreme morphological defects including split and malformed nota and greatly reduced eyes. Because patroclinous males (Xmau) are viable (
Female hybrids with D. sechellia had much lower viability than D. mauritiana or D. simulans hybrids (Table 1C). Female hybrids at 25° were essentially lethal with all five D. sechellia stocks tested; rare escapers were severely necrotic. Even at 18° female hybrids between two different stocks (v and Iso 24) and Oregon-R were only 10% viable, and many of the surviving adults had rough eyes.
The data presented in Table 1 are derived from a small number of strains and therefore may not be representative of the range of variability within each species. However, the relative designations of D. mauritiana, D. simulans, and D. sechellia female hybrids as having high, intermediate, and low viabilities, respectively, seems to be a justified generalization. We note the striking observation that these qualitative descriptions for each species are the same for the strength of suppression of hybrid male lethality by Hmr1 (
Suppression of female lethality by Hmr1:
We began our investigation of temperature-sensitive hybrid female lethality after obtaining the unexpected mapping results shown in Table 2. On the basis of its rescue of male hybrids, Hmr was mapped distally to ras (1-32.41) and estimated to be in cytological region 9D1-9E4 (
Suppression by In(1)AB and deficiencies:
In Table 3 we show that In(1)AB also suppressed the lethality of female hybrids with the D. simulans ryi83 stock, by comparing the viability of In(1)AB/Xsim females relative to their FM6/Xsim sisters (Fig 1A). As in Table 1, we have also estimated the viability of In(1)AB/Xsim females by scoring the total number of females that reached pharate adulthood and beyond. At 18° there was little difference in viability between the sibling classes, but at 25° and 29° only In(1)AB/Xsim hybrids survived; they were of normal morphology. We note that a similar cross using Hmr1/FM6 mothers also produced many viable female hybrids at 29°, and these were probably of genotype Hmr1/Xsim, but many had misshapen eyes and, thus, we could not unambiguously distinguish them from their FM6/Xsim (B/B+) siblings (data not shown). Hmr1/Xsim daughters of this cross did appear to be fully viable at 18° and 25° (Table 3).
Because this rescue of hybrid female lethality is dominant, we could determine whether homozygous lethal deletions in the Hmr region have similar rescuing properties. In crosses with 12 different deletions, +/Xsim females generally had similar viabilities relative to Df/Xsim siblings at 18° (Table 3). At 25° and particularly at 29°, however, the crosses fell into two discrete classes, those that included viable Df/Xsim females of normal morphology and lethal +/Xsim siblings and those that produced only occasional highly necrotic escapers of both genotypes (see Fig 2). We define the first class as being Hmr-; these deficiencies all delete cytological region 9D and place Hmr between the distal 9D1 breakpoint of Df(1)ras203, Df(1)B13, and Df(1)ras-v17 and the proximal 9D3-4 breakpoint of Df(1)N110 (Fig 3). The second class of nonrescuing deficiencies does not delete 9D. It is worth mentioning that most of the rescuing deficiencies were generated independently in unrelated screens, including Df(1)ras-v17, which was induced on the balancer chromosome Binsc (
Our results are consistent with previous mapping of Hmr to region 9D1-9E4 (
Quantification of pharate and posteclosion lethality:
The viabilities calculated in Table 3 assumed that Hmr-/Xsim and +/Xsim hybrid females are equally viable up to the pharate adult stage, with +/Xsim hybrids dying at high temperature as adults. To test this assumption, we performed crosses where dead hybrid females could be genotyped readily on the basis of whether they had wild-type (red) or white eyes (Table 4). This allowed us to measure both viability within each sibling class as well as relative viability between classes. In crosses to a D. simulans w strain, very few +/Xsim females survived at 29°, in contrast to their In(1)AB/Xsim or Df(1)N110/Xsim siblings. The majority (83 and 78%, respectively) of the absent +/Xsim hybrids, though, could be found among the dead adults.
Similar results were obtained with D. sechellia hybrids at 25°, where 75% of the relative viability difference was due to pharate adult and posteclosion lethality. At 29°, however, unrescued D. sechellia hybrids suffered from extensive prepharate lethality, as only 23–58% of +/Xsec hybrids reached the pharate adult stage relative to their rescued siblings. In some cases there was also significant lethality within the rescued class. For example, only 27% of the Df(1)N110/Xsec hybrids that reached the pharate adult stage were viable (Table 4C). These data suggest that D. sechellia female hybrids suffer from both Hmr-dependent and Hmr-independent lethality at high temperatures.
All five genotypes shown in Table 4 were crossed to D. mauritiana w males at 18°, 25°, and 29° (data not shown). No significant viability effects were found within or between sibling classes. At 29° the +/Xmau hybrids were 82% viable relative to reference siblings, and the maximum pharate/posteclosion lethality was 24%.
The lethal phase of hybrid females:
Hybrid females die predominantly as pharate adults or after eclosion at high temperatures, but the time of death does not reveal at what stage(s) development is disrupted. We therefore performed reciprocal temperature shifts of unrescued FM6/Xsim D. melanogaster/D. simulans hybrid females and compared their viability relative to Df(1)-N110/Xsim siblings (Fig 4). FM6/Xsim hybrids grown at 18° until approximately the mid-third instar larval stage (L3) and then shifted to 29° had high viability, while cultures shifted before L3 were poorly viable or lethal. There was little apparent difference between siblings in time of development, even in crosses where FM6/Xsim females were poorly viable. Escaper females often had rough eyes and necrotic leg patches, as seen in nontemperature shifted escapers (Fig 2B).
In the reciprocal shift from 29° to 18°, however, FM6/Xsim females were delayed in development by ~1–2 days relative to their Df(1)N110/Xsim siblings. We did not determine the precise phase of this developmental delay, but it was apparent in cultures shifted from 29° at 76 hr after egg laying (AEL), where FM6/Xsim hybrids were fully viable (but often had rough eyes). In cultures shifted from 29° at 96 hr AEL or later, the FM6/Xsim hybrids that eclosed first often had extreme morphological defects, including severely misshapen eyes, missing ocelli, and disarrayed notal microchaetes. Their wings were typically normal in length but reduced in width, with absent or incomplete crossveins (Fig 5B);
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These results suggest that culture at high temperature causes a general delay and disruption of development beginning in L2 or early L3 larvae that can be alleviated by transfer to low temperature, with the severity of lethality and morphological defects depending on how far development proceeds before the temperature shift. Both the general time course of viability and the developmental delay at high temperature are comparable to that observed for Hmr1-dependent rescue of D. melanogaster/D. mauritiana hybrid males (
Comparison of Hmr1, In(1)AB, and deficiencies:
In crosses to the D. simulans ryi83 stock described in Table 2 and Table 3, Hmr1 only weakly suppressed the lethality of female hybrids at 29° (data not shown), but Hmr- deficiencies fully suppressed lethality at 29° (Table 3). In contrast, the crosses with the D. sechellia w stock in Table 4 showed little difference between Hmr1 and deficiencies for high-temperature rescue. These discrepancies could reflect a difference between hybrid rescue in D. simulans and D. sechellia or could merely be a consequence of comparing results from different genetic backgrounds. To determine more directly whether or not rescue by Hmr1 and deletions are equivalent, we compared the viabilities of hybrids heterozygous for Hmr1, In(1)AB, and Hmr- deficiencies as sibling progeny of the same mothers (Table 5; Fig 1B). Hybrids were made with the D. sechellia v stock, which produced poorly viable hybrids with Oregon-R (Table 1). At 25° all pairwise comparisons had similar viabilities. At 29°, Hmr1/Xsec hybrids were ~50% viable compared to Df/Xsec siblings, and many had wing defects (Table 5A and Table 5B). Hmr1/Xsec hybrids were only 9% viable compared to In(1)AB/Xsec siblings; this cross used a different Hmr1 stock than the deficiency-containing crosses (Table 5C). In(1)AB/Xsec and Df(1)v-L11/Xsec hybrids were equally viable at 29°.
We conclude that Hmr1 is a somewhat weaker dominant suppressor of hybrid female lethality than In(1)AB or deficiencies. It is important to note, however, that the partial rescue by Hmr1 of D. melanogaster/D. sechellia female hybrids at 29° stands in marked contrast to its rescue of D. sechellia hybrid males, which is low at 18° and absent at higher temperatures (
Dominant rescue of exceptional female hybrids:
D. mauritiana and D. simulans hybrid females carrying two Xmel chromosomes are lethal (
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We constructed marked-Y stocks with In(1)AB/FM7, Df(1)ras203/FM7, and Df(1)N110/FM4 (see Table 6 for complete genotypes). Because Df(1)ras-v17 is present on the balancer chromosome Binsc, we constructed a marked-Y stock with Df(1)ras-v17 and the normal sequence X chromosome y v f. Control crosses with D. melanogaster males demonstrated the success of this technique in generating exceptional progeny. The In(1)AB, Df(1)ras203, and Df(1)ras-v17 marked-Y stocks produced exceptional females at between 57 and 72% the rate of nonexceptional In(1)AB/+ or Df/+ siblings (Table 6A, Table 6C, and Table 6D), while exceptional females from the Df(1)N110 stock were twice as frequent as nonexceptional siblings (Table 6B). Because these frequencies varied among the different stocks, the viabilities of exceptional female hybrids relative to regular siblings must be evaluated in comparison to the intraspecific control for each cross.
One caveat in the interpretation of these crosses is that Ymel or its markers might have effects on hybrid viability unrelated to Hmr. The Dp(1;Y)Bs chromosome present in crosses with Df(1)N110/FM4 could be scored in all progeny (Table 6B). Hybrid females with this Ymel were 65% viable relative to siblings without it (e.g., 106 Df(1)N110/FM4/Dp(1;Y)Bs vs. 162 Df(1)N110/FM4, in the cross to D. simulans v f2 at 18°); the high viability of exceptional Xsib/Ymel sons also suggests that this marked Y chromosome did not have significant viability effects. Dp(1;Y), y+ and especially Dp(1;Y), y+ v+ present in the Df(1)ras-v17/y v f stock (Table 6D) did appear to reduce Xsib/Ymel viability compared to the intraspecific controls, presumably due to the duplicated material. Such effects should be less severe in females (because of the absence of dosage compensation), and only one-half of the nonexceptional females will carry Ymel; nonetheless, any Ymel-induced viability reduction of these females would increase inappropriately the relative viabilities calculated for exceptional females.
The partial rescue of In(1)AB/FM7 D. mauritiana female hybrids at 18° confirms the discovery of
All three deficiencies also produced exceptional female hybrids with D. mauritiana; in some cases relative viability again approached that seen in intraspecific controls. The relative viability of exceptional females could not be precisely measured in crosses with Df(1)N110/FM4/Dp(1;Y)Bs (see Table 6, footnote a), but we believe the higher estimated limits shown in Table 6B for D. mauritiana hybrids are more accurate for two reasons: first, the nonexceptional hybrids are likely to be half Df(1)N110/Xmau and half FM4/Xmau on the basis of results with other deficiencies in Table 6 and other results described above, and second, the higher estimates are more consistent with the number of exceptional males observed.
Several unexpected features concerning rescue of exceptional D. simulans female hybrids deserve comment. First, viability at 25° was always similar to or even higher than viability at 18°, which is the opposite temperature profile consistently observed for nonexceptional Xmel/Xsib hybrids throughout this study. This phenomenon is most clearly demonstrated in the cross of Df(1)ras203/FM7/Dp(1;Y), y+ to D. simulans ryi83 males (Table 6C). The exceptional Df(1)ras203/FM7 females were not only significantly more viable at 25° than at 18°, but they were also more viable than their nonexceptional FM7/Xsim sisters. The same appeared to be true for hybrids between Df(1)N110/FM4 and D. simulans ryi83 (Table 6B). For this cross, we suspect that the higher relative viability estimate of exceptional females is more accurate at 18° (29%) and the lower is more accurate at 25° (55%) and 29° (4%), for reasons analogous to those noted above for the D. mauritiana crosses. An independent estimate of viability at 25° was provided by using the ectopic mesopleural hair phenotype associated with the sc8 marker of FM4. This phenotype was 50% penetrant in Df(1)N110/FM4 exceptional females and was observed in 8% of the nonexceptional females, allowing us to estimate that 16% of the Xmel/Xsim females in this cross were FM4/Xsim. We therefore estimate that the 238 total nonexceptional females included 38 (16%) FM4/Xsim and 200 (84%) Df(1)N110/Xsim; the viability of Df(1)N110/FM4 exceptions relative to Df(1)N110/Xsim would then be 65.5% (131/200).
A second intriguing result involves the genetic background difference between the ryi83 and v f2 D. simulans stocks. In these crosses and others (Table 1), the ryi83 stock caused much greater lethality to Xmel/Xsim hybrids at 25° and 29° than the v f2 stock; recall that the apparent variation appeared to be entirely autosomal (Table 1B). Yet both Df(1)N110/FM4 and Df(1)ras203/FM7 exceptional hybrids were more viable at 25° with D. simulans ryi83 than with the v f2 stock. These dissimilar genetic background and temperature effects on Xmel/Xmel vs. Xmel/Xsim hybrids suggest that X-linked factors other than Hmr may influence hybrid viability (see DISCUSSION).
No exceptional female D. sechellia hybrids were recovered at either 18° or 25° with Df(1)N110 (crossed to D. sechellia v and f stocks) or with Df(1)ras203 and Df(1)ras-v17 crossed to the D. sechellia w stock (data not shown). We also generated exceptional females heterozygous for Hmr1 with a stock of y Hmr1 v/FM7/Dp(1;Y), y+. A high frequency of exceptional females was produced in control crosses to D. melanogaster males, but none were observed in crosses to D. mauritiana w or Iso 197 males at either 18° or 25° (data not shown). This negative result is consistent with the data of
Effects of an Hmr+ duplication in female hybrids:
The above results show that Hmr1 and deficiencies in the 9D region are qualitatively equivalent in suppressing hybrid lethality and thus imply that the wild-type Hmr+ product is deleterious to hybrids. We therefore tested whether increasing the dosage of Hmr+ would decrease the viability of hybrids, using the Hmr+ duplication Dp(1;2)v+75d (Table 7).
We used two different stocks to assay the effect of Dp(1;2)v+75d in the presence of an Hmr+ Xmel (diagrammed in Fig 1D). The second stock used (Table 7C) generally produced stronger lethal effects than the first (Table 7B), but qualitatively, the results were similar. At 25°, Dp(1;2)v+75d reduced the viability of D. mauritiana hybrids and, more strongly, that of D. simulans hybrids. D. sechellia female hybrids carrying Dp(1;2)v+75d were lethal at both 18° and 25° (Table 7B).
The one notable exception involved the D. simulans Lhr stock (Table 7B and Table 7C). Dp(1;2)v+75d had no significant effect on female viability in crosses to Lhr males, suggesting that Lhr suppressed the deleterious effect of duplicating Hmr+. The opposite effect was observed in male progeny, where Dp(1;2)v+75d appeared to strongly suppress the rescue activity of Lhr. Duplication-containing sons were 
7% viable relative to nonduplication brothers at all temperatures. These reciprocal effects support a model where the Hmr+ and Lhr+ loci form a pair of interacting genes that causes hybrid lethality (see DISCUSSION).
The distal breakpoint of Dp(1;2)v+63i is at 9E, which is very close to the proximal limit of the Hmr region defined by deficiencies (Fig 3).
Effects of an Hmr+ duplication in male hybrids:
The results described above show that an extra copy of Hmr+ reduces the viability of Xmel/Xsib D. simulans and D. mauritiana hybrid females, but does not cause unconditional lethality. Yet Xmel/Ysib hybrid males, which have an equivalent Hmr+ dosage, are invariably lethal. Does this discrepancy reflect a sex-specific effect of Hmr+, or the fact that hybrid males are hemizygous for all Xmel genes, including Hmr+? One way to address this question is to measure the effect of the Hmr+ duplication on Xsib/Ymel hybrids derived from compound-X D. melanogaster mothers. Assuming that the duplication is fully dosage compensated, these males will have the same dosage of Hmr+ as Xmel hybrid males. In Table 8 we have compared the viability of Xsib/Ymel; Dp(1;2)v+75d, Hmr+/2sib hybrids with their nonduplication-carrying brothers (diagrammed in Fig 1E).
Control crosses with D. melanogaster showed that nonhybrid males heterozygous for Dp(1;2)v+75d have reduced viability; this result was not unexpected considering the large size of the duplication. Xsim/Ymel; Dp(1;2)v+75d/2sim hybrid males showed little reduction in viability at 18° and 25° but were essentially lethal at 29°. Xsec/Ymel; Dp(1;2)v+75d/2sec males were completely lethal at both 18° and 25°; scoring of dead animals showed that most of the lethality must have occurred before the pharate adult stage (Table 8, footnotes d and e). Attempts to make hybrids with a D. mauritiana v stock failed to produce any progeny. The results with D. simulans hybrids in Table 7 and Table 8 show that Hmr+ reduces the viability of both male and female hybrids, but also that unconditional lethality requires hemizygosity of Xmel. While a male-like dosage of Hmr+ appears to be sufficient to kill both male and female D. sechellia hybrids, other results suggest that additional Xmel genes also influence viability (see Dose dependence of Hmr+ in DISCUSSION).
Dominant effects of Hmr+ in hybrids from D. simulans mothers:
The reciprocal cross of D. simulans females to D. melanogaster males produces viable sons but poorly viable daughters. The lethality of these female hybrids is embryonic and can be rescued by the D. melanogaster mutation Zhr and the D. simulans mutation mhr, but not by Hmr1. These rescued hybrids are also sensitive to pupal and posteclosion lethality at 23°, but not at 18° (
The viability of female hybrids from D. simulans mothers is highly dependent on genetic background variation (
A second crossing scheme (Table 9B) used a homozygous viable w+ P element inserted in 9E to distinguish Hmr+ from Hmr1 males. Female viability was lower than in scheme A and there was also substantial variation among different cultures of identical genotypes. For example, female viability in crosses from Hmr1 fathers ranged from 3 to 10% at 25°. As in scheme A, however, temperature-dependent late lethality of female hybrids was observed and only in female progeny of Hmr+ sons. At 25° these hybrids were essentially lethal with ~12% of the females dying as pharate adults or posteclosion (Table 9B, footnotes e and f).
Effects of Hmr- deletions:
We also assayed two Hmr- deficiencies for their ability to suppress late lethality in daughters of mhr mothers. Xsim/Df(1)Hmr-; 2sim/2mel females were compared with their Xsim/Df(1)Hmr-; 2sim/Dp(1;2)v+75d, Hmr+ siblings (Table 10, diagrammed in Fig 1G). At 25°, Xsim/Df(1)N110; 2sim/Dp(1;2)v+75d females were lethal, while Xsim/Df(1)HC133; 2sim/Dp(1;2)v+75d females were nearly lethal at 29° and had reduced viability at 25° compared to their nonduplication siblings. Although dead animals were not genotyped for whether or not they carried the duplication, the number of dead females in each cross was in approximate correspondence to the expected number of missing Xsim/Df(1)Hmr-; 2sim/Dp(1;2)v+75d females. In combination with the data in Table 9, the results of Table 10 suggest that Hmr1 and Hmr- deficiencies are dominant suppressors of late lethality in female hybrids of D. simulans mothers and D. melanogaster fathers.
Xsim/Ymel; 2sim/Dp(1;2)v+75d sons of mhr mothers also were less viable than their nonduplication brothers at 25°, with the number of dead animals again suggesting that the missing duplication-carrying males were dying after the pupal stage (Table 10). Together with the results of Table 8, these data suggest that Xsib males are sensitive to Hmr+ dosage, regardless of the direction of crossing. Deleterious effects of Dp(1;2)v+75d on hybrid male viability have also been observed independently by H. A. ORR and S. IRVING (personal communication).
| DISCUSSION |
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| TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Temperature-sensitive pupal lethality in hybrids:
Hybrid Xmel sons and Xmel/Xmel daughters of D. melanogaster mothers die as larvae or pseudopupae (
We quantified female viability in hybrids between D. melanogaster and its three sibling species at three temperatures (Table 1). D. mauritiana hybrids had the highest viability, followed by D. simulans and finally by D. sechellia hybrids, which were not fully viable even at 18°. The genetic basis of these species-specific differences in hybrid viability is unknown. Although F1 hybrid males of the sibling species are sterile, interspecific heterozygous introgressions created by repeated backcrossing of hybrid females are often male fertile (
Even with the small number of strains sampled, there was substantial variation in hybrid lethality among different stocks of each species, as observed in previous studies of D. melanogaster/D. simulans hybrids (
The substantial genetic background variation observed can complicate the analysis of hybrid viability to the point where meaningful conclusions about particular genotypes cannot be easily reached from any single cross. On a more positive note, however, understanding the evolutionary forces responsible for the origin and maintenance of this type of variation is relevant to understanding the process of speciation. Several other studies have identified intraspecific variation for traits that cause hybrid breakdown and reproductive isolation.
The wild-type Hmr+ causes hybrid lethality:
One important question raised by the discovery of rescue alleles such as Lhr and Hmr1 is whether the wild-type allele of the rescue gene causes hybrid lethality. Addressing this requires the ability to manipulate the wild-type gene in hybrids. We have done so for Hmr and found that Hmr- deficiencies and an Hmr+ duplication have reciprocal effects on hybrid viability. The qualitatively similar activities of Hmr1 and Hmr- deficiencies further suggest that Hmr1 rescues hybrids by reducing the level of Hmr+, as proposed by
Two previous studies failed to detect any effect on hybrid female viability of deletions that we have defined here as being Hmr-. This discrepancy probably reflects the fact that viability was assayed under conditions less stringent than used in this study:
On the basis of his pioneering analysis of D. melanogaster/D. simulans hybrids,
These predictions are in contrast to our suggestion that the activity of Hmr+ causes hybrid lethality and that reducing its function is sufficient to rescue hybrids. The most direct demonstration of this point is that simply removing one copy of Hmr+ partially rescued exceptional Xmel/Xmel female hybrids (Table 6)—Xsib is clearly not absolutely required for hybrid viability. The rescue of hybrid males by Lhr, Hmr1, and In(1)AB first suggested that Xsib is not required for hybrid viability, but was subject to the reservation that the precise nature of these alleles is unknown. Although it remains possible that Xsib may have some positive effect on hybrid viability (see Dose dependence of Hmr below), in accordance with Sturtevant's second hypothesis, our results strongly support a third, alternative hypothesis that hybrid lethality results from the presence of Xmel and, more specifically, Hmr+.
Are larval and pupal lethality caused by the same mechanism?
If we wish to use the temperature-sensitive pupal lethality of hybrid females as a new assay for investigating Hmr, it is important to consider whether this lethality is caused by the same mechanism that causes larval lethality.
The strongest available evidence that larval and pupal lethality are caused by the same mechanism is that both are suppressed by the rescue mutations Hmr1, In(1)AB, and Lhr. Using similar logic,
However, the patterns of conditional variability for larval and pupal lethality are not entirely equivalent. First, larval lethality was more severe with the D. simulans v f2 stock than with the ryi83 stock, while the opposite was true for pupal lethality (Table 1 and Table 6; note that larval lethality here refers to that found in Xmel/Xmel exceptional females). Second, pupal lethality is clearly temperature sensitive, with little or no lethality detected at 18° and increasing lethality at higher temperatures. Larval lethality, however, appears to be temperature insensitive (below 29°) or even somewhat cold sensitive. Rescue was generally equivalent or lower at 18° than at 25° for In(1)AB males (Table 3; see also
Unknown gene(s) on the X chromosome are probably responsible for these differences between larval and pupal lethality, since the autosomal component is identical in all classes of hybrids, but whether Xmel, Xsib, or both are involved is unknown. Our interpretation of the possible role of Xsib differs from
Hmr+ causes lethality in both directions of crossing:
Hybrid daughters of sibling mothers that are rescued from embryonic lethality die as pupae or young adults if cultured at high temperature (
Has Hmr diverged in the melanogaster complex?
It is important to emphasize that none of the available data prove that the different effects of Xmel and Xsib in hybrids are caused by species-specific differences at the Hmr locus itself. An alternative possibility, first raised by
Modeling hybrid viability:
Our conclusions regarding the relationship between Hmr+ dosage and hybrid viability rest on several assumptions. First, we assume that the effects of Hmr1, Dp(1;2)v+75d, and the deficiencies defined as Hmr- (Fig 3) reflect the activity of a single gene in region 9D. Although we will discuss the rescue activity of the In(1)AB chromosome in comparison to Hmr1, there is no evidence that they are in fact allelic. We do know that neither breakpoint of In(1)AB (9E7-8; 13E1-2) is itself likely to cause hybrid rescue. The distal breakpoint of In(1)AB is very close to the genes sesB/Ant2 (
A second caveat is that Dp(1;2)v+75d is the only Hmr+ duplication available. Our model assumes that it contains full Hmr+ activity and is fully dosage compensated in hybrid males.
Our final assumption, that the viability differences between male and female hybrids are due to their different composition of sex chromosomes, and not their sexual phenotype per se, is supported by several findings.
It remains possible, however, that sexual phenotype may have some influence on hybrid viability.
Dose dependence of Hmr+:
In Table 11 we have summarized the range of viabilities observed in different genotypes of D. melanogaster/D. simulans hybrids. The ordering of genotypes (other than those involving Lhr) can also generally be applied to hybrids with D. mauritiana and D. sechellia, provided that one shifts the viability designations upward and downward, respectively. This observation suggests that the same general mechanism of lethality exists in all three species hybrids, with uncharacterized species-specific modifiers affecting the penetrance of lethality.
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Complete lethality of hybrids requires two conditions: two doses of D. melanogaster Hmr+ and two "doses" of Xmel. Full viability, in turn, requires either a strong reduction in or removal of one of these conditions. The ranking in Table 11 of intermediate cases such as Xmel/Xsim females is somewhat problematic because their viability tended to be highly variable, depending on genetic background and temperature.
It is clear, however, that two doses of Hmr+ are not sufficient to account fully for the unconditional lethality of Xmel/Ysib and Xmel/Xmel/Ysib hybrids because hybrids carrying Dp(1;2)v+75d were not invariably lethal (Table 7 and Table 8) and exceptional females heterozygous for Hmr- deficiencies were not fully rescued (Table 6), even at low temperatures where pupal lethality is not observed. The "remaining" lethality must result from the activity of additional dosage-sensitive deleterious gene(s) on Xmel, the loss of activity of essential Xmel genes (and thus the absence of Xsib), or both. A positive effect on hybrid viability of the wild-type Hmrsib is one possible explanation of the hypothetical Xsib effect. Whatever the mechanism of these additional hypothetical X-linked alleles may be, their effects on hybrid viability are difficult to predict, other than to suggest that they are likely to be synergistic with Hmr+. Since at present we can detect their phenotypic effects only in the context of manipulating the entire X, it seems premature to make any detailed mechanistic speculations.
Recall that while Dp(1;2)v+75d-induced lethality was fully penetrant in D. sechellia hybrids, no rescue was observed in the exceptional female assay (see RESULTS). These data suggest that while two doses of Hmr+ are sufficient to cause complete lethality, even in the absence of Xmel, the effects of the additional Xmel genes proposed above can also be observed in D. sechellia hybrids.
Hmr1 retains 50% of the activity of Hmr+:
The direct comparison of Hmr1 and deficiencies for dominant rescue in Xmel/Xsec hybrid females (Table 5) suggests that Hmr1 is a hypomorphic mutation, as proposed by 50% of the function of Hmr+.
Using similar arguments, In(1)AB is a stronger loss-of-function allele than Hmr1. In(1)AB rescues male hybrids better than does Hmr1 (Table 3;
Hmr and Lhr interact:
The Dobzhansky/Muller model of hybrid lethality and sterility states that hybrid incompatibilities must be caused by a minimum of two interacting genes, one from each species. The second chromosome D. simulans Lhr allele rescues hybrid males and has been proposed to correspond to a gene that interacts with Hmr to cause hybrid lethality (
These data from partial hybrids suggest that hybrid lethality may result from an interaction involving (at least) three loci, and furthermore, that removing any one of the three causal alleles is sufficient to suppress lethality. A study using interspecific introgression between D. buzzatii and D. koepferae has also found evidence for a system of hybrid lethality involving three loci (
How many genes cause hybrid lethality?
We have discussed three lines of evidence that suggest that additional unknown gene(s) on both the X and third chromosomes contribute to larval and pupal hybrid lethality: (1) the existence of distinct systems of variation that modify larval and pupal lethality; (2) the incomplete penetrance of lethality and rescue associated with an Hmr+ duplication and Hmr- deficiencies, respectively; and (3) data from experiments with partial hybrids. Two reports have recently surveyed the literature of hybrid genetics and concluded that hybrid inviability in D. melanogaster (and in other Drosophila as well) is likely to be caused by a relatively small number of genes (
The only systematic search for inviability genes in D. melanogaster hybrids is that of
The screen of
Hmr and Haldane's rule:
A widespread pattern of hybrid breakdown is described by Haldane's rule.
Haldane's rule for hybrid lethality appears to be best explained by the X:A imbalance of hybrid males (
A model dubbed the "dominance theory" has been developed to quantify the conditions under which X:A imbalances will lead to Haldane's rule (
The genetic properties of Hmr are consistent with both the X:A imbalance model and the dominance theory. We emphasize, however, that our data suggest that female viability is not due to the heterospecific X "preventing" or "masking" the deleterious effect of Hmr+, as recessive hybrid lethals are often described (
We also note that while the fitness effects of Hmr+ can be described accurately as recessive at low temperatures, where Haldane's rule holds, Hmr+ is a dominant lethal at high temperatures. The conditional nature of dominance properties with respect to genetic background and environmental variation is not unexpected in hybrids (
Like the results presented here, the hybrid lethality effects reported by
Implications of Hmr-like effects:
Considering the limited data available from other species, the potential generality of conclusions drawn from the study of Hmr and D. melanogaster hybrids is unknown. But it is instructive to consider the implications if other examples of hybrid lethality are caused by similar alleles of large effect. Surveys of the literature on hybrid breakdown suggest that examples of Haldane's rule for inviability are infrequent (in male-heterogametic species), compared to examples of hybrid sterility (
| ACKNOWLEDGMENTS |
|---|
We thank the Drosophila Species Center, the Bloomington and Umeå stock centers, and Jerry Coyne for fly stocks. We gratefully acknowledge Ben Yudkin for preliminary experiments done as a Part II Genetics student and Terri Morley and Glynnis Johnson for technical assistance. We thank Allen Orr for sharing unpublished data and Andrew Davis, Pierre Hutter, Allen Orr, Kyoichi Sawamura, and Michael Turelli for helpful comments on the manuscript. We were supported by a grant from the UK Medical Research Council to M.A., D. Gubb, and S. R. H. Russell and a National Science Foundation and Alfred P. Sloan Foundation Fellowship to D.A.B.
Manuscript received September 20, 1999; Accepted for publication December 29, 1999.
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