During meiosis in sexually reproducing organisms, a reductive cell division produces haploid gametes (sperm and egg) that give rise to offspring. A foundation of Mendelian genetics is the equal meiotic segregation and gamete transmission of parental alleles (or chromosomes). Meiotic drive defies Mendelian genetics by biasing gamete transmission (> 50 %) of one parental chromosome or set of alleles over competing homologous chromosomes (homolog) [1]. Genetic elements, called drivers, are present on meiotic drive chromosomes and cause transmission bias by disrupting the competing homolog from segregating into gametes (e.g., egg) or by influencing post-meiotic gamete fitness (e.g., sperm) [1]. Female meiotic drivers in mammals can promote their own meiotic segregation into the oocyte, leaving the competing homolog to the non-transmitted polar body [2]. Male meiotic drivers can act post-meiotically to disrupt the fitness of developing sperm carrying the competing homolog [2]. Regardless of the mechanism, one or more drivers on the chromosome exhibiting meiotic drive cooperate to impair transmission of homologs to offspring [1].

This review focuses on two prominent genomic signatures of meiotic drive: (1) suppressed meiotic crossing over (hereafter termed recombination) and (2) acquisition of rapidly evolving, multicopy gene families. Most meiotic drivers are found in large chromosomal regions of suppressed recombination [1], [2], [3]. Suppressed recombination is beneficial to the evolution of drivers because it (1) allows multiple drivers to evolve in genetic linkage and cooperate, (2) limits drivers from being lost or uncoupled by recombination, and (3) enables driver alleles to evolve independently of syntenic, non-driving alleles on competing homologs [1], [3]. The evolution of drivers can lead to suppressors on the competing homolog or elsewhere to restore equal transmission [3]. The tug-of-war between drivers and suppressors can result in an evolutionary arms race whereby competing loci repeatedly duplicate into multicopy gene families that facilitate rapid evolution to gain a transmission advantage [3], [4], [5], [6]. While additional genomic signatures of drive likely exist, suppressed recombination and acquisition of rapidly evolving, multicopy, gene families are prominent genomic signatures in chromosomes exhibiting meiotic drive.

The mouse t-haplotype and Drosophila melanogaster segregation distorter (SD) are two notable autosomal meiotic drivers highlighting the importance of suppressed recombination and multicopy gene families on chromosomes with meiotic drive. The t-haplotype is a variant of mouse chromosome 17 transmitted to nearly 99 % of offspring from heterozygous males [7], [8]. At least four large inversions have suppressed recombination between the t-haplotype and non-t-haplotype chromosome 17 [9], [10], [11], [12], [13]. Within the region of suppressed recombination, members of multicopy gene families with male germline expression contribute to biased t-haplotype transmission by disrupting post-meiotic fitness of non-t-haplotype-bearing sperm [8], [14]. Like the t-haplotype, D. melanogaster SD is a variant of chromosome 2, resulting in nearly 100 % transmission over non-SD chromosome 2 (SD+) in heterozygous males [15], [16]. SD has two overlapping paracentric inversions suppressing recombination with SD+ and is genetically linked to Sd, a meiotic driver gene that arose via gene duplication [17], [18], [19], [20], [21]. Sd interacts with target loci on SD+ post-meiosis to disrupt the development of SD+-bearing sperm, thus biasing transmission of SD [15]. For both the t-haplotype and SD, rare recombination events disrupt genetic linkage between multiple driver loci and reduce transmission bias, thus underscoring the selective advantage of suppressed recombination for cooperating meiotic drivers to evolve [22], [23], [24], [25], [26]. The similarities between the t-haplotype and SD in mice and flies support suppressed recombination and the acquisition of rapidly evolving, multicopy gene families as genomic signatures of meiotic drive.

Heteromorphic sex chromosomes are similar to autosomal meiotic drive chromosomes because they can have large regions of suppressed recombination and enrichment of rapidly evolving, multi-copy gene families [27], [28], [29], [30], [31]. In Mus musculus, the sex chromosomes recently acquired rapidly evolving multicopy driver gene families on the X and Y chromosomes that compete to skew the number of male versus female offspring (i.e. sex ratio distortion) [4], [32]. Similarly, D. simulans have at least three independent, multi-copy meiotic drivers (Winters, Durham, and Paris) on the X chromosome that contribute to female-biased sex ratios when suppressors are absent [33], [34], [35], [36], [37], [38]. Indeed, heteromorphic sex chromosomes are considered ‘hotspots’ for the origination and recurrent evolution of meiotic drivers [39]. However, there is an ascertainment bias in detecting X versus Y chromosome meiotic drive systems because of the easily observable sex ratio distortion. Autosomal meiotic drive may be as pervasive as sex chromosome meiotic drive but is difficult to detect without an easily observable phenotype, like male versus female sex. Despite our limited knowledge of autosomal meiotic drivers, they still share the genomic signatures of meiotic drive found on sex chromosomes.

Shared genomic signatures of meiotic drive on autosomes and sex chromosomes begs the question: could meiotic drive initiate sex chromosome evolution and continually reshape sex chromosomes by acquiring new drivers? We define sex chromosome evolution as the divergence between heteromorphic sex chromosomes. While it is challenging to demonstrate that meiotic drivers initiate sex chromosome evolution, there are multiple examples of how meiotic drive shapes the ongoing evolution of heteromorphic XY sex chromosomes in animals [40]. In this review, we first propose a model of how meiotic drive can influence the initiation and ongoing evolution of sex chromosomes. Second, we discuss experimental approaches to study the evolution and identification of meiotic drivers in non-traditional model organisms with recently evolved sex chromosomes. This review focuses on shared genomic signatures of meiotic drive and sex chromosome evolution in XY sex chromosome systems of multicellular organisms. While several concepts from this review can be applied to ZW chromosome evolution, meiotic drive in unicellular organisms and molecular mechanisms of drive, these topics are the focus of reviews covered by others [2], [3], [5], [41], [42], [43], [44].

Recombination suppression is a key feature for the initiation and ongoing evolution of heteromorphic sex chromosomes (e.g. XY), as it allows two homologous regions to evolve independently and diverge from one another. The selective advantage driving the initiation of recombination suppression between heteromorphic sex chromosomes lacks experimental support. Prevailing views suggest an accumulation of male beneficial alleles, sexually antagonistic alleles, and sex-determining loci on one of the two sex chromosomes provides a selective advantage for recombination suppression [27], [45], [46]. However, this evolutionary theory has been challenging to support empirically. We propose meiotic drive can initiate and sustain the ongoing divergence of heteromorphic sex chromosomes. Recent accumulation of high-quality genome assemblies across diverse species with independently evolved sex chromosomes reveals convergent genomic signatures of meiotic drive (i.e., suppressed recombination and acquisition of multicopy gene families) regardless of their origin or sex determination mechanism [31], [47], [48], [49], [50]. Experimentally testing meiotic drive as a selective force underlying heteromorphic sex chromosome evolution may expand our perspective of how and why sex chromosomes evolve. Based on shared genomic features of meiotic drive among independently evolved sex chromosomes, we consider a meiotic drive-based model of how some sex chromosomes are initiated and continuously shaped by newly acquired meiotic drivers (Fig. 1).

Our model begins with a pair of homologous autosomes undergoing recombination suppression (e.g., via an inversion) and acquisition of a meiotic driver mutation. It is difficult to determine whether an inversion or meiotic driver mutation happens first, and either scenario is possible. However, since large inversions are widespread, polymorphic within populations, and a common source of genetic variation, we favor a large inversion preceding the acquisition of a driver mutation [51], [52], [53], [54], [55]. Suppressed recombination within an inversion creates a permissible genomic environment for one or more meiotic drivers to evolve independently on the inverted or non-inverted chromosome [51]. In most known cases of meiotic drive, multiple driver loci can arise within a region of suppressed recombination and cooperate in cis to promote their own transmission over the competing homolog [1], [2], [3]. For instance, the mouse t-haplotype is polymorphic in wild mouse populations and independently acquired driver mutations not present on the non-t-haplotype chromosome 17 [8], [56]. Within the mouse t-haplotype, a central meiotic driver (i.e., responder) functions in a common pathway with at least four other drive loci (i.e. distorters) that have an additive effect on transmission bias of the t-haplotype [8]. Once meiotic drive initiates, it can lead to strong selective pressures for the genome to adapt.

Transmission distortion of meiotic drivers can lead to their rapid fixation within a population unless suppressors evolve to compete with existing meiotic drive chromosomes and restore Mendelian transmission. Without suppression, meiotic drivers can quickly reach fixation such that all individuals in a population are homozygous and transmission distortion is absent [44]. Evidence of such cryptic meiotic drivers can be unveiled by hybrid crosses between distinct populations [44], [57]. Alternatively, strong selective pressure for suppressor mutations on the competing homolog or elsewhere in the genome can combat meiotic driver transmission distortion. For example, an X-linked suppressor of D. melanogaster SD restores transmission ratios in SD/SD+ males, and certain mouse genetic backgrounds completely suppress t-haplotype transmission distortion [58], [59]. Successful suppressors can also become fixed within populations to maintain Mendelian transmission, or face counter-adaptations from existing or new meiotic drivers that initiate a cycle of meiotic drive.

When suppressors of meiotic drive evolve, selection for counter adaptations on driver chromosomes can initiate a cycle of ongoing meiotic drive. First, repeated duplication of existing drivers and suppressors can facilitate their rapid evolution and selection for a transmission advantage, thus giving rise to rapidly evolving, multicopy gene families [2], [3], [5], [6]. Second, new rapidly evolving driver genes may evolve that subvert existing suppressors or strengthen existing drivers. Additional inversions can facilitate the evolution of new drivers that could elicit another bout of competition, repeated duplications, and rapid evolution. For instance, recent inversions linked to SD in D. melanogaster restore meiotic drive on an otherwise suppressed SD haplotype [60]. Additionally, independent inversions on the mouse t-haplotype have an additive effect on transmission distortion, suggesting acquisition of new meiotic drivers with each inversion [8]. The full scope of meiotic drivers responsible for restoring or strengthening meiotic drive on SD and t-haplotype chromosomes are not yet known. Thus, the cycle of ongoing meiotic drive can lead to step-wise recombination suppression and evolutionary arms races among rapidly evolving multicopy genes giving rise to heteromorphic chromosomes [4], [39], [61], [62].

Once meiotic drive establishes a path toward heteromorphic chromosome evolution, the competing chromosomes are primed to become X or Y chromosomes by acquiring sex determining function. Sex determination pathways can change quickly [48], [63], [64]; thus, chromosomes with meiotic drive provide fertile genomic environments for new sex determination pathways to evolve. A sex determining function may evolve as a single master regulator gene, a collection of genes influencing male versus female fates, or even a meiotic driver could acquire sex determining function. Regardless of how sex determination establishes the competing chromosomes as sex chromosomes, the ongoing acquisition of new meiotic drivers and suppressors (i.e., meiotic drive cycling) can continue to shape their genomic landscape.

Once established, sex chromosomes can face ongoing meiotic drive via cycling of drivers and suppressors, or from novel chromosomes that arise via rearrangements of existing sex chromosomes. Meiotic drive cycling can replace “old” drivers with “new” drivers. An example of meiotic drive cycling on sex chromosomes is found in D. simulans where three X-linked meiotic drive systems, Winters, Durham and Paris, cause X chromosome transmission bias (and female-biased sex ratios) when autosomal suppressors or Y-linked competing loci are absent [33], [34], [35], [36], [37], [38]. Winters and Durham are ancient meiotic drivers suprressed by competing loci on the Y chromosome. However, Paris is a recently evolved X-linked meiotic driver not suppressed by drive-resistant Y-chromosomes of Winters and Durham, thus highlighting a cycle of meiotic drive on sex chromosomes. The Winters, Durham and Paris meiotic drivers are rapidly evolving multi-copy gene families presumed to influence the corresponding rapid evolution of Y-linked repetitive sequences that serve as targets for or suppressors of drivers, emphasizing the influence of meiotic drive on the genomic landscape.

In some cases, rearrangement of existing sex chromosomes gives rise to a third sex chromosome that can enter the meiotic drive competition between existing sex chromosomes. For instance, chromosomal fusions involving sex chromosomes (e.g. autosome-X/Y or X-Y fusion) can create novel regions of suppressed recombination for “new” drivers to evolve and replace “old” drivers (see below examples in Creeping vole and D. miranda) [65], [66]. Rearrangements on an existing sex chromosome, such as a large inversion, also create novel regions of suppressed recombination where new meiotic drivers can evolve. For example, in the wood lemming (Myopus schisticolor), a large X-linked inversion gave rise to a variant X* chromosome presumed to have male sex reversing mutations leading to X*Y females, and meiotic drive mutations resulting in complete X* chromosome drive in X*Y females (i.e. 100 % X* transmission) [67], [68], [69], [70], [71]. X*X females transmit each X chromosome equally, but X*Y females eliminate Y-bearing oocytes in the developing germline to produce only female offspring [71], [72], [73]. The wood lemming X* chromosome possibly arose as a meiotic driver that competes with the existing Y chromosome. Regardless of rearrangement mechanism, meiotic drive may provide a selective advantage for new sex chromosomes to co-exist with, or replace, existing sex chromosomes [74], [75], [76].

Our model posits that chromosomes harboring meiotic drivers provide “fertile” ground to initiate formation of “new” sex chromosomes. The emergence of “new” meiotic driving sex chromosomes could replace (i.e., turnover) ancestral or “old” sex chromosomes. An example of sex chromosome turnover is the Drosophila dot chromosome, aformer X chromosome replaced by new sex chromosomes that evolved from a pair of autosomes [77]. The Drosophila dot chromosome highlights that sex chromosomes are not terminal points in evolution, but rather part of a cycle of sex chromosome turnover. It is not known whether meiotic drive underlies sex chromosome turnover in Drosophila, but meiotic drive competition creates intense selective pressure that could overcome the fitness costs of sex chromosome turnover [78], [79], [80], [81]. Based on our model, meiotic drive plays a central role in the lifecycle of sex chromosome turnover. However, despite the striking parallels between meiotic drive chromosomes and sex chromosomes on which our model is founded, not all chromosomes with meiotic drive will become sex chromosomes, nor will sex chromosomes always harbor meiotic drivers. As genome assemblies and gene-editing approaches improve and novel sex chromosomes are discovered, we can delve deeper into experimental strategies to test meiotic drive-based models of sex chromosome evolution.