Segregation Distorter System Research Articles

Overdrive is essential for targeted sperm elimination by Segregation Distorter.

Intra-genomic conflict driven by selfish chromosomes is a powerful force that shapes the evolution of genomes and species. In the male germline, many selfish chromosomes bias transmission in their own favor by eliminating spermatids bearing the competing homologous chromosomes. However, the mechanisms of targeted gamete elimination remain mysterious. Here, we show that Overdrive (Ovd) , a gene required for both segregation distortion and male sterility in Drosophila pseudoobscura hybrids, is broadly conserved in Dipteran insects but dispensable for viability and fertility. In D. melanogaster, Ovd is required for targeted Responder spermatid elimination after the histone-to-protamine transition in the classical Segregation Distorter system. We propose that Ovd functions as a general spermatid quality checkpoint that is hijacked by independent selfish chromosomes to eliminate competing gametes.

Origin, evolution, and population genetics of the selfish Segregation Distorter gene duplication in European and African populations of Drosophila melanogaster.

Meiotic drive elements are a special class of evolutionarily "selfish genes" that subvert Mendelian segregation to gain preferential transmission at the expense of homologous loci. Many drive elements appear to be maintained in populations as stable polymorphisms, their equilibrium frequencies determined by the balance between drive (increasing frequency) and selection (decreasing frequency). Here we show that a classic, seemingly balanced, drive system is instead characterized by frequent evolutionary turnover giving rise to dynamic, rather than stable, equilibrium frequencies. The autosomal Segregation Distorter (SD) system of the fruit fly Drosophila melanogaster is a selfish coadapted meiotic drive gene complex in which the major driver corresponds to a partial duplication of the gene Ran-GTPase activating protein (RanGAP). SD chromosomes segregate at similar, low frequencies of 1-5% in natural populations worldwide, consistent with a balanced polymorphism. Surprisingly, our population genetic analyses reveal evidence for parallel, independent selective sweeps of different SD chromosomes in populations on different continents. These findings suggest that, rather than persisting at a single stable equilibrium, SD chromosomes turn over frequently within populations.

Birth, Death, and Replacement of Karyopherins in Drosophila

Nucleocytoplasmic transport is a broadly conserved process across eukaryotes. Despite its essential function and conserved mechanism, components of the nuclear transport apparatus have been implicated in genetic conflicts in Drosophila, especially in the male germ line. The best understood case is represented by a truncated RanGAP gene duplication that is part of the segregation distorter system in Drosophila melanogaster. Consistent with the hypothesis that the nuclear transport pathway is at the heart of mediating genetic conflicts, both nucleoporins and directionality imposing components of nuclear transport have previously been shown to evolve under positive selection. Here, we present a comprehensive phylogenomic analysis of importins (karyopherins) in Drosophila evolution. Importins are adaptor molecules that physically mediate the transport of cargo molecules and comprise the third component of the nuclear transport apparatus. We find that importins have been repeatedly gained and lost throughout various stages of Drosophila evolution, including two intriguing examples of an apparently coincident loss and gain of nonorthologous and noncanonical importin-α. Although there are a few signatures of episodic positive selection, genetic innovation in importin evolution is more evident in patterns of recurrent gene birth and loss specifically for function in Drosophila testes, which is consistent with their role in supporting host genomes defense against segregation distortion.

Defects in nuclear transport enhance Segregation Distortion

The Segregation Distorter (SD) system in Drosophila melanogaster causes the transmission of the SD chromosome at the expense of the SD+ chromosome. This occurs through a defect in sperm-specific chromatin condensation of the SD+-bearing spermatids of the SD/SD+ male. The Sd gene encodes a truncated form of RanGAP that is missing a nuclear export signal and is therefore trapped in the nucleus; normally RanGAP is found at the periphery of the nuclear membrane and is required for normal Ran-mediated nuclear transport. The presence of active RanGAP in the nucleus interferes with nuclear export and causes distortion. We show that mutations that affect nuclear import and export can enhance distortion in an SD background, thus verifying that the defect in nuclear transport is responsible for the unequal transmission of chromosomes. In addition, we identify several genes involved in chromatin condensation which also cause distortion in an SD background, opening the way to the dissection of the mechanism of segregation distortion.

Does genetic conflict drive rapid molecular evolution of nuclear transport genes in Drosophila?

The Segregation Distorter (SD) system of Drosophila melanogaster is one the best-characterized meiotic drive complexes known. SD gains an unfair transmission advantage through heterozygous SD/SD(+) males by incapacitating SD(+)-bearing spermatids so that virtually all progeny inherit SD. Segregation distorter (Sd), the primary distorting locus in the SD complex, is a truncated duplication of the RanGAP gene, a major regulator of the small GTPase Ran, which has several functions including the maintenance of the nucleocytoplasmic RanGTP concentration gradient that mediates nuclear transport. The truncated Sd-RanGAP protein is enzymatically active but mislocalizes to the nucleus where it somehow causes distortion. Here I present data consistent with the idea that wild-type RanGAP, and possibly other loci able to influence the RanGTP gradient, has been caught up in an ancient genetic conflict that predates the SD complex. The legacy of this conflict could include the unexpectedly rapid evolution of nuclear transport-related proteins, the accumulation of chromosomal inversions, the recruitment of gene duplications, and the turnover of repetitive sequences in the centric heterochromatin.

Responder (Rsp) alleles in the segregation distorter (SD) system of meiotic drive in Drosophila may represent a complex family of satellite repeat sequences.

In D. melanogaster males carrying Segregation Distorter (SD) second chromosomes, sperm receiving sensitive alleles of the Responder (Rsp) locus are subject to high rates of dysfunction. The Rsp region is located in 2R immediately adjacent to the centromere in heterochromatic band 39, and covers roughly 600 kb of material, of which approximately 85 kb is comprised of several hundred copies of a 240-bp satellite DNA sequence. Cytological observations as well as molecular analysis of rearrangements which bisect h39 indicate that sensitivity of the Rsp target to SD action is also subdivisible, and sensitivities of the component pieces appear to be correlated with copy number of the 240 bp repeat. In an attempt to examine possible higher order sequence structure for these blocks, PCR using single primers derived from a canonical repeat was used to identify potential reversals of direction of tandem arrays; that is, head-to-head or tail-to-tail junctions. Surprisingly, for two different Rsp alleles, only a single such reversal product for each was identified, differing in size and sequence between alleles. Sequencing of PCR products identified diverged copies of the canonical repeats that would not have been found using the levels of DNA stringency employed in earlier studies. Examination of Southern digests and slot-blots for DNA quantification indicates that adding the estimated numbers of such diverged copies to the canonical repeat copies discovered earlier is potentially sufficient to account for the entire 600 kb Rsp region. This adds strength to the hypothesis that this extended family of repeats is in fact the target of SD-mediated sperm dysfunction. Implications of these results for understanding the evolution of repetitive DNA are also discussed.

Meiotic drive in female mice: an essay.

Since the rediscovery of Mendel's laws, geneticists have accumulated various examples in which equal meiotic segregation in heterozygotes is violated. However, only a few natural meiotic drive systems have been characterized in detail and the majority of these are sex chromosome linked (Hurst and Pomiankovski 1991a). In animals, only two autosomal meiotic drive systems have been thoroughly investigated: the t complex in Mus musculus (Lyon 1991; Silver 1993) and the Segregation Distorter system (SD) in Drosophila melanogaster (Lyttle 1991). Both affect heterozygous males. Recently Agulnik and associates (1990a, 1993c, 1993d) have found and described a new meiotic drive system that disturbs normal segregation in heterozygous female mice. The system is the main target of this review, which also includes a comparative analysis of other drive systems to establish a likely scenario of their origin, evolution, and stability in natural populations.

The evolution of lethals in the t-haplotype system of the mouse.

The evolution of lethal haplotypes in the t-haplotype segregation distortion system of Mus is examined by mathematical and computer models. The models assume that there is reproductive compensation for the loss of lethal embryos, such that the net reproductive success of a females is not reduced in proportion to the frequency of lethal offspring which she produces. The initial population consists of a mixture of wild-type and homozygous male-sterile t-haplotypes. The failure of sterile males to reproduce may cause a higher fitness cost to mothers heterozygous for t-haplotypes than does elimination of a recessive lethal. Under certain conditions, a recessive lethal will spread and come to a polymorphic equilibrium. Wild-type, lethal and non-lethal haplotypes are all present at this equilibrium. If a second lethal mutation arises on a non-lethal t-haplotype in such an equilibrium population, it will increase in frequency and eventually displace the non-lethal t-haplotypes. A third lethal t-haplotype introduced at a low frequency into an equilibrium with two lethals can sometimes be selected for, although this is less likely if compensation is strong. The theoretical predictions are compared with data on natural populations.

Chromosome rearrangement patterns of an SD chromosome (SDKona-2) in Drosophila melanogaster caused by hybrid dysgenesis.

The types and frequencies of spontaneous chromosome rearrangements caused by hybrid dysgenesis were studied in a second chromosome autosome of Drosophila melanogaster. This second chromosome, being an SD chromosome, had two important advantages over other autosomes for this study: (i) it had the two inversions characteristic of a standard SD-72 chromosome type, which distinguished it from its homolog in polytene chromosome spreads, and (ii) because of the meiotic drive associated with the segregation distorter system, it was preferentially transmitted to the next generation. The chromosome mutation frequency of this chromosome (given the name SDKona-2) was 8.3 and 11.7% in the F2 and F3 generations, respectively. The types of new chromosome rearrangements observed in the first four generations included paracentric inversions, pericentric inversions, duplications, deletions, reciprocal translocations (involving the third chromosome), and transpositions. Small paracentric inversions were the most common type of new rearrangement. Later, over 35 generations, some of these new rearrangements changed, either by becoming more complex or by being replaced with yet another new chromosome rearrangement. Duplications were unstable and were replaced by paracentric inversions whose breakpoints were on either side of the duplication. Transpositions arose both from a single multibreak event and from a series of two-break events.

Why is mendelian segregation so exact?

The precise 1:1 segregation of Mendelian heredity is ordinarily taken for granted, yet there are numerous examples of 'cheating' genes that perpetuate themselves in the population by biasing the Mendelian process in their favor. One example is the Segregation Distortion system of Drosophila melanogaster, in which the distorting gene causes its homologous chromosome to produce a nonfunctional sperm. This system depends on three closely linked components, whose molecular basis is beginning to be understood. The system is characterized by numerous modifiers changing the degree of distortion. Mathematical theory shows that unlinked modifiers that change the degree of distortion in the direction of Mendelism always increase in the population. This provides a mechanism for removing cheaters and preserving the honesty of the Mendelian gene-shuffle.

Transposition of the Responder element (Rsp) of the Segregation distorter system (SD) to the X chromosome in Drosophila melanogaster.

In order to test whether the meiotic drive system Segregation distorter (SD) can operate on the X chromosome to exclude it from functional sperm, we have transposed the Responder locus (Rsp) to this element. This was accomplished by inducing detachments of a compound-X chromosome in females carrying a Y chromosome bearing a Rsps allele. Six Responder-sensitive-bearing X chromosomes, with kappa values ranging from 0.90 to 1.00, were established as permanent lines. Two of these have been characterized more extensively with respect to various parameters affecting meiotic drive. SD males with a Responder-sensitive X chromosome produce almost exclusively male embryos, while those with a Rsp-Y chromosome produce almost exclusively female embryos. This provides a genetic system of great potential utility for the study of early sex-specific differentiation events as it allows the collection of large numbers of embryos of a given sex.

The effect of novel chromosome position and variable dose on the genetic behavior of the Responder (Rsp) element of the Segregation distorter (SD) system of Drosophila melanogaster.

In the Segregation distorter (SD) system of meiotic drive, a minimum of two trans-acting elements [Sd and E(SD)] act in concert to cause a certain probability of dysfunction for sperm carrying a sensitive allele at the Responder (Rsp) target locus. By employing a number of insertional translocations of autosomal material into the long arm of the Y chromosome, Rsp can be mapped as the most proximal locus in the 2R heterochromatin as defined both by cytology and lethal complementation tests. Several of these insertional translocations result in the transposition of Rsp to the Y chromosome, where its sensitivity remains virtually unaltered. This argues that Rsp is separable from the second chromosome centromere, that its behavior does not depend on its gross chromosomal position, and that meiotic pairing of the chromosomes carrying the various SD elements is not a prerequisite for sperm dysfunction. Several other translocations apparently leave both resulting chromosomes at least partially sensitive to SD action, suggesting that Rsp is a large subdivisible genetic element. This view is compatible with observations published elsewhere that suggest that Rsp is a cytologically large region of highly repetitive AT-rich DNA. The availability of Y-linked copies of Rsp also allows the construction of SD males carrying two independently segregating Rsp alleles; this in turn allows the production of sperm with zero, one or two Rsp copies from the same male. Examination of the relative recovery proportions of progeny arising from these gametes suggests that sperm with two Rsp copies survive at much lower frequencies than would be predicted if each Rsp acted independently in causing sperm dysfunction. Possible explanations for such behavior are discussed.

INTERACTION IN TRANSMISSION FREQUENCY BETWEEN THE SECOND AND THE THIRD CHROMOSOMES IN DROSOPHILA MELANOGASTER

Wild second and third chromosomes from isofemale lines established from wild-inseminated females captured in natural populations of Drosophila melanogaster in Hawaii, New York, North Carolina and Texas were made heterozygous in males with marked second and third chromosomes from a laboratory strain, and the transmission frequencies of the wild second (= k( 2)) and the third (= k(3)) chromosomes from the heterozygous male parents were measured. Based upon the preliminary tests of k( 2), the isofemale lines were classified into two groups; group A included those lines showing average k(2) values considerably smaller than the Mendelian expectation of 0.5, and group B included those lines showing average k(2) values close to 0.5. Effects of the wild second chromosomes on k(2) in group A were suppressed (the average k(2) values increased) by the presence of the wild third chromosomes, whereas the wild second chromosomes in this group, in turn, caused a decrease in k(3) of the wild third chromosomes. The intensities of the observed effects were more or less comparable in their absolute values, and these phenomena do not appear to be due to differential viabilities of zygotes. No such interaction was observed between the wild second and third chromosomes in group B. An extention of the model of the Segregation Distorter system of D. melanogaster, as well as a model based upon the P-M system of hybrid dysgenesis, may explain the observed results.

"SEX-RATIO" TRAIT, SEX COMPOSITION, AND RELATIVE ABUNDANCE IN DROSOPHILA PSEUDOOBSCURA.

A considerable number of theoretical and laboratory studies of segregation distortion systems have provided insight into their biological consequences (see Zimmering et al. [1970], or Crow [1979] for a review). Yet these studies have provided few clues into the behavior of such systems in natural populations. Sex-ratio trait (SR) is particularly interesting, not only as a naturally occurring segregation distortion system, but also for its effects on the proportion of females in the offspring of SR males and the consequent effects on the sex composition of the population and on population growth. The trait in Drosophila pseudoobscura is associated with three non-overlapping inversions of the X-chromosome. Males carrying SR produce progenies consisting almost entirely of females. The presence of SR in a female, whether heterozygous or homozygous, has no effect on the sex composition of her progeny. The system is a widely occurring polymorphism in natural populations of D. pseudoobscura, reaching gene frequencies as high as 0.3 near the boundary of Arizona and Mexico. Its frequency declines both with increasing altitude and latitude, and it disappears at about the latitude of northern California (Sturtevant and Dobzhansky, 1936). The frequency of SR exhibits wide seasonal fluctuations in some localities (Dobzhansky, 1943), but aside from this seasonal cycle, it was found to be stable over a period of 20 years (Dobzhansky, 1958). Although SR is apparently held in equilibrium in many natural populations, in population cages it rapidly declines in frequency (Wallace, 1948; Anderson, 1974). In Wallace's experimental populations, SR was rapidly eliminated from the 25 C cages and dropped below a frequency of 0.1 in the cages maintained at 16.5 C. These results appear to conflict with the observations on natural populations: SR is present at higher temperatures (low altitudes and latitudes) and absent in regions characterized by lower temperatures. In this study, we analyze the relationships among temperature, the frequency of the SR trait, the frequency of females, and the frequency of Drosophila pseudoobscura in a mixed species Drosophila population studied for several years in Southern California.

Evidence for two regions in the mouse t complex controlling transmission ratios.

SUMMARYFour newthaplotypes,tTu1throughtTu4, are described, three of them derived from thetw12tfhaplotype and one (tTu4) from thetw2haplotype. ThetTu1andtTu4haplotypes cause taillessness inT/tTu1orT/tTu4heterozygotes, lack the lethality factor, weakly suppress recombination in theT−H−2interval, and are transmitted to offspring fromtTu/+ males at nearly Mendelian ratios. ThetTu3haplotype resemblestTu1andtTu4except for the fact that theT/tTu3heterozygotes have normal-length tails. ThetTu2haplotype probably carries the lethal factor oftTu12tf, suppresses crossing-over in theT-H-2andtf-H-2intervals, and displays a slightly subnormal transmission ratio. In the compound heterozygotetTu1/tTu2, the male transmission ratio of thetTu1chromosome is close to that of the originaltTu12tfhaplotype. A similar effect is observed in thetTu3/tTu2heterozygote. This observation is interpreted as evidence for two regions within thetcomplex controlling the male transmission ratios. One of the regions is close to the tail-modifying region, the other is close to the lethality factor. Our findings parallel closely those made in the segregation distorter system inDrosophila.

A MODIFIED MODEL OF SEGREGATION DISTORTION IN DROSOPHILA MELANOGASTER

Elements of the Segregation Distorter (SD) system of Drosophila melanogaster, Sd and Rsp, were analyzed and the following points were established: (1) The model of multiple alleles at the Rsp(s) locus proposed by Martin and Hiraizumi (1979) is supported by our observations. (2) A modifier of SD, tentatively symbolized M(SD), was found close to cn (2R-57.5). (3) Sd heterozygous males were found to show, under certain genotypic condition, almost complete sterility.-Based upon these observations, the following modified model of segregation distortion is proposed: (1) The M(SD) locus produces a multimeric repressor protein that binds to the Rsp locus as a necessary condition for normal spermiogenesis. M(SD) homozygotes produce a repressor M(SD)/M(SD); whereas, a homozygote for its normal allele M(+)(SD) produces a M(+)(SD)/M(+)(SD) repressor. M(SD)/M(+)(SD) heterzygotes produce a M(SD)/M(+)(SD) repressor. (2) The Sd locus produces a certain product that, like an inducer in the lactose system of E. coli, tends to bind with the repressor complexed with the Rsp locus. This binding disrupts the repressor-Rsp complex, causing Rsp locus to be turned on. The product of Rsp transcription, in turn, results in sperm dysfunction. (3) Rsp(i), an allele of Rsp, has a strong complexing affinity with the repressor such that the Rsp(i)-repressor complex is "resistant" to the inducing activity of Sd product. Rsp(s), on the other hand, has a weaker complexing affinity than that of Rsp(i), and the degree of affinity varies among different Rsp(s) alleles.-A possible extension of the above model is discussed.

ON THE MODELS OF SEGREGATION DISTORTION IN DROSOPHILA MELANOGASTER

The Segregation Distorter system of Drosophila melanogaster consists of two major elements, Sd and Rsp. There are two allelic alternatives of Rsp-sensitive (Rsp(s)) and insensitive (Rsp(i)); a chromosome carrying Rsp(i) is not distorted. According to the model proposed by Hartl (1973), these two elements interact to cause segregation distortion. For a sperm to complete the maturation process, it is assumed that the Rsp locus has to be complexed with the product of the Sd locus. This product is assumed to be a multimetric regulatory protein. Three kinds of regulatory multimers may be distinguished: Sd(+)/Sd(+), which is assumed to complex with both Rsp(s) and Rsp(i); Sd(+)/Sd heteromultimers, which complex preferentially with Rsp(i); and Sd/Sd homomultimers, which complex with neither Rsp(s) nor Rsp(i). Most of the regulatory protein in the Sd(+)/Sd heterozygous male is assumed to be the Sd(+)/Sd heteromultimer.--Some modifications of Hartl's model were made by Ganetzky (1977). Rather than the binding of a product of Sd at the Rsp locus being a necessary condition for normal spermigenesis, this binding causes sperm dysfunction. It is assumed that the product of Sd complexes more readily with Rsp(s) than with Rsp(i) and that the amount of Sd product is limited with respect to the number of binding sites available. No function is ascribed to the Sd(+) locus. In order to explain reduced male fertility of some genotypes, Ganetzky further assumes that the Sd product, when not competed for by an Rsp(s) locus, can bind to an Rsp(i) locus.--Two consequences of these models were critically examined: according to these models (1) an Sd Rsp(s)/Sd(+)Rsp(s) male should not show any segregation distortion, and (2) an Sd Rsp(s)/Sd Rsp(s) male should show much reduced fertility, if not complete sterility.--The results of the present study bear on these two points. (1) Rsp(s) locus seems to consist of multiple alleles, each having a different degree of ability to interact with the product of the Sd locus. An Sd Rsp(s)/Sd(+)Rsp(s) male shows a certain degree of segregation distortion when the two Rsp(s) alleles are different, but it shows a normal Mendelian segregation ratio when the Rsp(s) alleles are homozygous. The first prediction of the models is supported by actual observation when the two Rsp(s) alleles are the same. (2) There is a suggestion of slight reduction in fertility, but generally Sd Rsp(s)/Sd Rsp(s) males are quite fertile. Thus, the second prediction is not supported by actual observation. The mechanism of segregation distortion is still open for future studies.

Genetic dissection of segregation distortion II. Mechanism of suppression of distortion by certain inversions.

In(2L+2R)Cgamma and In(2LR)Pm2 are inversion-bearing chromosomes, the former carrying a paracentric inversion in each arm and the latter carrying a long pericentric. Both chromosomes produce normal segregation ratios when present in heterozygous males with certain segregation distorter chromosomes. The apparent suppression of distortion by these chromosomes was long attributed to a failure of synapsis, but this hypothesis has fallen out of favor recently because a large number of chromosome aberrations, particularly translocations and inversions, suppress distortion even though their breakpoints fall into no recognizable pattern. Although failure of synapsis does not appear to be the mechanism of suppression of distortion, what is responsible for the suppression remains unknown. In this paper it is shown that In(2L+2R)Cgamma and In(2LR)Pm2 suppress segregation distortion because they carry Rsp, a component of the segregation distorter system that renders a chromosome insensitive to distortion. Both chromosomes induce "suicide" of chromosomes carrying Sd Rsp+.

Population genetics of modifiers of meiotic drive. II linkage modification in the segregation distortion system

The conditions are found under which the frequency of a new gene altering the recombination fraction between two loci controlling meiotic drive will increase. When the model mimics the recombination reducing effects of a chromosomal rearrangement, such as an inversion or duplication, then the result is that the frequency of the chromosomal rearrangement in the population will increase. This may help explain the presence of inversions and duplications (or insertions) in the segregation-distorter system in Drosophila. In some cases it is found that if the new gene causes any alteration in the recombination fraction between the two loci, the frequency of the gene will increase.

Segregation-distortion in the B-chromosome system of Tettigidea lateralis (Say) (Orthoptera: Tetrigidae).

A marginal population ofTettigidea lateralis was found to be polymorphic with respect to a large, mitotically stable supernumerary (B) chromosome. Male and female individuals may carry one or two B-chromosomes. In the male sex the frequency of individuals with one B was 33.8% whereas that of 2B-carriers was 2.9 %. A comparison with a small sample of female individuals suggests similar frequencies of B-chromosome carriers in the two sexes. The pycnocity cycle of the B's is virtually identical to that of the X chromosome which is always distinguishable by virtue of its larger size and other structural details. Persistent heterochromatic associations between the B and the X, which may last until metaphaseanaphase I, lead to a preferential migration of the B with the X to the same pole in male carriers of a single supernumerary. This distortional segregation of the B-chromosome may produce a differential transmission of the supernumerary to the two sexes if the various types of gametes are equally functional. Achiasmate, persistent B-B associations in 2B individuals can also cause segregation-distortion. The two supernumeraries segregate to the same pole in approximately 1/3 of the spermatocytes, but their poleward movement relative to that of the X is random. Both −B and +B individuals show only a single chiasma per individual bivalent. However, the presence of a single B raises very significantly the frequency at which the chiasma forms at the extreme distal ends of the L1-L2 and M3-M4 autosomes. The effect on recombination exerted by the supernumeraries and the possible implications of the segregation-distortion system ofT. lateralis are discussed in the light of recent studies on comparable B-chromosome polymorphisms.