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Segregation Distorter (SD) is a selfish, coadapted gene complex on chromosome 2 of Drosophila melanogaster that strongly distorts Mendelian transmission; heterozygous SD/SD(+) males sire almost exclusively SD-bearing progeny. Fifty years of genetic, molecular, and theory work have made SD one of the best-characterized meiotic drive systems, but surprisingly the details of its evolutionary origins and population dynamics remain unclear. Earlier analyses suggested that the SD system arose recently in the Mediterranean basin and then spread to a low, stable equilibrium frequency (1-5%) in most natural populations worldwide. In this report, we show, first, that SD chromosomes occur in populations in sub-Saharan Africa, the ancestral range of D. melanogaster, at a similarly low frequency (approximately 2%), providing evidence for the robustness of its equilibrium frequency but raising doubts about the Mediterranean-origins hypothesis. Second, our genetic analyses reveal two kinds of SD chromosomes in Africa: inversion-free SD chromosomes with little or no transmission advantage; and an African-endemic inversion-bearing SD chromosome, SD-Mal, with a perfect transmission advantage. Third, our population genetic analyses show that SD-Mal chromosomes swept across the African continent very recently, causing linkage disequilibrium and an absence of variability over 39% of the length of the second chromosome. Thus, despite a seemingly stable equilibrium frequency, SD chromosomes continue to evolve, to compete with one another, or evade suppressors in the genome., Competing Interests: The authors have declared that no competing interests exist.

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.

Two of Mendel's three laws were quickly discarded as information on the organization and transmission of genes accumulated at the beginning of this century, but his law of segregation has shown remarkable staying power. In fact, within most of population genetic theory for sexual diploids is buried the tacit assumption that heterozygous alleles are represented in gametes in a 1:1 ratio. Nevertheless, there is a small, but important, group of genetic systems that subvert the law of segregation, and show 'meiotic drive'.

Evidence from in situ hybridizations of DNA from the transposable element hobo to polytene salivary gland chromosome squashes reveals that hobo occupies both cytological breakpoints of three of four endemic inversions sampled from natural populations of Drosophila melanogaster in the Hawaiian islands. The fourth endemic inversion has a single hobo insert at one breakpoint. Cosmopolitan inversions on the same chromosomes do not show this association. Frequencies of both endemic and cosmopolitan inversions in Hawaiian populations fall in ranges typical for natural populations of D. melanogaster sampled worldwide, suggesting that these results may be typical of other regions besides Hawaii. This appears to be the first direct demonstration that transposable elements are responsible for causing specific rearrangements found in nature; consequently, it is also the first direct demonstration that chromosome rearrangements can arise in nature in a manner predicted by results of hybrid dysgenic crosses in the laboratory. Possible population genetic and evolutionary consequences are discussed.

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 experimental population genetics of Y-chromosome drive in Drosophila melanogaster is approximated by studying the behavior of T(Y;2),SD lines. These exhibit "pseudo-Y" drive through the effective coupling of the Y chromosome to the second chromosome meiotic drive locus, Segregation distorter (SD). T(Y;2),SD males consequently produce only male offspring. When such lines are allowed to compete against structurally normal SD(+) flies in population cages, T(Y;2),SD males increase in frequency according to the dynamics of a simple haploid selection model until the cage population is eliminated as a result of a deficiency in the number of adult females. Cage population extinction generally occurs within about seven generations.-Several conclusions can be drawn from these competition cage studies:(1) Fitness estimates for the T(Y;2),SD lines (relative to SD(+ )) are generally in the range of 2-4, and these values are corroborated by independent estimates derived from studies of migration-selection equilibrium. (2) Fitness estimates are unaffected by cage replication, sample time, or the starting frequency of T(Y;2),SD males, indicating that data from diverse cages can be legitimately pooled to give an overall fitness estimate. (3) Partitioning of the T(Y;2),SD fitnesses into components of viability, fertility, and frequency of alternate segregation (Y + SD from X + SD(+)) suggests that most of the T(Y;2),SD advantage derives from the latter two components. Improvements in the system might involve increasing both the viability and the alternate segregation to increase the total fitness. While pseudo-Y drive operates quite effectively against laboratory stocks, it is less successful in eliminating wild-type populations which are already segregating for suppressors of SD action. This observation suggests that further studies into the origin and rate of accumulation of suppressors of meiotic drive are needed before an overall assessment can be made of the potential of Y-chromosome drive as a tool for population control.

A large array of satellite DNA sequences are always associated with the Responder (Rsp) element of Segregation Distorter in D. melanogaster. In the appropriate genetic backgrounds, Rsp causes aberrant chromatin condensation in spermiogenesis, leading to dysfunction of sperm carrying Rsp, and meiotic drive. The repeat array is deleted or translocated to the Y chromosome whenever Rsp is. Moreover, the translocation of part of Rsp to Y is associated with the translocation of an incomplete repeat array. The number of repeats among 35 independently derived chromosomes correlates nearly perfectly with sensitivity to distortion. We hypothesize that this satellite repeat array represents Responder itself. Finally, the molecular structure of this locus is extremely variable, indicating a very active process of change.

Laboratory populations of Drosophila melanogaster were challenged by pseudo-Y drive, which mimics true Y-chromosome meiotic drive through the incorporation of Segregation Distorter (SD) in a T(Y;2) complex. This causes extreme sex-ratio distortion and can ultimately lead to population extinction. Populations normally respond by the gradual accumulation of drive suppressors, and this reduction in strength of distortion allows the sex ratio to move rapidly able to neutralize the effects of sex-ration distortion by the accumulation of sex-chromosome aneuploids (XXy, XYY). THis apparently occurs because XX-bearing eggs, produced in relatively high numbers ( approximately 4%) by XXY genotypes, become the main population source of females under strong Y-chromosome drive. Computer simulation for a discrete generation model incorporating random mating with differences in fitness and segregation permits several predictions that can be compared to the data. First, sex-chromosome aneuploids should rapidly attain equilibrium, while stabilizing the population at approximately 60% males. This sex ratio should be roughly independent of the strength of the meiotic drive. Moreover, conditions favoring the accumulation of drive suppressors (e.g., weak distortion, slow population extinction) are insufficient for maintaining aneuploidy, while conditions favoring aneuploidy (e.g., strong distortion, low production of females) lead to population extinction before drive suppressors can accumulate. Thus, the different mechanisms for neutralizing sex-ratio distortion are complementary. In addition, Y drive and sex-chromosome aneuploidy are potentially co-adaptive, since under some conditions neither will survive alone. Finally, these results suggest the possibility that genetic variants promoting sex-chromosome nondisjunction may have a selective advantage in natural populations faced with sex-ratio distortion.

gamma-Irradiation of a laboratory strain of the Hawaiian species Drosophila heteroneura yielded 310 breaks in the five major acrocentric polytene chromosomes. Their map positions conform to the Poisson distribution, unlike most of the 436 natural breaks mapped in 105 closely related species endemic to Hawaii. Genome element E is longer and has more induced breaks than the others. Both in Hawaiian and related species groups, this element shows increased polymorphism and fixation of naturally occurring inversions. The X chromosome (element A) also accumulates many natural breaks; the majority of the resulting aberrations become fixed rather than remain as polymorphisms. Although size may play a small role in initial break distribution, the major effects relative to the establishment of a rearrangement in natural populations are ascribed to the interaction of selection and drift. Nonconformance of the natural breaks to the Poisson distribution appears to be due to the tendency for breaks to accumulate both in the proximal euchromatic portion of each arm and in heterochromatic regions that are not replicated in the polytene chromosomes.

Many translocations between the Y chromosome and a major autosome have no effect on the fertility of Drosophila melanogaster males. However, when such translocation-bearing males also carry an X chromosome deficient for a large portion of the centric heterochromatin, they are generally sterile. This has been interpreted to be the result of an interaction between the deficiency and the subterminally capped autosome. Using this observation as a starting point, we have developed a selection scheme for radiation-induced translocation resealings that depends on the prediction that fertility in the presence of such a deficient X is restored whenever the displaced autosomal tip is brought back in association with an autosomal centromere. The observation and the prediction form the basis for what is referred to as the autosomal continuity model for male fertility.-Such a mutagenesis scheme offers several advantages. (1) It is efficient, producing upward of 1% resealings in some cases. (2) It is simple; since fertility is the basis for the selective screen, many males can be tested in a single vial. (3) It can be used to simultaneously generate both duplications and deficiencies specific for chromosomal material adjacent to the original translocation breakpoints. (4) The target for mutagenesis can be mature sperm.-Analysis of the pattern of male-fertile rearrangements obtained from several translocation lines using this protocol indicates that continuity of the autosomal tips and their centromeres is neither a necessary nor sufficient condition for male fertility in the presence of a bobbed-deficient X. Thus, the simple autosomal continuity model is not adequate to explain this complicated mechanism of chromosomal control of fertility and will have to be revised accordingly. Potential future lines of inquiry toward this goal are discussed.

A laboratory strain of Drosophila mercatorum has existed for 20 years without males and therefore without natural selection operating to maintain the genetic basis of female mating behavior. The females of this strain have recently experienced a genetic impairment of mating capacity. This observation exemplifies the mode of evolution of vestigial characters and supports Muller's theory that random mutation will tend to destroy the genetic basis of a character from which selection has been removed.

Identification of allelic variability at the two major loci (Sd and Rsp) that interact to cause sperm dysfunction in Segregation distorter (SD) males of D. melanogaster has been hampered by the difficulty in separating the elements recombinationally. In addition, small differences in the strength of Sd alleles or sensitivities of Rsp alleles to Sd are difficult to measure against background genetic or environmental variation. Viability effects of the markers used to score progeny classes may also introduce a bias. Removal of Sd and E(SD) from their second chromosome location to create a Dp(2;Y)Sd E(SD) chromosome eliminates these problems, since any combination of Rsp alleles can be easily tested without resorting to recombinational techniques. Further, since these pairs of Rsp alleles are compared in their response to Dp Sd E(SD) in the same individual males, background variation and viability effects can be easily removed to allow fine-scale resolution of Rsp differences. Tests of all possible pairwise combination of six laboratory chromosomes in this way revealed at least three and possibly four different Rsp allelic classes. In addition, the hierarchical nature of the tests further allowed for determination of the presence of linked suppressors or enhancers of Sd activity. A sample of 11 second chromosomes selected from a group recently isolated from a natural population was also unambiguously ordered as to Rsp allelic status using this approach. The resultant pattern was similar to that obtained for the laboratory chromosomes, except for the not unexpected observation that the natural population apparently harbored more drive suppressors. The pattern of results obtained from these pairwise combinations of Rsp alleles supports the notion that there are no dominance interactions within the group, but that each responds more or less independently to Sd in giving sperm dysfunction.

A portion of the Segregation distorter (SD) chromosome, including both the Sd and E(SD) loci, has been moved by insertional translocation from SD Roma into Y(L ). This Dp(2;Y)SD chromosome shows a negligible reduction in its ability to cause dysfunction of Rsp( s)-bearing sperm when compared to the parent SD chromosome, suggesting that SD can still act effectively, even when removed from its normal second chromosome milieu, and that its activity level does not depend on pairing with a normal autosomal homologue. Male genotypes have been constructed using this Dp(2;Y)SD along with a standard SD chromosome (either SD Roma or R( SD-36)-1(bw)) and a third chromosome suppressor of SD (TM6) in all possible three-way combinations. The observed level of SD-mediated dysfunction in each case is most compatible with a model that assumes that all SD elements act additively (in terms of M, the probit transformation of the probability of sperm dysfunction), rather than multiplicatively. The additive action of SD elements contrasts with the independent response to SD activity exhibited by multiple Rsp(s) copies.

The accumulation of modifiers of the meiotic-drive locus Segregation Distorter (SD) in Drosophila melanogaster was monitored by measuring the changes in the mean and variance of drive strength (in terms of "make" value) that occur in laboratory populations when SD and SD+ chromosomes are in direct competition. The particular SD lines used are T(Y;2),SD translocations showing pseudo-Y drive. Four sets of population cages were analyzed. Two sets were monitored for changes in SD fitness and drive strength (presumed to be positively correlated) and analyzed for the presence of autosomal dominant or X-linked modifiers after long periods of time. The remaining two sets were made up of cages either made isogenic or variable for background genetic material, and these were used to test whether the rate of accumulation of modifiers was dependent on initial genetic variability.-Contrary to previous studies in which most suppression of SD action could apparently be attributed to a few dominantly acting modifiers of large effect, the conclusion here is that laboratory populations that are initially free of such major dominant loci evolve to suppress SD action by accumulating polygenic, recessive modifiers, each of small effect, and that much of the required genetic variability can be generated de novo by mutation. Possible explanations for these seemingly incompatible results and the evolutionary implications for SD are considered.

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.