Supergenes are clusters of linked loci that control variation in complex phenotypes. Some supergenes mediate adaptive polymorphisms that are maintained by some form of frequency- or density-dependent natural selection, as in, for example, mimicry in butterflies, self-incompatibility in plants, plumage polymorphisms in birds, and heteromorphic sex chromosomes (see Schwander et al., 2014; Thompson and Jiggins, 2014, for review). Other supergenes are maintained by selfish social behaviors that enhance the fitness of carriers at the expense of non-carriers, as in some ant species (Keller and Ross, 1998; Wang et al., 2013). Still other supergenes are maintained by their ability to achieve selfish, better-than-Mendelian transmission during gametogenesis, as in the so-called meiotic drive complexes found in fungi, insects, and mammals (Lyon, 2003; Larracuente and Presgraves, 2012; Lindholm et al., 2016; Svedberg et al., 2018; Fuller et al., 2020).

Meiotic drive complexes gain transmission advantages at the expense of other loci and their hosts. In heterozygous carriers of male drive complexes in animals, the driver disables spermatids that bear drive-sensitive target alleles (Larracuente and Presgraves, 2012; Lindholm et al., 2016). To spread in the population, the driver must be linked in a cis-arrangement to a drive-resistant (insensitive) target allele (Charlesworth and Hartl, 1978). Recombination between the driver and target can result in a ‘suicide’ haplotype that distorts against itself (Sandler and Carpenter, 1972; Hartl, 1974). These epistatic interactions between driver and target lead to selection for modifiers of recombination that tighten linkage, such as chromosomal inversions (Charlesworth and Hartl, 1978; Schwander et al., 2014; Thompson and Jiggins, 2014; Charlesworth, 2016). Like most supergenes (Charlesworth and Charlesworth, 1975; Turner, 1977), meiotic drive complexes originate from two or more loci with some degree of initial linkage. Successful drivers thus tend to be located in regions of low recombination, such as non-recombining sex chromosomes (Hamilton, 1967; Hurst and Pomiankowski, 1991), centromeric regions, or in chromosomal inversions of autosomes (Lyon, 2003; Larracuente and Presgraves, 2012; Lindholm et al., 2016; Svedberg et al., 2018).

The short-term benefits of reduced recombination can entail long-term costs. Chromosomal inversions that lock supergene loci together can also incidentally capture linked loci, which causes large chromosomal regions to segregate as blocks. Due to reduced recombination, the efficacy of natural selection in these regions is compromised: deleterious mutations can accumulate, and beneficial ones are more readily lost (Muller, 1964; Hill and Robertson, 1968; Felsenstein, 1974; Charlesworth et al., 2009). Many meiotic drive complexes are thus homozygous lethal or sterile. The degeneration of drive haplotypes is not inevitable, however. Different drive haplotypes that complement one another may be able to recombine, if only among themselves (Dod et al., 2003; Presgraves et al., 2009; Brand et al., 2015). Gene conversion from wildtype chromosomes may also ameliorate the genetic load of supergenes (Uyenoyama, 2005; Wang et al., 2013; Tuttle et al., 2016; Branco et al., 2018; Stolle et al., 2019; Brelsford et al., 2020). Male meiotic drive complexes thus represent a class of selfish supergenes that evolve and persist via the interaction of drive, recombination, and natural selection.

Here, we focus on the evolutionary genetics of Segregation Distorter (SD), a well-known autosomal meiotic drive complex in Drosophila melanogaster (Sandler et al., 1959). In heterozygous males, SD disables sperm bearing drive-sensitive wildtype chromosomes via a chromatin condensation defect (Hartl et al., 1967; Temin et al., 1991). SD has two main components: the driver, Segregation Distorter (Sd), is a truncated duplication of the gene RanGAP located in chromosome arm 2L (Powers and Ganetzky, 1991; Merrill et al., 1999; Kusano et al., 2001); and the target of drive, Responder (Rsp), is a block of satellite DNA in the pericentromeric heterochromatin of 2R. Previous studies of SD chromosomes have detected linked upward modifiers of drive, including Enhancer of SD (E[SD]) on 2L and several others on 2R (Sandler and Hiraizumi, 1960; Miklos, 1972; Ganetzky, 1977; Hiraizumi et al., 1980; Brittnacher and Ganetzky, 1984), but their molecular identities are unknown. Sd-RanGAP and Rsp straddle the centromere, a region of reduced recombination, and some SD chromosomes bear pericentric inversions that presumably further tighten linkage among these loci. In heterozygotes with a pericentric inversion, recombination in the inverted region generates aneuploids and therefore reduced fertility, although this effect might be mitigated by strong suppression of recombination (Coyne et al., 1993). Many SD chromosomes also bear paracentric inversions on 2R (reviewed in Lyttle, 1991; Larracuente and Presgraves, 2012). Although recombination between paracentric inversions and the main components of SD is possible, their strong association implies a role for epistatic selection in the evolution of these supergenes (Larracuente and Presgraves, 2012).

While SD is present at low population frequencies (<5%) around the world (Temin et al., 1991; Larracuente and Presgraves, 2012), Sd-RanGAP appears to have originated in sub-Saharan Africa, the ancestral geographic range of D. melanogaster, survived the out-of-Africa bottleneck, and spread to the rest of the world (Presgraves et al., 2009; Brand et al., 2015). Multiple factors likely contribute to the low frequency of SD in populations: negative selection, insensitive Rsp alleles, and unlinked suppressors (reviewed in Larracuente and Presgraves, 2012). Two independent longitudinal studies suggest that SD haplotypes can replace each other in populations over short time scales (<30 years) (Temin and Kreber, 1981; Brand et al., 2015) without major changes in the overall population frequency of SD (Temin and Kreber, 1981). The predominant SD variant in Africa is SD-Mal, which recently swept across the entire continent (Presgraves et al., 2009; Brand et al., 2015). SD-Mal has a pair of rare, African-endemic, overlapping paracentric inversions spanning ~40% of 2R:In(2R)51B6–11;55E3–12 and In(2R)44F3–12;54E3–10, hereafter collectively referred to as In(2R)Mal (Aulard et al., 2002; Presgraves et al., 2009). SD-Mal chromosomes are particularly strong drivers, with ~100% transmission. Notably, recombinant chromosomes bearing the Sd-RanGAP duplication from this haplotype but lacking the inversions do not drive (Presgraves et al., 2009), suggesting that In(2R)Mal is essential for SD-Mal drive. We therefore expect strong epistatic selection to enforce the association of Sd-RanGAP and In(2R)Mal. The functional role of In(2R)Mal for drive is still unclear: do these inversions function to suppress recombination between Sd-RanGAP and a major distal enhancer on 2R, or do they contain a major enhancer?

Here, we combine genetic and population genomic approaches to study SD-Mal haplotypes sampled from a single population in Zambia, the putative ancestral range of D. melanogaster (Pool et al., 2012). We address four issues. First, we reveal the structural features of the SD-Mal haplotype, including the organization of the insensitive Rsp allele and the In(2R)Mal rearrangements. Second, we characterize the genetic function of In(2R)Mal and its role in drive. Third, we infer the population genetic history of the rapid rise in frequency of SD-Mal in Zambia. And fourth, we explore the evolutionary consequences of reduced recombination on SD-Mal haplotypes. Our results show that SD-Mal experienced a recent chromosome-scale selective sweep mediated by epistatic selection and has, as a consequence of its reduced population recombination rate, accumulated excess non-synonymous mutations and transposable element (TE) insertions. The SD-Mal haplotype is a supergene that evolves as a small, semi-isolated subpopulation in which complementing SD-Mal chromosomes can recombine inter se via crossing over and with wildtype chromosomes via gene conversion. These results have implications for supergene evolution and may explain the enigmatic evolutionary turnover of SD haplotypes in different populations around the world.

To investigate the evolutionary genomics of SD-Mal, we sequenced haploid embryos from nine driving SD-Mal haplotypes sampled from a single population in Zambia (Brand et al., 2015), the putative ancestral range of D. melanogaster (Pool et al., 2012). Illumina read depth among samples ranged between ~46 and 67× (Supplementary file 1; BioProject PRJNA649752 in NCBI). Additionally, we obtained ~12× coverage with long-read Nanopore sequencing of one homozygous viable line, SD-ZI125, to create a de novo assembly of a representative SD-Mal haplotype (BioProject PRJNA649752 in NCBI; assembly in Navarro-Dominguez et al., 2022a). We use these data to study the evolution of SD-Mal structure, diversity, and recombination.

Chromosomal features of the SD-Mal supergene

The SD-Mal haplotype has at least three key features: the main drive locus, the Sd-RanGAP duplication on 2L; an insensitive Responder (Rspⁱ) in 2R heterochromatin; and the paracentric In(2R)Mal arrangement on chromosome 2R (Figure 1). We used our long-read and short-read sequence data for SD-ZI125 to confirm the structure of the duplication (Figure 1A) and then validated features in the other SD-Mal haplotypes. All SD-Mal chromosomes have the Sd-RanGAP duplication at the same location as the parent gene on chromosome 2L (see also Brand et al., 2015). The Rsp locus, the target of SD, corresponds to a block of ~120 bp satellite repeats in 2R heterochromatin (Figure 1B; Wu et al., 1988). The reference genome, Iso-1, has a Rsp^s allele corresponding to a primary Rsp locus containing two blocks of tandem Rsp repeats—Rsp-proximal and Rsp-major—with ~1000 copies of the Rsp satellite repeat interrupted by TEs (Khost et al., 2017). A small number of Rsp repeats exist outside of the primary Rsp locus, although they are not known to be targeted by SD. There are three of these additional Rsp loci in Iso-1: ~ 10 copies in 2R, distal to the major Rsp locus (Rsp-minor); a single copy at the distal end of 2R (60A); and ~12 copies in 3L (Houtchens and Lyttle, 2003; Larracuente, 2014; Khost et al., 2017). The genomes of SD flies carry ~20 copies of Rsp (Wu et al., 1988; Pimpinelli and Dimitri, 1989), but the organization of the primary Rsp locus on SD chromosomes is unknown. To characterize the Rsp locus of the SD-Mal haplotype, we mapped SD-Mal reads to an Iso-1 reference genome (see Khost et al., 2017). As expected, reads from Iso-1 reference are distributed across the whole Rsp-major region. For SD-Mal chromosomes, however, very few reads map to the Rsp repeats at the Rsp-major (Figure 1B). This suggests that all SD-Mal have a complete deletion of the primary Rsp locus containing Rsp-proximal and Rsp-major and that the only Rsp copies in the SD-Mal genomes are the minor Rsp loci in chromosomes 2R and 3L (Figure 1—figure supplement 1).

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The complex In(2R)Mal inversion is distal to the Rsp locus on chromosome 2R (Figure 1C). We used our SD-ZI125 assembly to determine the precise breakpoints of these inversions. Relative to the standard D. melanogaster 2R scaffold (BDGP6), SD-ZI125 has three large, rearranged blocks of sequence corresponding to In(2R)Mal (Figure 1C): a 1.03 Mb block collinear with the reference but shifted proximally; a second inverted 5.74 Mb block; and a third inverted 3.16 Mb block. From this organization, we infer that the distal inversion, which we refer to as In(2R)Mal-d, occurred first and spanned 4.18 Mb (approx. 2R:14,591,003–18,774,475). The proximal inversion, which we refer to as In(2R)Mal-p, occurred second and spanned 6.76 Mb, with 1.02 Mb overlapping with the proximal region of In(2R)Mal-d (approx. 2R:8,855,602–17,749,310). Note that any rearrangement different than distal first, proximal second, leads to a different outcome (Figure 1—figure supplement 2). All four breakpoints of the In(2R)Mal rearrangement involve simple joins of unique sequence. Three of these four breakpoints span genes (Figure 1—figure supplement 3): sns (2R:8,798,489–8,856,091), CG10931 (2R:17,748,935–17,750,136), and Mctp (2R:18,761,758–18,774,824). The CDSs of both sns and Mctp remain intact in the In(2R)Mal arrangement, with the inversion disrupting their 3’ UTRs. Neither of these two genes is expressed in testes (https://flybase.org/reports/FBgn0024189; https://flybase.org/reports/FBgn0034389; Chintapalli et al., 2007; FB2021_06; Larkin et al., 2021), making it unlikely that they affect drive. In(2R)Mal-p disrupts the CDS of CG10931, which is a histone methyltransferase with high expression levels in testis (https://flybase.org/reports/FBgn0034274; Chintapalli et al., 2007; FB2021_06; Larkin et al., 2021). Even for genes that are not directly interrupted by the inversion breakpoints, the chromosomal rearrangements may disrupt the regulation of nearby genes if, for example, they affect the organization of topologically associating domains (TADs; reviewed in Spielmann et al., 2018). The In(2R)Mal inversion breakpoints disrupt physical domains reported in Hou et al., 2012, however inversion-mediated disruptions of TAD boundaries do not necessarily affect gene expression (Ghavi-Helm et al., 2019). Future work is required to determine if the inversions affect gene expression near the breakpoints and if CG10931 has a role in the SD-Mal drive phenotype.

In African populations, chromosomes bearing Sd but lacking In(2R)Mal do not drive (Presgraves et al., 2009; Brand et al., 2015). The functional role of In(2R)Mal in drive is, however, unclear. As expected, In(2R)Mal suppresses recombination: in crosses between a multiply marked chromosome 2, b c px, and SD-Mal (Figure 1—figure supplement 4), we find that In(2R)Mal reduces the b–c genetic distance by 54.6% and the c–px genetic distance by 92.4%, compared with control crosses between b c px and Oregon-R (Table 1). Our crosses confirm that In(2R)Mal is indeed required for drive: if we generate recombinants along an SD-Mal chromosome, all recombinants with both Sd and In(2R)Mal show strong drive (Table 2, rows 1 and 2), whereas none of the recombinants that separate Sd and In(2R)Mal drive (Table 2, rows 3 and 4). We conclude that SD-Mal drive requires both Sd and In(2R)Mal, which implies that one or more essential enhancers, or co-drivers, is located within or distal to In(2R)Mal.

Table 1

Cross	N	n	nR (b–c)	nR (c–px)	d (b–c)	d (c–px)
OreR/b c px x b c px/b c px	15	1,716	418	372	26.62	23.21
SD-Mal/b c px x b c px/b c px	11	1,820	211	32	11.81	1.76

1. N, number of crosses; n, total progeny scored; n_R, number of recombinants, d, genetic distance in cM, Kosambi-corrected.

Table 2

	Genotype	Markers	N	n	±SE	k	±SE	k*	±SE	p-value (k* = 0.5)
1	Sd In(2R)Mal	+ + + and b + +	112	90.3	6.03	0.99	0.00	0.98	0.00	<0.0001
2	Sd In(2R)Mal	+ + px	71	118.8	9.48	0.97	0.01	0.96	0.01	<0.0001
3	Sd In(2R)Mal+	+ c px	19	147.6	14.39	0.54	0.01	0.51	0.01	0.3082
4	Sd+ In(2R)Mal	b + +	24	124.8	10.31	0.68	0.02	0.55	0.03	0.0572
5	Sd+ In(2R)Mal+	+ c px	65	120.4	8.32	0.53	0.01	0.51	0.01	0.3586

1. Chromosome 2 markers are black (b), curved (c), and plexus (px). N, number of crosses; n, average number of progeny from the crosses; SE, standard error; k, average proportion of progeny inheriting the recombinant SD_r chromosome from SD_r/b c px males; k*, average proportion of progeny inheriting the partial SD_r chromosome from SD_r/b c px males, corrected for viability. p-values reported by a single sample t-test with a null hypothesis of k* = 0.5, as expected for Mendelian segregation. b + + flies were PCR-genotyped for the presence (row 1) or absence (row 4) of Sd-RanGAP.

The temporal order of inversions (first In(2R)Mal-d, then In(2R)Mal-p) suggests two possible scenarios. In(2R)Mal-d, occurring first, may have captured the essential enhancer, with the subsequent In(2R)Mal-p serving to further reduce recombination between Sd and the enhancer. Alternatively, an essential enhancer may be located distal to In(2R)Mal-d, and the role of both In(2R)Mal inversions is to reduce recombination with Sd. To distinguish these possibilities, we measured drive in b⁺ Sd c⁺ In(2R)Mal px recombinants, which bear Sd and In(2R)Mal but have recombined between the distal breakpoint of In(2R)Mal (2R:18,774,475) and px (2R:22,494,297). All of these recombinants show strong drive (n = 71; Table 2, row 2). Assuming that recombination is uniformly distributed throughout the 3.72 Mb interval between the In(2R)Mal-d distal breakpoint and px, the probability of failing to separate an essential co-driver or distal enhancer among any of our 71 recombinants is <0.014. Furthermore, using molecular markers (see Materials and methods), we detected two recombinants within 100 kb of the distal breakpoint of In(2R)Mal, both with strong drive (k > 0.99; Supplementary file 2). We therefore infer that the co-driver resides inside or within 100 kb of the In(2R)Mal arrangement. More specifically, we speculate that the In(2R)Mal-d inversion both captured the co-driver and reduced recombination with Sd, whereas In(2R)Mal-p tightened linkage between centromere-proximal components of SD-Mal and In(2R)Mal-d.

Despite the recruitment of these inversions, recombination occurs readily between Sd and the proximal break of In(2R)Mal (Table 2; Presgraves et al., 2009; Brand et al., 2015). Nevertheless, we observe long-range linkage disequilibrium between Sd and In(2R)Mal. Among 204 haploid genomes from Zambia (Lack et al., 2016; see Materials and methods), we identified 198 wildtype haplotypes (Sd⁺ In(2R)Mal⁺), 3 SD-Mal haplotypes (Sd In(2R)Mal), and 3 recombinant haplotypes (three Sd In(2R)Mal⁺, zero Sd⁺ In(2R)Mal). While Sd and In(2R)Mal each have individually low sample frequencies (0.0294 and 0.0147, respectively), they tend to co-occur on the same chromosome (r² = 0.493; Fisher’s exact p = 1.4 × 10^–5). We calculated the expected decay of linkage disequilibrium between Sd and In(2R)Mal in the absence of any natural selection (Hill and Robertson, 1968), assuming a conservative sex-averaged recombination frequency corresponding to a map distance between Sd and In(2R)Mal of ~2.5 cM (FlyBase; FB2021_06; Larkin et al., 2021) and an effective population size of 10⁶. Under these assumptions, the observed estimated coefficient of linkage disequilibrium, D = 0.0143, has an expected half-life of just ~28 generations (2.8 years) and, decays to negligible levels (i.e., expected D and r² both ~10^–3) in <100 generations (<10 years). We therefore conclude that the SD-Mal supergene haplotype is maintained by strong epistatic selection.

Rapid increase in frequency of the SD-Mal supergene

We used population genomics to infer the evolutionary history and dynamics of SD-Mal chromosomes. We called SNPs in our Illumina reads from nine complete SD-Mal haplotypes from Zambia (see Materials and methods). For comparison, we also analyzed wildtype (SD⁺) chromosomes from the same population in Zambia (Lack et al., 2016), including those with chromosome 2 inversions: 10 with the In(2L)t inversion and 10 with the In(2R)NS inversion (see Materials and methods). Table 3 shows that nucleotide diversity (π) is significantly lower on SD-Mal haplotypes compared to uninverted SD⁺ chromosome arms (Table 3; Figure 2A). The relative reduction in diversity on SD-Mal haplotypes is distributed heterogeneously: π is sharply reduced for a large region that spans ~25.8 Mb, representing 53% of chromosome 2 and extending from Sd-RanGAP on 2L (2L:19,441,959; Figure 2—figure supplement 1), across the centromere, and to ~2.9 Mb beyond the distal breakpoint of In(2R)Mal (2R:18,774,475; Table 3, rows 3, 5, and 6; Figure 2A). Thus, the region of reduced nucleotide diversity on SD-Mal chromosomes covers all the known essential loci for the drive phenotype: Sd-RanGAP, Rspⁱ, and In(2R)Mal.

Table 3

			π ( ± st. dev.)			p-value
	Chr.	Region	SD+	SD-Mal	SD+ × f	SD-Mal vs. SD+	SD-Mal vs. SD+*f
1	2L	Distal to Sd-RanGAP	1.03E-02	1.03E-02	1.52E-04	0.5727	0.00E + 00
			(±3.01E-03)	(±3.09E-03)	(±4.43E-05)
2	2L	Proximal to Sd-RanGAP	4.44E-03	9.39E-05	6.52E-05	5.84E-90	0.0027
			(±2.75E-03)	(±1.66E-04)	(±4.04E-05)
3	2R	In(2R)Mal	8.94E-03	7.97E-05	1.31E-04	0.00E + 00	1.42E-33
			(±2.95E-03)	(±1.18E-04)	(±4.33E-05)
4	2L-2R	SD-Mal supergene	6.42E-03	7.98E-05	9.43E-05	0.00E + 00	2.60E-06
			(±4.03E-03)	(±1.32E-04)	(±5.92E-05)

1. Average nucleotide diversity (π) per site and empirical standard deviation estimated in 10-kb windows along chromosome 2, for SD⁺, SD-Mal, and SD⁺ scaled by the estimated frequency of SD-Mal chromosomes (SD⁺× f, where f = 1.47%). Outside of the linked region (row 1), π_SD-Mal ~ π_SD⁺. Inside of the linked region (rows 2–4), π_SD-Mal < π_SD⁺; even after scaling π_SD⁺ by the frequency of SD-Mal in the population, π_SD-Mal < π_SD⁺× f. Due to non-independence of SNPs in non-recombining regions, we also estimated variance in π based on Charlesworth and Charlesworth, 2010; which is 5.30E-05 for In(2R)Mal and 6.27E-05 for the entire SD-Mal supergene. p-values reported by paired t-test between 10-kb windows.

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The reduced nucleotide diversity among SD-Mal might be expected given its low frequency in natural populations (see below; Presgraves et al., 2009; Brand et al., 2015). SD persists at low frequencies in populations worldwide, presumably reflecting the balance between drive, negative selection, and genetic suppression and/or resistance (Hartl, 1975; Charlesworth and Hartl, 1978; Larracuente and Presgraves, 2012). If the SD-Mal supergene has been maintained at stable drive-selection-suppression equilibrium frequency for a long period of time, then its nucleotide diversity may reflect a mutation-drift equilibrium appropriate for its effective population size. Under this scenario, we expect diversity at the supergene to be similar to wildtype (SD⁺) diversity scaled by the long-term equilibrium frequency of SD. We estimated SD-Mal frequency to be 1.47% by identifying the Sd duplication and In(2R)Mal breakpoints in 204 haploid genomes from Zambia (3/204, comparable to Presgraves et al., 2009; Brand et al., 2015; data from Lack et al., 2016; see Materials and methods). To approximate our expectation under mutation-drift equilibrium, we scaled average π from the SD⁺ sample by 1.47% in 10-kb windows across the region corresponding to the SD-Mal supergene, defined as the region from Sd-RanGAP to the distal breakpoint of In(2R)Mal. While nucleotide diversity outside of the SD-Mal supergene region is comparable to SD⁺ (Table 3, row 1), diversity in the supergene region is significantly lower than expected even when scaled by its frequency (Table 3, row 4), suggesting that the low population frequency of SD-Mal cannot fully explain its reduced diversity. This observation suggests two possibilities: the SD-Mal supergene historically had an equilibrium frequency less than 1.47% in Zambia; or the SD-Mal supergene, having reduced recombination, has experienced hitchhiking effects due to background selection and/or a recent selective sweep.

To distinguish between these possibilities, we analyzed summaries of the site frequency spectrum. We find strongly negative Tajima’s D mirroring the distribution of reduced diversity, indicating an excess of rare alleles (Figure 2B). Such a skew in the site frequency spectrum suggests a recent increase in frequency of the SD-Mal supergene in Zambia. Given the low recombination frequency between SD-Mal and SD⁺ chromosomes, we treat them as two subpopulations and estimate their differentiation using Wright’s fixation index, F_ST. The high differentiation of SD-Mal from SD⁺ chromosomes from the same population similarly suggests a large shift in allele frequencies. F_ST in the SD-Mal supergene region is unusually high for chromosomes from the same population (Figure 3A). Neither of the SD⁺ chromosomes with cosmopolitan inversions show such high differentiation, and mean nucleotide differences (d_XY) between SD-Mal and SD⁺ are comparable to the other inversions, implying that the differentiation of the SD-Mal supergene is recent. Our results—low diversity, strongly negative Tajima’s D, high F_ST and relatively low d_XY—are thus consistent with a rapid increase in frequency of the SD-Mal haplotype that reduced nucleotide diversity within SD-Mal and generated large differences in allele frequencies with SD⁺ chromosomes (e.g., Charlesworth, 1998; Cruickshank and Hahn, 2014).

Figure 3

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To estimate the timing of the recent expansion of the SD-Mal supergene, we used an approximate Bayesian computation (ABC) method with rejection sampling in neutral coalescent simulations. We do not know if SD chromosomes acquired In(2R)Mal in Zambia or if the inversions occurred de novo on an SD background. For our simulations, we assume that the acquisition of the second inversion (or the double inversion by crossover) was a unique event that enhanced drive strength and/or efficiency and that the onset of the selective sweep occurred following this event. Under this scenario, extant SD-Mal chromosomes have a single origin. We therefore simulated this history in a coalescent framework as an absolute bottleneck to a single chromosome. We performed simulations considering a sample size of n = 9 and assumed no recombination in the ~9.92 Mb region of In(2R)Mal. We simulated with values of S drawn from a uniform distribution ±5% of the observed number of segregating sites in non-coding regions of In(2R)Mal. We considered a prior uniform distribution of the time of the expansion (t) ranging from 0 to 4N_e generations (0–185,836 years ago), assuming that D. melanogaster N_e in Zambia 3,160,475 (Kapopoulou et al., 2018), a In(2R)Mal frequency of 1.47%, and 10 generations per year (Li and Stephan, 2006; Thornton and Andolfatto, 2006; Laurent et al., 2011; Kapopoulou et al., 2018). Using the ABC with rejection sampling conditional on our observed estimates of π and Tajima’s D for In(2R)Mal (π_In(2R)Mal = 584.60, D = –1.33; note that π_In(2R)Mal is an overall, unscaled estimate of nucleotide diversity for the whole In(2R)Mal region and that only non-coding regions were considered), we infer that the SD-Mal expansion began ~0.0884 (95% CIs 0.0837–0.1067) × 4N_e generations ago or, equivalently, ~1644 years ago (1.11% rejection sampling acceptance rate; Figure 4). To account for possible effects of gene conversion between SD and SD⁺ chromosomes (see below), we discarded SNPs shared with SD⁺ chromosomes (see below), and recalculated π and Tajima’s D using only private SNPs (π_In(2R)Mal = 427.72, D = –1.45). Based on these parameters, the estimated SD-Mal expansion occurred ~0.0679 (95% CIs 0.0647–0.0868) 4N_e generations ago, ~1261 years (1.02% rejection sampling acceptance rate; Figure 4). To calculate the posterior probability of the model, we performed 100,000 simulations under three models: a model assuming a stable frequency of SD-Mal; a model assuming an exponential growth of SD-Mal, based on parameters estimated for Zambia (Kapopoulou et al., 2018); and a selective sweep model (assuming t_all = 0.0884 and t_{shared_excl} = 0.0679) (Figure 4—figure supplement 1). The simulated data are inconsistent with a long-term stable frequency of SD-Mal (all SNPs, p_π = 0.0522, p_D = 0.096; private, p_π = 0.0266, p_D = 0.0668) or long-term exponential growth (all SNPs, p_π = 0.0465, p_D = 0.0907; private, p_π = 0.0215, p_D = 0.0605). Instead, our simulations suggest that a recent selective sweep is more consistent with the data (all SNPs, p_π = 0.3554, p_D = 0.5952; private, p_π = 0.3480, p_D = 0.6142). Taken together, evidence from nucleotide diversity, the site frequency spectrum, population differentiation, and coalescent simulations suggests a rapid non-neutral increase in frequency of the SD-Mal supergene that began <2000 years ago.

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The sweep signal on the SD-Mal haplotypes begins immediately distal to Sd-RanGAP on 2L and extends ~3 Mb beyond the distal boundary of In(2R)Mal on 2R. To understand why the sweep extends so far beyond the In(2R)Mal-d distal breakpoint, we consider three, not mutually exclusive, possibilities. First, chromosomal inversions can suppress recombination ~1–3 Mb beyond their breakpoints (in both multiply inverted balancer chromosomes, [Miller et al., 2016; Crown et al., 2018; Miller et al., 2018] and natural inversions [Stevison et al., 2011; Fuller et al., 2017]), extending the size of the sweep signal. To determine the extent of recombination suppression caused by In(2R)Mal, we estimated recombination rates in the region distal to the inversion. The expected genetic distance between the distal breakpoint of In(2R)Mal (2R:18.77 Mb) and px (2R:22.49 Mb) is ~13.87 cM (Fiston-Lavier et al., 2010). Measuring recombination between SD-Mal and standard arrangement chromosomes for the same (collinear) interval, we estimate a genetic distance of ~1.76 (Table 1), an 87.3% reduction. In(2R)Mal strongly reduces recombination beyond its distal boundary. Second, although we have inferred that the essential enhancer(s) reside(s) within the In(2R)Mal inversion (see above), we have not excluded the possibility of weak enhancers distal to the inversion which might contribute to the sweep signal. We find that SD-Mal chromosomes with In(2R)Mal-distal material recombined away (b⁺ Sd c⁺ In(2R)Mal px) have modestly but significantly lower drive strength (k = 0.96 vs. 0.98; Table 2, lines 1–2), suggestive of one or more weak distal enhancers. Third, there may be mutations distal to In(2R)Mal that contribute to the fitness of SD-Mal haplotypes but without increasing the strength of drive, for example, compensatory mutations that ameliorate the effects of SD-Mal-linked deleterious mutations.

Most supergenes show long-range LD, reduced nucleotide diversity, and differentiation when compared with their wildtype counterparts. While some meiotic drive supergenes show evidence of recurrent selective sweeps (Dyer et al., 2007) or a signature of epistatic selection without strong selective sweeps (Fuller et al., 2020), others show no signatures of recent or ongoing positive selection (Kelemen and Vicoso, 2018). The relatively recent origin (~38.5 kya; Brand et al., 2015) of SD might explain the constant turnover, as there may not have been enough time to reach a stable equilibrium compared to older drive systems like the t-haplotype, whose first inversion arose 3 mya (Hammer and Silver, 1993).

Recombination on SD-Mal supergenes

While nearly all SD-Mal haplotypes are individually homozygous lethal and do not recombine with wildtype chromosomes in and around In(2R)Mal, ~90% of pairwise combinations of different SD-Mal chromosomes (SD_i/SD_j) are viable and fertile in complementation tests (Presgraves et al., 2009; Brand et al., 2015). Therefore, recombination via crossing over may occur between SD-Mal chromosomes in SD_i/SD_j heterozygous females. To determine if SD-Mal chromosomes recombine, we estimated mean pairwise linkage disequilibrium (r²) between SNPs located within the In(2R)Mal arrangement. We found that mean r² between pairs of SNPs declines as a function of the physical distance separating them (Figure 5A), a hallmark of recombination via crossing over (Hill and Robertson, 1968; Miyashita and Langley, 1988; Schaeffer and Miller, 1993; Awadalla et al., 1999; Conway et al., 1999). Pairwise LD is higher and extends further in In(2R)Mal than in the equivalent region of SD⁺ chromosomes or in any of the other two cosmopolitan inversions, In(2L)t and In(2R)NS (Figure 5A). This pattern is not surprising: the low frequency of SD-Mal makes SD_i/SD_j genotypes, and hence the opportunity for recombination, rare. (The smaller sample size of SD (n = 9) vs. SD⁺ (n = 10) may also contribute weakly to its higher estimated LD.) To further characterize the history of recombination between SD-Mal haplotypes, we used 338 non-singleton, biallelic SNPs in In(2R)Mal to trace historical crossover events. From these SNPs, we estimate that Rm (Hudson and Kaplan, 1985), the minimum number of recombination events, in this sample of SD-Mal haplotypes is 15 (Figure 5C). Thus, assuming that these SD-Mal haplotypes are ~16,436 generations old (Figure 4), we estimate that recombination events between SD-Mal haplotypes occur a minimum of once every ~1096 generations. We can thus confirm that crossover events are relatively rare, likely due to the low population frequency of SD-Mal and the possibly reduced fitness of SD_i/SD_j genotypes.

Figure 5

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While crossing over is suppressed in SD-Mal/SD⁺ heterozygotes, gene conversion and/or double crossover events may still occur, accounting for the shared SNPs between SD-Mal and SD⁺ chromosomes within In(2R)Mal. As both events exchange tracts of sequence, we expect shared SNPs to occur in runs of sites at higher densities than private SNPs, which should be distributed randomly. Accordingly, in In(2R)Mal, SNP density is five times higher for runs of shared SNPs (0.63 SNPs/kb) than for runs of SD-private SNPs (0.12 SNPs/kb), as expected if SD⁺ chromosomes, which have higher SNP densities, were donors of conversion tract sequences. Although we cannot exclude the contribution of double crossovers, we note that 62.2% (89 out of 143) of the shared SNP runs are <1 kb, 80.4% (115 out of 143) are <10 kb (Figure 5B), and the longest run is ~50.2 kb. These sizes are more consistent with current estimates of gene conversion tract lengths in D. melanogaster than with double cross-overs (Comeron et al., 2012; Miller et al., 2016). Surprisingly, these inferred gene conversion events are unevenly distributed across In(2R)Mal, being more frequent in the In(2R)Mal-p than in In(2R)Mal-d (Supplementary file 3). Our discovery that SD-Mal haplotypes can recombine with each other distinguishes the SD-Mal supergene from supergenes that are completely genetically isolated (Wang et al., 2013; Charlesworth, 2016; Tuttle et al., 2016). The lack of crossing over with SD⁺ chromosomes, however, means that SD-Mal haplotypes evolve as a semi-isolated subpopulation, with a nearly 100-fold smaller N_e and limited gene flow from SD⁺ via gene conversion events. The reduced recombination, low N_e, and history of epistatic selection may nevertheless lead to a higher genetic load on SD-Mal than SD⁺ chromosomes. We therefore examined the accumulation of deleterious mutations, including non-synonymous mutations and TEs, on the SD-Mal supergene.

Consequences of reduced recombination, small effective size, and epistatic selection

We first studied the effects of a reduced efficacy of selection on SNPs in In(2R)Mal. As many or most non-synonymous polymorphisms are slightly deleterious (Ohta, 1976; Fay et al., 2001; Eyre-Walker et al., 2002; Keightley and Eyre-Walker, 2007; Eyre-Walker and Keightley, 2009), relatively elevated ratios of non-synonymous to synonymous polymorphisms (N/S ratio) can indicate a reduced efficacy of negative selection. For the SNPs in In(2R)Mal, the overall N/S ratio is 2.3-fold higher than that for the same region of SD⁺ chromosomes (Table 4). Notably, the N/S ratio for private SNPs is 3.1-fold higher (Table 4), whereas the N/S ratios for shared SNPs do not significantly differ from SD⁺ chromosomes (Table 4, Figure 6—figure supplement 1). These findings suggest that gene conversion from SD⁺ ameliorates the accumulation of potentially deleterious non-synonymous mutations on SD-Mal chromosomes (see also Kelemen and Vicoso, 2018; Pieper and Dyer, 2016).

Table 4

	Genotype	N	S	N/S	Fold change	p-value
All SNPs	SD-Mal	79	114	0.69	2.27	<0.0001
	SD+	10,470	34,301	0.31
Private SNPs	SD-Mal	61	55	1.11	3.10	<0.0001
	SD+	6782	18,938	0.36
Shared SNPs	SD-Mal	18	59	0.31	1.27	0.3722
	SD+	3688	15,363	0.24

1. Counts of non-synonymous (N) and synonymous (S) SNPs in the In(2R)Mal region of SD-Mal chromosomes, and the equivalent region of uninverted, SD⁺ chromosomes. N/S ratio per genotype, fold-change of N/S ratios between SD-Mal and SD⁺. p-values reported by Pearson’s χ² test of independence.

Gene conversion may not, however, rescue SD-Mal from deleterious TEs insertions, as average TE length exceeds the average gene conversion tract length (Kaminker et al., 2002). TEs accumulate in regions of reduced recombination, such as centromeres (Charlesworth et al., 1994) and inversions, especially those at low frequency (Eanes et al., 2009; Sniegowski and Charlesworth, 1994). Indeed, TE densities for the whole euchromatic region of chromosome 2R are significantly higher for SD-Mal compared to SD⁺ chromosomes (Figure 6A). This increased TE density on SD-Mal is driven by the low recombination regions of the haplotype: In(2R)Mal has significantly higher TE density than SD⁺ whereas the distal region of 2R outside of the sweep region does not (Figure 6B). The most overrepresented families in In(2R)Mal relative to standard chromosomes are M4DM, MDG1, ROO_I, and LINE elements (Figure 6—figure supplement 2)—TEs that are currently or recently active (Kaminker et al., 2002; Kofler et al., 2015; Diaz-González and Dominguez, 2020)—consistent with the recent origin of the SD-Mal haplotype. Thus, the differences in shared vs. private SNPs suggests that gene conversion from SD⁺ chromosomes may slow the accumulation of deleterious point mutations but not the accumulation of TEs. Despite occasional recombination, the small N_e of SD-Mal haplotypes has incurred a higher genetic load.

Figure 6 with 3 supplements see all

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Raw sequence data are deposited in NCBI's short read archive under project accession PRJNA649752. All code for data analysis and figure generation is available in Github (https://github.com/bnavarrodominguez/sd_popgen, copy archived at swh:1:rev:e012c1df579871600334847e254a1ecc6c053592). Data and code will be deposited in Dryad digital repository.

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Author details

1. Beatriz Navarro-Dominguez

   Department of Biology, University of Rochester, Rochester, United States

   Present address

   Departamento de Genética, Universidad de Granada, Granada, Spain

   Contribution

   Formal analysis, Investigation, Methodology, Software, Validation, Visualization, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-4077-8696

2. Ching-Ho Chang

   Department of Biology, University of Rochester, Rochester, United States

   Present address

   Fred Hutchinson Cancer Research Center, Seattle, United States

   Contribution

   Formal analysis, Investigation, Software, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-9361-1190

3. Cara L Brand

   Department of Biology, University of Rochester, Rochester, United States

   Present address

   Department of Biology, University of Pennsylvania, Philadelphia, United States

   Contribution

   Investigation, Writing – review and editing

   Competing interests

   No competing interests declared

4. Christina A Muirhead

   1. Department of Biology, University of Rochester, Rochester, United States
   2. Ronin Institute, Montclair, United States

   Contribution

   Investigation, Methodology, Software, Writing – review and editing

   Competing interests

   No competing interests declared

5. Daven C Presgraves

   Department of Biology, University of Rochester, Rochester, United States

   Contribution

   Conceptualization, Formal analysis, Funding acquisition, Investigation, Project administration, Resources, Supervision, Writing – original draft, Writing – review and editing

   For correspondence

   daven.presgraves@rochester.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-4337-4072

6. Amanda M Larracuente

   Department of Biology, University of Rochester, Rochester, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Software, Supervision, Writing – original draft, Writing – review and editing

   For correspondence

   alarracu@UR.Rochester.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-5944-5686

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