www.nature.com/hdy ARTICLE OPEN Fragile, unfaithful and persistent Ys—on how meiosis can shape sex chromosome evolution 1,2,4 ✉ ✉ Aurora Ruiz-Herrera and Paul D. Waters3,4 © The Author(s) 2022 Sex-linked inheritance is a stark exception to Mendel’s Laws of Heredity. Here we discuss how the evolution of heteromorphic sex chromosomes (mainly the Y) has been shaped by the intricacies of the meiotic programme. We propose that persistence of Y chromosomes in distantly related mammalian phylogroups can be explained in the context of pseudoautosomal region (PAR) size, meiotic pairing strategies, and the presence of Y-borne executioner genes that regulate meiotic sex chromosome inactivation. We hypothesise that variation in PAR size can be an important driver for the evolution of recombination frequencies genome wide, imposing constraints on Y fate. If small PAR size compromises XY segregation during male meiosis, the stress of producing aneuploid gametes could drive function away from the Y (i.e., a fragile Y). The Y chromosome can avoid fragility either by acquiring an achiasmatic meiotic XY pairing strategy to reduce aneuploid gamete production, or gain meiotic executioner protection (a persistent Y). Persistent Ys will then be under strong pressure to maintain high recombination rates in the PAR (and subsequently 1234567890();,: genome wide), as improper segregation has fatal consequences for germ cells. In the event that executioner protection is lost, the Y chromosome can be maintained in the population by either PAR rejuvenation (extension by addition of autosome material) or gaining achiasmatic meiotic pairing, the alternative is Y loss. Under this dynamic cyclic evolutionary scenario, understanding the meiotic programme in vertebrate and invertebrate species will be crucial to further understand the plasticity of the rise and fall of heteromorphic sex chromosomes. Heredity (2022) 129:22–30; https://doi.org/10.1038/s41437-022-00532-2 SEX CHROMOSOMES AND RECOMBINATION ARE EXCEPTIONS differentiated heteromorphic sex chromosomes show different TO MENDELIAN INHERITANCE inheritance patterns to those on autosomes (non-sex chromo- Mendel’s paramount observations can be considered one of the somes). In addition, the sex-limited chromosome (the Y or W) does great discoveries in biology and are summarised into three laws of not undergo recombination, with the exception of the pseudoau- heredity: (i) Law of Independent Assortment; (ii) Law of tosomal region (PAR) (Hinch et al. 2014; Raudsepp and Chowdhary Dominance; and (iii) Law of Segregation (Castle 1903). Under the 2015), so genes on them do not assort independently. This first law (independent assortment), genes for different traits are contrasts with autosomes, in which a recombination event occurs inherited independently of one another. Under the second law during the formation of germ cells (in a single generation) that can (dominance), in crosses between homozygous parents for a break gene assemblies that are physically linked. contrasting character, only one character of the parent appears in Here we discuss how the intricacies of the meiotic programme the first generation. Finally, the third law (segregation) postulates have shaped the evolution of differentiated heteromorphic sex that each egg or sperm cell receives just one of two copies of each chromosomes (mainly the Y), resulting in exceptions to Mendelian chromosome during germ cell production, with the copy inheritance. We walk through basic concepts of meiotic progres- randomly allocated to gametes. sion and chromosome dynamics in germ cells (meiocytes), George Mendel himself soon realised that his observations in coupled with a description of variation in recombination rates peas presented some limitations, and over the century and a half between phylogroups and the sexes (heterochiasmy). We then that followed his investigations exceptions to Mendelian inheri- present an integrative hypothesis on how the cellular control of tance have arisen. These include phenomena such as co- the meiotic programme and the mechanistic constraints of dominance, incomplete dominance, epistasis, pleiotropy and recombination can shape sex chromosome evolution. Although lethal alleles, among others (Castle 1903; Bateson 1909; Castle we focus mainly on mammals (i.e., system for which most and Little 1910; Wright 1968; Stearns 2010). Sex-linked inheritance information is available), our proposed model could apply to any represents one of these exceptions, as genes carried on differentiated XY or ZW sex chromosome system. 1 Genome Integrity and Instability Group, Institut de Biotecnologia i Biomedicina (IBB), Universitat Autònoma de Barcelona (UAB), Cerdanyola del Vallès 08193, Spain. 2 Departament de Biologia Cel·lular, Fisiologia i Immunologia, Universitat Autònoma de Barcelona (UAB), Cerdanyola del Vallès 08193, Spain. 3School of Biotechnology and Biomolecular Sciences, Faculty of Science, UNSW Sydney, Sydney, NSW 2052, Australia. 4These authors contributed equally: Aurora Ruiz-Herrera, Paul D. Waters. Associate editor: Barbara Mable. ✉email: aurora.ruizherrera@uab.cat; p.waters@unsw.edu.au Received: 14 December 2021 Revised: 27 March 2022 Accepted: 28 March 2022 Published online: 22 April 2022 A. Ruiz-Herrera and P.D. Waters 23 MEIOSIS AND RECOMBINATION recombination events or DSB sites in meiotic cells; Pan et al. 2011; Recombination is essential for sexual reproduction due to its dual Dumont and Payseur 2011; Smagulova et al. 2011; Brick et al. 2012; role in: (i) assembling new combinations of allelic variants that Segura et al. 2013; Fowler et al. 2014; Ruiz-Herrera et al. 2017) or generate and maintain genotypic diversity; and (ii) establishing indirect measurements of recombination (i.e., estimation of physical associations between homologous chromosomes to recombination rates using linkage data; Ellegren et al. 2012; Chan enable their faithful segregation during meiosis. From extensive et al. 2012; Munch et al. 2014; Sparks et al. 2019; Turbek et al. work done in model organisms (i.e., yeast, fruit flies, nematodes, 2021). mice) and humans it is known that recombination occurs during Empirical studies using both direct and indirect approaches the first meiotic prophase, which is organised into five stages: have described variation in recombination rates within meiotic leptonema, zygonema, pachynema, diplonema and diakinesis (Fig. cells of the same individual, between individuals, populations, 1A). At leptonema, programmed double-strand breaks (DSBs) are sexes and species, influencing patterns of heritability (Capilla et al. generated and homologous chromosomes start to condense, pair 2016; Stapley et al. 2017; Wang et al. 2019; Vara et al. 2021; and synapse. Chromosomes adhere to the nuclear envelope by Johnston et al. 2016; Kawakami et al. 2019). DSBs induced in early their telomeres in the bouquet structure (reviewed in Reig-Viader prophase I are higher in number than the final CO number, in et al. 2016), prompting the formation of the proteinaceous some cases substantially more (≥10-fold) (Cole et al. 2012). The structure of the synaptonemal complex (SC) that, together with DSBs:COs ratio can vary between species, from 10:1 in mice to 3:1 meiotic cohesins, acts as a scaffold for chromosome synapsis and in carnivores (Segura et al. 2013), likely influencing the observed recombination. differences in recombination rates. The formation of DSBs activates the DNA damage response Early genetic studies (Carpenter 1988) noticed that COs were (DDR) mechanism (Baudat et al. 2010; Myers et al. 2010; Parvanov non-randomly distributed along chromosomes (i.e., recombina- et al. 2010), an integral part of the meiosis programme. Both DSB tion hotspots), which were later identified by the immunodetec- formation and DDR are tightly regulated by meiotic checkpoints, tion of MLH1 (Baker et al. 1996; Anderson et al. 1999; Lynn et al. including (i) the response to unrepaired DSBs; (ii) transcriptional 2002). After decades of study in different organisms it is repression called meiotic silencing of unsynapsed chromatin currently accepted that the chromosomal distribution of COs (MSUC); and (iii) the spindle assembly checkpoint (Subramanian exhibits four specific features, which are conserved in most and Hochwagen 2014) (Fig. 1A). Sex chromosomes are subjected species (Fig. 2A): (i) the presence of an obligatory CO; (ii) the to transcriptional silencing during the first male meiotic division phenomenon of CO interference; (iii) the centromeric effect; and by a phenomenon called meiotic sex chromosome inactivation (iv) CO homeostasis. (MSCI), a sex chromosome-specific extension of MSUC (Turner (i) Obligatory CO: there is normally a minimum of one CO per 2005) (Fig. 1B). This is observed in pachynema spermatocytes as chromosome arm or chromosome, the so-called obligatory the ‘sex body’, which is enriched for repressive histone modifica- chiasma (Bishop and Zickler 2004; Zickler and Kleckner 2015). tions (Handel 2004). This serves to establish a necessary physical connection between Importantly, the SC establishes the chromosomal context in homologous chromosomes during prophase I to avoid aneuploi- which synapsis and recombination between homologues take dies after chromosome segregation. This is a widely conserved place (Fig. 1C). The successful progression of early prophase I is pattern in eukaryotes (Zickler and Kleckner 1999; de Villena and dependent on the assembly of chromatin loops into chromosomal Sapienza 2001; Segura et al. 2013). axes and the formation and repair of DSBs (Keeney et al. 1997; (ii) CO interference: when a CO forms at one site of the Romanienko and Camerini-Otero 2000; Longhese et al. 2009). chromosome this interferes with the establishment of COs at Crucially, the higher-order meiotic chromosome structure reg- adjacent sites due to ‘interference’, resulting in evenly spaced COs ulates the number and distribution of DSBs, and hence the final (Muller 1916; Kleckner et al. 2003; Wang et al. 2015). This process is number of crossovers (COs) per cell (Zickler and Kleckner 1999; pervasive, and although the mechanisms behind it are not Kleckner 2006; Vara et al. 2021). This, in turn, results in a close currently fully understood, two types of models to explain CO interplay between SC length and DNA loop size, influencing CO interference: mechanical models and diffusion-based models distribution (Zickler and Kleckner 1999; Kleckner 2006). So it (reviewed in von Diezmann and Rog 2021). appears that SC axis length is a quantitative characteristic of (iii) Centromeric effect: centromeres normally act as ‘cold’ synapsis that is strongly associated with recombination rate (Ruiz- regions, with a reduction of COs (Beadle 1932; Mather 1939; Herrera et al. 2017; Wang et al. 2019). Importantly, in humans, the Cappelletti et al. 2019). Low rates of recombination at centromeres varied recombination rates within and between individuals have were initially described in Drosophila using genetic maps, and later been linked to differences in SC length (Lynn et al. 2002). This was confirmed in different taxa ranging from plants to humans (Lynn later confirmed in other taxa (Ruiz-Herrera et al. 2017; Wang et al. et al. 2002; Colome-Tatche et al. 2012). The mechanisms 2019), with a potential impact on the evolution of recombination governing centromere effect are far from understood, but this rates (Wang et al. 2019; Sardell and Kirkpatrick 2020). conserved phenomenon probably indicates the presence of strong selective constraints to avoid disruption of pericentric sister chromatid cohesion (Talbert and Henikoff 2010). PATTERNS OF VARIATION IN RECOMBINATION RATES (iv) CO homeostasis: this phenomenon buffers the system As meiotic recombination influences genome evolution, mamma- against deficits (and excesses) of DSBs in meiocytes (Martini et al. lian recombination landscapes are a reflection of the selective 2006; Yokoo et al. 2012; Cole et al. 2012; Wang et al. 2015). It was forces that affect the DNA sequence itself, the chromosomal initially defined as the maintenance of CO frequency even though distribution of COs (see below), and the three-dimensional precursors of DSBs are fewer (Martini et al. 2006). CO homeostasis genome folding in germ cells (Vara et al. 2021; Vara and Ruiz- balances the ratio between CO and NCOs to maintain the Herrera 2022). Traditionally, theoretical work on the evolution of obligatory CO on each chromosome. This homeostasis is recombination rates has outnumbered the empirical evidence of mechanistically linked to CO interference. As such, COs are recombination variation, especially in natural populations. This maintained in a given cell at the expense of NCOs (Martini et al. was mainly due to the intrinsic difficulties of directly measuring 2006). recombination events. However, this has improved over recent In addition to the four features described above, sex can also years as different approaches have been developed to estimate influence recombination rates. Heterochiasmy (sexual dimorphism the number and genomic distribution of COs. These approaches in recombination rates) has been reported in many taxa, from can be classified as direct measurements (i.e., direct measure of invertebrates to mammals (Morgan 1912; Lynn et al. 2002). Early Heredity (2022) 129:22 – 30 A. Ruiz-Herrera and P.D. Waters 24 Fig. 1 Schematic representation of spermatogenesis. A Stages of spermatogenesis. Spermatogonia commit to meiosis and after DNA duplication, primary spermatocytes undergo meiotic prophase I: leptonema, zygonema, pachynema and diplonema. Double-strand breaks (DBSs) are formed at leptonema, repaired in zygonema, resulting in crossovers (COs) in pachynema. Two meiotic checkpoints are activated in this stage: (i) response to unrepaired DSBs; and (ii) MSUC (meiotic silencing of unsynapsed chromatin) and MSCI (meiotic sex chromosome inactivation). The first and second meiotic divisions result in secondary spermatocytes and round spermatids (RS), respectively. The spindle assembly checkpoint (SAC) is activated during division (metaphase-to-anaphase transition). Spermiogenesis includes the histone to protamine transition and the differentiation of RS into elongated spermatids (ES) and finally spermatozoa. Adapted from (Vara and Ruiz- Herrera 2022). Numbers between parentheses indicate the diploid (2n) haploid (n) number for each cell type and the number of chromatids per chromosome (4c, 2c, or c). B Schematic representation of chromosome pairing and MSCI dynamics during prophase I progression. Description of general patterns is based on evidence in mouse meiosis (adapted from Waters and Ruiz-Herrera 2020). C The formation and repair of DSBs occurs in the context of the SC (Adapted from Dapper and Payseur 2019). The proteins central to different steps during the formation and repair of DSBs, including homology search and strand invasion; synapsis; CO and NCO decision; and CO resolution. Briefly, the DSBs machinery is formed by the MCD recombinosome (MEI4-Containing DSB-promoting), a proteinaceous complex that includes MEI4, REC114 and IHO1 (Robert et al. 2016). Once the double-stranded DNA is resected, SPO11 is erased and posteriorly depleted from the recombination site, leaving 3’ single-stranded overhangs at both sites of DSBs (Lam and Keeney 2015). These 3’ single-stranded overhangs are coated by RPA (Robert et al. 2016), which recruits the recombinases RAD51 and DMC1 to facilitate the homologous search of single-stranded DNA filaments. After resected strands have undergone homology searching and strand invasion, DSBs will be repaired either as crossovers (COs) or non-crossovers (NCOs), with each process modulated by different proteins. COs are Holliday junctions (HdJ) resolved by the MutL complex (composed of MLH1 and MLH3), which is recruited by TEX11 (Dapper and Payseur 2019). HEI10 is also recruited to the SC together with the MutL complex, antagonistically regulating RNF212 (Reynolds et al. 2013). cytological work on human meiocytes observed a co-variation (Fig. 2B). SC length is longer and CO numbers are higher in between SC length and recombination rates in both sexes oocytes than in spermatocytes (Wang et al. 2017), resulting in (Wallace and Hultén 1985; Baker et al. 1996; Lynn et al. 2002) higher recombination rates in females (Fig. 2C). Increased SC Heredity (2022) 129:22 – 30 A. Ruiz-Herrera and P.D. Waters 25 Fig. 2 Crossover patterning. A Specific features that reduce local frequency (red box) of COs (red crosses). Chromosomal distribution of COs is influenced by the obligatory CO, centromeric effect and CO interference. B Schematic representation of general patterns of heterochiasmy in eutherian mammals with high recombination rates in females. C Chromosomes with short chromosomal axes (males) tend to show longer DNA loops than those with long chromosomal axes (females). These longer axes and shorter DNA loops in females result in increased COs (red stars). CO crossover, CEN centromere, TEL telomere, CO crossovers. Table 1. Models of Y evolution. Hypothesis Main features Prediction Reference Dominant Y Dominant testis determining Y chromosome remains as carrier of sex- Reviewed in Marshall chromosome determining genes Graves (2000) Selfish Y Accumulates genes beneficial to males Y chromosome remains as attractor for selfish growth Reviewed in Marshall factors Graves (2000) Wimpy Y Degraded relic of the X having lost In the advent that Y chromosome no longer bears any Aitken and Marshall almost all genes genes required for general functions it will be lost Graves (2002) Fragile Y Small PARs result in aneuploid gametes, Taxa that evolve achiasmatic segregation during male Blackmon and resulting in pressure to remove gene meiosis will rarely lose the Y chromosome Demuth (2014, 2015) function from the Y Persistent Y Meiotic executioner genes are required Only rare transposition events to the X, where they remain Waters and Ruiz- for MSCI, and then must be silenced by subject to obligate meiotic silencing, are heritable, posing Herrera (2020) this mechanism strong evolutionary constraint for the Y chromosome to persist length and heterochiasmy has also been observed in mouse (Lynn (Rice 1996). This absence of recombination signalled the initial et al. 2002), zebrafish (Wallace and Wallace 2003), planarian (Jones demise of Y-borne gene function, leading to its degradation. and Croft 1989) and plants (Drouaud et al. 2007; Capilla-Pérez et al. The mechanisms leading to suppressed recombination have 2021). been extensively debated in the literature (Kratochvíl et al. 2021). We have described that it is important to consider both the It was long thought that inversions on the Y resulted in large cellular context and the molecular constraints underlying the regions of recombination suppression in single events (Lahn and genomic distribution and frequency of meiotic recombination. Page 1999). However, other mechanisms for suppression of But, in order to understand the interplay between sex, recombina- recombination have been proposed, including (i) pre-existing tion and the meiotic programme, we need to explore Y low recombination rates on autosomes that become sex chromo- chromosome evolution. somes (Bergero et al. 2019; Rifkin et al. 2021; Xue et al. 2021); (ii) gradual expansion of suppressed recombination rather than large stepwise suppression (Darolti et al. 2020); (iii) different reproduc- THEORIES OF Y CHROMOSOME EVOLUTION tive strategies (Mackiewicz et al. 2018); and (iv) even a neutral Although the current therian X and Y chromosomes have very model of suppressed recombination (Jeffries et al. 2021). These different structure and gene content, they were once an ordinary models are not necessarily mutually exclusive, with different sex pair of autosomes (Ohno 1967). In the therian ancestor chromosome systems likely losing recombination via one or more (approximately 180 MYA), the proto-Y obtained the testis deter- of these mechanisms (Kratochvíl et al. 2021). Irrespective of how mining gene SRY (Foster et al. 1992). It has been hypothesised that recombination was suppressed, in mammals Y degradation once this new sex-determining system was established, male followed, resulting in the sex-specific chromosome becoming a beneficial alleles accumulated nearby (in linkage disequilibrium) relic of its former self. so that they were more likely inherited in males. Ultimately Once thought to be a dominant element in the genome recombination was suppressed between the X and Y across this (because of its dominant testis determining action), the current region, generating the first male-specific region of the Y degenerated nature of mammalian Y suggests that it is largely a Heredity (2022) 129:22 – 30 A. Ruiz-Herrera and P.D. Waters 26 Fig. 3 Circular nature of therian Y chromosome evolution. Initially, an ordinary pair of autosomes (purple chromosomes) became the therian sex chromosomes (blue chromosome). The proto-Y acquired a testis determining allele (new genetic sex determination [GSD], blue horizontal line) in the therian ancestor, around which male beneficial alleles accumulated (black horizontal lines). Recombination (grey circles between chromosome pairs) was suppressed across this region, signalling that the Y had become wimpy (purple ovals). As PAR size is reduced, the Y becomes fragile. Once a Y is fragile, there are four possible trajectories of evolution: (i) achiasmatic XY meiotic pairing (i.e., all marsupials); (ii) PAR rejuvenation (i.e., addition of pink autosomal material to the PAR in the ancestor to all eutherians); (iii) Y loss; or, (iv) gaining executioner protection (red horizontal line) to become persistent (i.e., still observed in almost all eutherians). Executioner protection could evolve on the Y at any stage that it is fragile; however, it is only shown after rejuvenation of the PAR in the eutherian ancestor. Persistent Y chromosomes, and those with achiasmatic meiotic pairing, are stable with no observation of being lost (green ovals). In a few unusual rodents (e.g., Lasiopodomys mandarinus, Dicrostonyx torquatus, Myopus schistocolor, Mus minutoides; Gil-Fernández et al. 2021; Saunders and Veyrunes 2021), persistent Ys have gained achiasmatic meiotic pairing. In a few other unusual rodent groups (e.g., Ellobius and Ryukyu spiny rats; Arakawa et al. 2002; Matveevsky et al. 2017) executioner protection has been removed, resulting once more in a wimpy and fragile Y, permitting its loss in some species (orange ovals). In these species, different autosomes must have become new sex chromosomes (either XY or ZW), completing the cycle. Green arrows represent evolutionary trajectories that have been observed in different mammal groups. Where there are two green arrows exiting a node, the groups of mammals that those trajectories have occurred in are shown. Grey arrows are proposed evolutionary trajectories despite a lack of observation in nature. Dashed arrows represent the completion of the circle, with a new pair of autosomes to become sex chromosomes. wimpy relic of the X (the so-called wimpy Y—reviewed in Marshall the population. To prevent this aneuploidy stress and movement Graves (2000)) (Table 1). Y chromosome decay has not been linear; of function away from the Y, faithful achiasmatic mechanisms for instead, there were waves of gene loss, presumably from new XY segregation needs to evolve. In marsupial, a dense plate male-specific regions of the Y soon after recombination was structure, rich in SC proteins, ensures faithful segregation in the suppressed with the X (reviewed in Charlesworth 2021). absence of synapsis and recombination during the first meiotic Y chromosomes have also been proposed to be fragile (Table 1) division (Page et al. 2003; Marín-Gual et al. 2022). Alternatively, the (Blackmon and Demuth 2014, 2015). Under the fragile Y PAR can be rejuvenated (extended) by the addition of autosomal hypothesis, a small PAR results in a less faithful pairing of the X material, as occurred in the eutherian ancestor under the addition- and Y during male meiosis, subsequently increasing the stress of attrition hypothesis (Graves 1995). However, as new regions of the aneuploid gamete production as a result of improper segregation. PAR stop recombining, PAR size is reduced and the Y degrades This may impose a selective pressure to remove functions (i.e., further, becoming fragile once more. PAR rejuvenation is only a genes) from the Y chromosome, predisposing it to being lost from temporary reprieve from fragility. So, in the absence of Heredity (2022) 129:22 – 30 A. Ruiz-Herrera and P.D. Waters 27 achiasmatic sex chromosome segregation, it appears that loss faithful pairing and segregation of the sex chromosomes, so the from the population is the inevitable fate of Y (or W) chromo- generation of Y-less gametes is less frequent. Or perhaps a somes in heteromorphic sex chromosome systems (Fig. 3). combination of both results in the observation of fewer XO However, Y chromosomes remain in all but a few therian individuals. That is, larger PARs result in less mis-segregation and a mammal species (i.e., Ryukyu spiny rat and some Ellobius species) more lethal haploinsufficiency effect. (Arakawa et al. 2002; Matveevsky et al. 2017; Furman et al. 2020; Vicoso 2019) since it arose approximately 181 MYA (Cortez et al. Recombination in the PAR 2014). Indeed, the current human Y is relatively stable (Bellott et al. Progressive degeneration of the Y chromosome has led to the 2014, 2017; Cortez et al. 2014). This contrasts with observations in evolution of meiotic mechanisms that ensure faithful XY segrega- other vertebrate clades, in which there is regular sex chromosome tion during male meiosis. In eutherian mammals, most species turnover (Ezaz et al. 2006, 2010). In amphibians, there are some have a PAR (reviewed in Raudsepp and Chowdhary 2016) that has frogs with at least 13 sex chromosome turnover events in evolved at high rates of recombination to ensure an obligate CO 28 species, which occurred within approximately 55 million years during male meiosis (Kauppi et al. 2011). In contrast to autosomes (Jeffries et al. 2018). where DSBs occur every 10 Mbp (Kauppi et al. 2011), PARs are characterised by a recombination rate 10–20-fold higher than the genome average (e.g., 1–2 DSBs every 1 Mbp in rodents) (Kauppi PERSISTENT YS IN THE MEIOTIC CONTEXT et al. 2011). Initial studies proposed that this prevalence of DSB Meiosis in general, and recombination (or the absence of it) more formation in the PAR was induced by a high-order chromosome specifically, are both key elements to sex chromosome evolution. structure distinct from that of the autosomes, such as the However, a unifying framework that accounts for how the meiotic presence of abundant short DNA loops in a relatively long cellular programme can influence sex chromosome evolution is chromosomal axis (Kauppi et al. 2011). This was later demon- still missing. This has been mainly due to the intrinsic difficulties of strated by the accumulation of cis- and trans-acting DSB- directly measuring recombination events and monitoring meiosis promoting proteins in the PAR during early prophase I (Papanikos progression in germ cells of key representative phylogroups. So, et al. 2019; Acquaviva et al. 2020). Whether this observation in despite being perceived as a fragile wimpy, why does the Y mouse holds for other eutherian mammals remains to be chromosome persist across large evolutionary time scales in the experimentally demonstrated. However, evidence of a correlation majority of mammalian species? Here we present an integrative between DSBs, DNA loop size and chromosomal axes length in view on how the meiotic programme and its mechanistic different taxa (Ruiz-Herrera et al. 2017; Wang et al. 2019) suggests constraints can shape the evolution of differentiated sex chromo- this to be the case. somes. We propose that the persistence of Y chromosomes in We propose that in species where the heterogametic sex is different phylogroups can be explained in the context of several achiasmate (that is, sex chromosomes do not pair and recombine), interrelated aspects of sex chromosome biology and meiosis: (i) the absence of a PAR would not impose selective pressure to variation in PAR size; (ii) high recombination rates in the PAR to initiate excessive numbers of DSBs genome wide to ensure a CO in ensure proper segregation; and (iii) MSCI and the presence of a small PAR. Marsupials, which lack a PAR, are characterised by Y-borne executioner genes. some of the lowest recombination rates within mammals (Zenger et al. 2002; Segura et al. 2013) and low number diploid numbers Variation in PAR size: implications for Y evolution (which range from 2n = 10 to 2n = 32, Deakin and O’Neill 2020). In eutherian mammals, the PAR represents a small portion of the Y These low levels of recombination in marsupials could result from chromosome. PAR rejuvenation occurred in the eutherian a reduction of DSB formation genome wide (Marín-Gual et al. ancestor (after marsupial divergence, but pre-eutherian radiation) 2022). As a result of no PAR, DSBs are only required at a frequency under the addition-attrition model of sex chromosome evolution sufficient to result in obligatory COs on the few large autosomes. (Graves 1995). After PAR extension by this autosomal addition (Fig. 3), recombination was further suppressed between the X and MSCI and the presence of Y-borne executioner genes Y. Different rates of Y degradation and recombination suppression Whether the heterogametic sex is achiasmate (i.e., marsupials and within phylogroups resulted in variation of PAR size among some rodent species), or not (i.e., eutherian mammals), MSCI mammals, from ≈700 Kbp in mice to ≈10 Mbp in alpaca (Raudsepp occurs and is a necessary checkpoint to ensure proper meiotic et al. 2012). In some eutherian clades (e.g., some bat, rodents, progression. It was recently proposed that the unique features of bovids and primates) the PAR has been rejuvenated, (Murata et al. MSCI might explain the persistence of the Y chromosome in most 2012; Britton-Davidian et al. 2012; Rahn et al. 2016; Vozdova et al. eutherian species (Waters and Ruiz-Herrera 2020). That is, Y-borne 2016) presumably resulting in new Y specific material after the meiotic executioner genes, integral to meiotic checkpoints, lead to suppression of recombination between the X and Y in the the persistence of Y chromosomes in species with MSCI (i.e., a extended PAR. persistent Y, Table 1). Meiotic executioners are pachytene lethal if Variation in PAR size is an important driver for Y evolution under they escape MSCI (Royo et al. 2010; Vernet et al. 2016), resulting in the fragile Y hypothesis (Blackmon and Demuth 2014, 2015) the production of inviable gametes. In addition to executing the (Table 1). Y losses in the offspring (i.e., XO individuals) are cell when ectopically expressed, to be a truly selfish element that frequently found in species with small PARs (0.7–2.7 Mb, i.e., protects the Y, executioners are also required for the initiation of human, mouse and horse; reviewed in Raudsepp and Chowdhary MSCI (Royo et al. 2010; Vernet et al. 2016). The result is a gene that 2016) with negative (often fatal) consequences for the individual if has evolved to become its own sensor. not mosaic as reported in human and horse (Raudsepp et al. Under the persistent Y hypothesis (Waters and Ruiz-Herrera 2012). This aneuploidy stress would put pressure on the critical 2020), once a Y chromosome is under execution protection, it functions to be moved from the Y to the autosomes, as has been cannot be lost from the population. The Y as a unit is required for observed in mammals (Hughes et al. 2015). successful MSCI, to which it must then be subject. Under no In contrast, in domestic species with larger PARs (>5 Mb, i.e., circumstance can viable Y-less gametes be produced. Should an ruminants, pigs and carnivores; reviewed in Raudsepp and executioner be translocated to an autosome, MSCI proceeds but Chowdhary 2016) XO individuals are infrequently observed, the executioner escapes silencing and the cell dies. The only potentially as a result of more haploinsufficient genes being location in the genome to which an executioner gene can move is lethal (Raudsepp et al. 2012). However, it is tempting to speculate the X chromosome. From there it must retain its function to that under the fragile Y hypothesis, a larger PAR results in more properly initiate MSCI, so that it is appropriately silenced, Heredity (2022) 129:22 – 30 A. Ruiz-Herrera and P.D. Waters 28 permitting meiosis to proceed. Indeed, the movement of REFERENCES executioner genes from the Y to the X preceded Y chromosome Acquaviva L, Boekhout M, Karasu ME, Brick K, Pratto F, Li T et al. (2020) Ensuring loss in Y-less rodent species (reviewed in Waters and Ruiz-Herrera meiotic DNA break formation in the mouse pseudoautosomal region. Nature 2020). In eutherian mammals, Zfy acts as the executioner, and its 582:426–431 translocation to an autosome explains complete azoospermia Aitken RJ, Marshall Graves JA (2002) Human spermatozoa: the future of sex. Nature reported in a horse (Ruiz et al. 2019; Bugno-Poniewierska and 415:963–963 Anderson LK, Reeves A, Webb LM, Ashley T (1999) Distribution of crossing over on Raudsepp 2021). It is important to note that persistent Ys are only mouse synaptonemal complexes using immunofluorescent localization of possible in clades with MSCI already established, providing a MLH1 protein. Genetics 151:1569–1579 haven from which genes can evolve a selfish executioner function. Arakawa Y, Nishida-Umehara C, Matsuda Y, Sutou S, Suzuki H (2002) X-chromosomal The evolution of executioner function is a fascinating question, localization of mammalian Y-linked genes in two XO species of the Ryukyu especially in light of the fact that Zfy was part of an addition to the spiny rat. Cytogenetic Genome Res 99:303–309 sex chromosomes in the eutherian ancestor, and remains Baker SM, Plug AW, Prolla TA, Bronner CE, Harris AC, Yao X et al. (1996) Involvement autosomal in marsupials (Waters et al. 2001). Being a pachytene of mouse Mlh1 in DNA mismatch repair and meiotic crossing over. Nat Genet lethal executioner gene, it is no surprise that Zfy expression is low 13:336–342 in the spermatocytes of representative eutherian species (Murat Bateson W (1909) Mendel’s principles of heredity. University Press, Cambridge Baudat F, Buard J, Grey C, Fledel-Alon A, Ober C, Przeworski M et al. (2010) PRDM9 is a et al. 2021). However, what function could it play from an major determinant of meiotic recombination hotspots in humans and mice. autosome in non-eutherian species? Science 327:836–840 In opossum, platypus and chicken, Zfy is annotated as its X Beadle GW (1932) A possible influence of the spindle fibre on crossing-over in homologue, Zfx. In each of these species, Zfx expression is Drosophila. Proc Natl Acad Sci USA 18:160–165 maintained in spermatocytes (Murat et al. 2021), suggesting that Bellott DW, Hughes JF, Skaletsky H, Brown LG, Pyntikova T, Cho TJ et al. (2014) the Zfx/y precursor was not pachytene lethal. Therefore, it could Mammalian Y chromosomes retain widely expressed dosage-sensitive reg- only have gained this aspect of executioner function after arriving ulators. Nature 508:494–499 on the eutherian Y chromosome. It is unclear if the Zfx/y precursor Bellott DW, Skaletsky H, Cho TJ, Brown L, Locke D, Chen N et al. (2017) Avian W and already had a function in initiating MSCI before its translocation to mammalian Y chromosomes convergently retained dosage-sensitive regulators. Nat Genet 49:387–394 the Y; however, it is tempting to speculate that it did. In opossum Bergero R, Gardner J, Bader B, Yong L, Charlesworth D (2019) Exaggerated hetero- and platypus, in which MSCI occurs, Zfx expression is elevated in chiasmy in a fish with sex-linked male coloration polymorphisms. Proc Natl spermatocytes compared to other cell types (Murat et al. 2021). Acad Sci USA 116:6924–6931 In contrast, Zfx expression in chickens is only elevated in pre- Bishop DK, Zickler D (2004) Early decision; meiotic crossover interference prior to meiotic cells (i.e., spermatogonia). But since birds have a ZW sex stable strand exchange and synapsis. Cell 117:9–15 chromosome system and males are the homogametic sex, there is Blackmon H, Demuth JP (2014) Estimating tempo and mode of Y chromosome no requirement for MSCI in the testis. Because MSCI is a turnover: explaining Y chromosome loss with the fragile Y hypothesis. Genetics prerequisite for the evolution of executioner genes, further studies 197:561–572 on the germline of the heterogametic sex in distantly related Blackmon H, Demuth JP (2015) The fragile Y hypothesis: Y chromosome aneuploidy as a selective pressure in sex chromosome and meiotic mechanism evolution. vertebrate linages will provide important insight into the potential BioEssays 37:942–950 for the evolution of executioner function. Brick K, Smagulova F, Khil P, Camerini-Otero RD, Petukhova GV (2012) Genetic recombination is directed away from functional genomic elements in mice. Nature 485:642–645 CLOSING THE CIRCLE Britton-Davidian J, Robinson TJ, Veyrunes F (2012) Systematics and evolution of the Here we have described how sex chromosomes result in African pygmy mice, subgenus Nannomys: a review. Acta Oecologica 42:41–49 exceptions to Mendelian inheritance, highlighting the importance Bugno-Poniewierska M, Raudsepp T (2021) Horse clinical cytogenetics: recurrent of functional and mechanistic meiotic constraints on sex chromo- themes and novel findings. Animals 11:1–26. some evolution. Under a dynamic (and possibly cyclical) evolu- Capilla L, Garcia Caldés M, Ruiz-Herrera A (2016) Mammalian meiotic recombination: a toolbox for genome evolution. Cytogenetic Genome Res 150:1–16 tionary trajectory (Fig. 3) we propose that Y persistence can be Capilla-Pérez L, Durand S, Hurel A, Lian Q, Chambon A, Taochy C et al. (2021) The explained in the context of recombination rates, PAR size and synaptonemal complex imposes crossover interference and heterochiasmy in Y-borne meiotic executioner genes that regulate MSCI. Arabidopsis. Proc Natl Acad Sci USA 118:e2023613118 Due to suppressed recombination, the PAR represents a small Cappelletti E, Piras FM, Badiale C, Bambi M, Santagostino M, Vara C et al. (2019) CENP- portion of the X and Y. We propose that these fragile Ys with small A binding domains and recombination patterns in horse spermatocytes. Sci PARs result in an increase of DSBs (and hence recombination Rep. 9:15800 rates) to ensure a CO event in the PAR, and reduce the deleterious Carpenter ATC (1988) Thoughts on recombination nodules, meiotic recombination, effect of aneuploidy. If PAR size is reduced so that the Y becomes and chiasmata. In: Kucherlapati R, Smith GR (eds) Genetic recombination. too fragile and aneuploidy stress causes loss of Y function, the Y American Society of Microbiology, Washington, DC, p 529–548 Castle WE (1903) Mendel’s Law of Heredity. Science 18:396–406 chromosome can become stable by (i) temporary PAR rejuvena- Castle WE, Little CC (1910) On a modified mendelian ratio among yellow mice. Sci- tion, (ii) evolving achiasmatic XY segregation, or (iii) acquiring ence 32:868–870 executioner protection (Fig. 3). A persistent Y will remain under Chan AH, Jenkins PA, Song YS (2012) Genome-wide fine-scale recombination rate strong constraints to maintain high recombination rates in the variation in Drosophila melanogaster. PLoS Genet 8(12):e1003090 PAR to ensure an obligatory CO, as losing the Y will have fatal Charlesworth D (2021) The timing of genetic degeneration of sex chromosomes. consequences for germ cells (i.e., aberrant MSCI). Almost all Philos Trans R Soc B: Biol Sci 376:20200093 eutherian Y chromosomes are at this stage. In the rare event that Cole F, Kauppi L, Lange J, Roig I, Wang R, Keeney S et al. (2012) Homeostatic control executioner protection is lost (i.e., translocation away from the Y of recombination is implemented progressively in mouse meiosis. Nat Cell Biol chromosome to the X), the Y chromosome can be maintained in 14(4):424–430 Colome-Tatche M, Cortijo S, Wardenaar R, Morgado L, Lahouze B, Sarazin A et al. the population by either PAR rejuvenation or evolving achiasmatic (2012) Features of the Arabidopsis recombination landscape resulting from the XY segregation, the alternative is Y loss. combined loss of sequence variation and DNA methylation. Proc Natl Acad Sci Under this dynamic cyclic evolutionary scenario, the intricacies USA 109:16240–16245 of the meiotic programme influence the fate of Y chromosomes. Cortez D, Marin R, Toledo-Flores D, Froidevaux L, Liechti A, Waters PD et al. (2014) Understanding the progression and regulation of the meiotic Origins and functional evolution of Y chromosomes across mammals. Nature programme in vertebrate and invertebrate species will be 508:488–493 important to further decipher the plasticity of the rise and fall of Dapper AL, Payseur BA (2019) Molecular evolution of the meiotic recombination heteromorphic sex chromosomes. pathway in mammals. Evolution 73:2368–2389 Heredity (2022) 129:22 – 30 A. Ruiz-Herrera and P.D. Waters 29 Darolti I, Wright AE, Mank JE (2020) Guppy Y chromosome integrity maintained by Lynn A, Koehler KE, Judis L, Chan ER, Cherry JP, Schwartz S et al. (2002) Covariation of incomplete recombination suppression. Genome Biol Evolution 12:965–977 synaptonemal complex length and mammalian meiotic exchange rates. Sci- de Villena FP (2001) Female meiosis drives karyotypic evolution in mammals. ence 296:2222–2225 Genetics 159:1179–1189 Mackiewicz D, Posacki P, Burdukiewicz M, Błażej P (2018) Role of recombination and Deakin JE, O’Neill RJ (2020) Evolution of marsupial genomes. Annu Rev Anim Biosci faithfulness to partner in sex chromosome degeneration. Sci Rep 8:1–15 8:25–45 Marín-Gual L, González-Rodelas L, Pujol G, Vara C, Martín-Ruiz M, Berríos S et al. (2022) Drouaud J, Mercier R, Chelysheva L, Bérard A, Falque M, Martin O et al. (2007) Sex- Strategies for meiotic sex chromosome dynamics and telomeric elongation in specific crossover distributions and variations in interference level along Ara- Marsupials. PLOS Genet 18:e1010040 bidopsis thaliana chromosome 4. PLoS Genet 3:e106 Marshall Graves JA (2000) Human Y chromosome, sex determination, and sperma- Dumont BL, Payseur BA (2011) Evolution of the genomic recombination rate in Murid togenesis—a feminist view. Biol Reprod 63:667–676 rodents. Genetics 187(3):643–57 Martini E, Diaz RL, Hunter N, Keeney S (2006) Crossover homeostasis in yeast meiosis. Ellegren H, Smeds L, Burri R, Olason PI, Backström N, Kawakami T et al. (2012) The Cell 126:285–295 genomic landscape of species divergence in Ficedula flycatchers. Nature 491 Mather K (1939) Crossing over and heterochromatin in the X chromosome of Dro- (7426):756–760 sophila melanogaster. Genetics 24:413–435 Ezaz T, Sarre SD, O’Meally D, Marshall Graves JA, Georges A (2010) Sex chromosome Matveevsky S, Kolomiets O, Bogdanov A, Hakhverdyan M, Bakloushinskaya I (2017) evolution in lizards: Independent origins and rapid transitions. Cytogenetic Chromosomal evolution in mole Voles ellobius (Cricetidae, rodentia): bizarre sex Genome Res 127:249–260 chromosomes, variable autosomes and meiosis. Genes 8:306 Ezaz T, Stiglec R, Veyrunes F, Graves JAM (2006) Relationships between vertebrate ZW Morgan T (1912) Complete linkage in the second chromosome of the male of Dro- and XY sex chromosome systems. Curr Biol 16:R736–R743 sophila. Science 36:719–720 Foster JW, Brennan FE, Hampikian GK, Goodfellow PN, Sinclair AH, Lovell-Badge R Muller HJ (1916) The mechanism of crossing-over. Am Naturalist 592:284–305 et al. (1992) Evolution of sex determination and the Y chromosome: SRY-related Munch K, Schierup MH, Mailund T (2014) Unraveling recombination rate evolution sequences in marsupials. Nature 359:531–533 using ancestral recombination maps. BioEssays 36(9):892–900 Fowler KR, Sasaki M, Milman N, Keeney S, Smith GR (2014) Evolutionarily diverse Murat F, Mbengue N, Winge SB, Trefzer T, Leushkin E, Sepp M, et al. (2021) The determinants of meiotic DNA break and recombination landscapes across the molecular evolution of spermatogenesis across mammals. Preprint at bioRxiv genome. Genome Res 24:1650–1664 2021.11.08.467712 Furman M, Darolti W, Sandkam Almeida S, Mank J (2020). Sex Chromosome Evolution: Murata C, Yamada F, Kawauchi N, Matsuda Y, Kuroiwa A (2012) The y chromosome of SoMany Exceptions to the Rules. Genome Biology and Evolution 12:750–763. the Okinawa spiny rat, Tokudaia muenninki, was rescued through fusion with an Gil-Fernández A, Ribagorda M, Martín-Ruiz M, López-Jiménez P, Laguna T, Gómez R autosome. Chromosome Res 20:111–125 et al. (2021) Meiotic behavior of achiasmate sex chromosomes in the african Myers S, Bowden R, Tumian A, Bontrop RE, Freeman C, MacFie TS et al. (2010) Drive pygmy Mouse Mus mattheyi offers new insights into the evolution of sex against hotspot motifs in primates implicates the PRDM9 gene in meiotic chromosome pairing and segregation in mammals. Genes 12:1434 recombination. Science 327:876–879 Graves JAM (1995) The origin and function of the mammalian Y chromosome and Y‐ Ohno S (1967) Sex chromosomes and sex-linked genes. Springer, Berlin, Germany borne genes – an evolving understanding. BioEssays 17:311–320 Page J, Berríos S, Rufas JS, Parra MT, Suja JA, Heyting C et al. (2003) The pairing of X Handel MA (2004) The XY body: a specialized meiotic chromatin domain. Exp Cell Res and Y chromosomes during meiotic prophase in the marsupial species Thyla- 296:57–63 mys elegans is maintained by a dense plate developed from their axial ele- Hinch AG, Altemose N, Noor N, Donnelly P, Myers SR (2014) Recombination in the ments. J Cell Sci 116:551–560 human pseudoautosomal region PAR1. PLoS Genet 10:e1004503 Pan J, Sasaki M, Kniewel R, Murakami H, Blitzblau HG, Tischfield SE et al. (2011) A Hughes JF, Skaletsky H, Koutseva N, Pyntikova T, Page DC (2015) Sex chromosome-to- hierarchical combination of factors shapes the genome-wide topography of autosome transposition events counter Y-chromosome gene loss in mammals. yeast meiotic recombination initiation. Cell 144:719–731 Genome Biol 16:1–9 Papanikos F, Clément JAJ, Testa E, Ravindranathan R, Grey C, Dereli I et al. (2019) Jeffries DL, Gerchen JF, Scharmann M, Pannell JR (2021) A neutral model for the loss Mouse ANKRD31 regulates spatiotemporal patterning of meiotic recombination of recombination on sex chromosomes. Philos Trans R Soc B 376:20200096 initiation and ensures recombination between X and Y Sex chromosomes. Mol Jeffries DL, Lavanchy G, Sermier R, Sredl MJ, Miura I, Borzée A et al. (2018) A rapid rate Cell 74:1069–1085.e11 of sex-chromosome turnover and non-random transitions in true frogs. Nat Parvanov ED, Petkov PM, Paigen K (2010) Prdm9 controls activation of mammalian Commun 9:1–11 recombination hotspots. Science 327:835 Johnston SE, Bérénos C, Slate J, Pemberton JM (2016). Conserved Genetic Archi- Rahn MI, Noronha RC, Nagamachi CY, Pieczarka JC, Solari AJ, Sciurano RB (2016) tecture Underlying Individual Recombination Rate Variation in a Wild Popula- Protein markers of synaptic behavior and chromatin remodeling of the neo-XY tion of Soay Shee p (Ovis aries). Genetics, 203:583–598. body in phyllostomid bats. Chromosoma 125:701–708 Jones GH, Croft JA (1989) Chromosome pairing and chiasma formation in sperma- Raudsepp T, Chowdhary BP (2015) The eutherian pseudoautosomal region. Cytoge- tocytes and oocytes of Dendrocoelum lactem (Turbellaria, Tricladida); a cyto- netic Genome Res 147:81–94 genetical and ultrastructural study. Heredity 63:97–106 Raudsepp T, Chowdhary BP (2016) Chromosome aberrations and fertility disorders in Kauppi L, Barchi M, Baudat F, Romanienko PJ, Keeney S, Jasin M (2011) Distinct domestic animals. Annu Rev Anim Biosci 4:15–43 properties of the XY pseudoautosomal region crucial for male meiosis. Science Raudsepp T, Das PJ, Avila F, Chowdhary BP (2012) The pseudoautosomal region and 331:916–920 sex chromosome aneuploidies in domestic species. Sex Dev 6:72–83 Kawakami T, Wallberg A, Olsson A, Wintermantel, D, de Miranda, JR, Allsopp M, et al. Reig-Viader R, Garcia-Caldés M, Ruiz-Herrera A (2016) Telomere homeostasis in (2019). Substantial Heritable Variation in Recombination Rate on Multiple Scales mammalian germ cells: a review. Chromosoma 125:337–351 in Honeybees and Bumblebees. Genetics, 212:1101–1119. Reynolds A, Qiao H, Yang Y, Chen JK, Jackson N, Biswas K et al. (2013) RNF212 is a Keeney S, Giroux NC, Kleckner N (1997) Meiosis-specific DNA double-strand breaks dosage-sensitive regulator of crossing-over during mammalian meiosis. Nat are catalyzed by Spo11, a member of a widely conserved protein family. Cell, Genet 45:269–278 88:375–384. Rice WR (1996) Evolution of the Y sex chromosome in animals Y chromosomes evolve Kleckner N (2006) Chiasma formation: chromatin/axis interplay and the role(s) of the through the degeneration of autosomes. BioScience 46:331–343 synaptonemal complex. Chromosoma 115:175–194 Rifkin JL, Beaudry FEG, Humphries Z, Choudhury BI, Barrett SCH, Wright SI (2021) Kleckner N, Storlazzi A, Zickler D (2003) Coordinate variation in meiotic pachytene SC Widespread recombination suppression facilitates plant sex chromosome length and total crossover/chiasma frequency under conditions of constant evolution. Mol Biol Evolution 38:1018–1030 DNA length. Trends Genet 19:623–628 Robert T, Nore A, Brun C, Maffre C, Crimi B, Guichard V et al. (2016) The TopoVIB-Like Kratochvíl L, Stöck M, Rovatsos M, Bullejos M, Herpin A, Jeffries DL et al. (2021) protein family is required for meiotic DNA double-strand break formation. Expanding the classical paradigm: what we have learnt from vertebrates about Science 351:943–949 sex chromosome evolution. Philos Trans R Soc B 376:20200097 Romanienko PJ, Camerini-Otero RD (2000). The Mouse Spo11 Gene Is Required for Lahn BT, Page DC (1999) Four evolutionary strata on the human X chromosome. Meiotic Chromosome Synapsis. Molecular Cell, 6:975–987. Science 286:964–967 Royo H, Polikiewicz G, Mahadevaiah SK, Prosser H, Mitchell M, Bradley A et al. (2010) Lam I, Keeney S (2015) Mechanism and regulation of meiotic recombination initia- Evidence that meiotic sex chromosome inactivation is essential for male ferti- tion. Cold Spring Harb Perspect Biol 7:a016634 lity. Curr Biol 20:2117–2123 Longhese MP, Bonetti D, Guerini I, Manfrini, N, Clerici M (2009). DNA double-strand Ruiz AJ, Castaneda C, Raudsepp T, Tibary A (2019) Azoospermia and Y breaks in meiosis: Checking their formation, processing and repair. DNA Repair, chromosome–autosome translocation in a Friesian stallion. J Equine Vet Sci 8:1127–1138. 82:102781 Heredity (2022) 129:22 – 30 A. Ruiz-Herrera and P.D. Waters 30 Ruiz-Herrera A, Vozdova M, Fernández J, Sebestova H, Capilla L, Frohlich J et al. (2017) Wright S (1968) Genetic and biometric foundations. University of Chicago Press, Recombination correlates with synaptonemal complex length and chromatin Chicago loop size in bovids—insights into mammalian meiotic chromosomal organi- Xue L, Gao Y, Wu M, Tian T, Fan H, Huang Y et al. (2021) Telomere-to-telomere zation. Chromosoma 126:615–631 assembly of a fish Y chromosome reveals the origin of a young sex chromo- Sardell JM, Kirkpatrick M (2020) Sex differences in the recombination landscape. Am some pair. Genome Biol 22:1–20 Naturalist 195:361–379 Yokoo R, Zawadzki KA, Nabeshima K, Drake M, Arur S, Villeneuve AM (2012) COSA-1 Saunders PA, Veyrunes F (2021) Unusual mammalian sex determination systems: a reveals robust homeostasis and separable licensing and reinforcement steps cabinet of curiosities. Genes 12:1770 governing meiotic crossovers. Cell 149:75–87 Segura J, Ferretti L, Ramos-Onsins S, Capilla L, Farré M, Reis F et al. (2013) Evolution of Zenger KR, McKenzie LM, Cooper DW (2002) The first comprehensive genetic linkage recombination in eutherian mammals: Insights into mechanisms that affect map of a marsupial: the tammar wallaby (Macropus eugenii). Genetics recombination rates and crossover interference. Proc R Soc B: Biol Sci 280:20131945 162:321–330 Smagulova F, Gregoretti IV, Brick K, Khil P, Camerini-Otero RD, Petukhova GV (2011) Zickler D, Kleckner N (1999) Meiotic chromosomes: integrating structure and func- Genome-wide analysis reveals novel molecular features of mouse recombina- tion. Annu Rev Genet 33:603–754 tion hotspots. Nature 472:375–378 Zickler D, Kleckner N (2015) Recombination, pairing, and synapsis of homologs during Sparks AM, Watt K, Sinclair R, Pilkington JG, Pemberton JM, McNeilly TN et al. (2019) meiosis. Cold Spring Harb Perspect Biol 7:a016626 The genetic architecture of helminth-specific immune responses in a wild population of Soay sheep (Ovis aries). PLoS Genetics 15:e1008461 Stapley J, Feulner PGD, Johnston SE, Santure AW, Smadja CM (2017) Variation in ACKNOWLEDGEMENTS recombination frequency and distribution across eukaryotes: patterns and AR-H is supported by the Ministry of Economy, Industry and Competitiveness processes. Philos Trans R Soc B: Biol Sci 372:20160455 (CGL2017-83802-P) and the Spanish Ministry of Science and Innovation (PID2020- Stearns FW (2010) One hundred years of pleiotropy: a retrospective. Genetics 112557GGB-I00). PDW is supported by the Australian Research Council 186:767–773 (DP170101147, DP180100931, DP210103512 and DP220101429). The authors are Subramanian VV, Hochwagen A (2014) The meiotic checkpoint network: step-by-step grateful to C. Vara for providing the first draft for Fig. 1A, C. through meiotic prophase. Cold Spring Harb Perspect Biol 6:a016675 Talbert PB, Henikoff S (2010) Centromeres convert but don’t cross. PLOS Biol 8:e1000326 Turbek SP, Semenov GA, Enbody ED, Campagna L, Taylor SA (2021) Variable sig- natures of selection despite conserved recombination landscapes early in AUTHOR CONTRIBUTIONS speciation. J Heredity 112:485–496 AR-H and PDW conceived, designed and wrote the manuscript. Turner JMA (2005) Sex chromosomes make their mark. Chromosoma 114:300–306 Vara C, Paytuví-Gallart A, Cuartero Y, Álvarez-González L, Marín-Gual L, Garcia F et al. (2021) The impact of chromosomal fusions on 3D genome folding and COMPETING INTERESTS recombination in the germ line. Nat Commun 12:1–17 The authors declare no competing interests. Vara C, Ruiz-Herrera A (2022) Unpacking chromatin remodelling in germ cells: implications for development and evolution. Trends Genet 38:422–425 Vernet N, Mahadevaiah SK, de Rooij DG, Burgoyne PS, Ellis PJI (2016) Zfy genes are ADDITIONAL INFORMATION required for efficient meiotic sex chromosome inactivation (MSCI) in sperma- Correspondence and requests for materials should be addressed to Aurora Ruiz- tocytes. Hum Mol Genet 25:5300–5310 Herrera or Paul D. Waters. Vicoso B (2019). Molecular and evolutionary dynamics of animal sex-chromosome turnover. Nature Ecology and Evolution. 3:1632–1641. Reprints and permission information is available at http://www.nature.com/ von Diezmann L, Rog O (2021) Let’s get physical – mechanisms of crossover inter- reprints ference. J Cell Sci 134:jcs255745 Vozdova M, Ruiz-Herrera A, Fernandez J, Cernohorska H, Frohlich J, Sebestova H et al. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims (2016) Meiotic behaviour of evolutionary sex-autosome translocations in in published maps and institutional affiliations. Bovidae. Chromosome Res 24:325–338 Wallace BMN, Hultén MA (1985) Meiotic chromosome pairing in the normal human female. Ann Hum Genet 49:215–226 Wallace BMN, Wallace H (2003) Synaptonemal complex karyotype of zebrafish. Her- Open Access This article is licensed under a Creative Commons edity 90:136–140 Attribution 4.0 International License, which permits use, sharing, Wang S, Hassold T, Hunt P, White MA, Zickler D, Kleckner N et al. (2017) Inefficient adaptation, distribution and reproduction in any medium or format, as long as you give crossover maturation underlies elevated aneuploidy in human female meiosis. appropriate credit to the original author(s) and the source, provide a link to the Creative Cell 168:977–989.e17 Commons license, and indicate if changes were made. The images or other third party Wang S, Liu Y, Shang Y, Zhai B, Yang X, Kleckner N et al. (2019) Crossover interference, material in this article are included in the article’s Creative Commons license, unless crossover maturation, and human aneuploidy. BioEssays 41:e1800221 indicated otherwise in a credit line to the material. If material is not included in the Wang S, Zickler D, Kleckner N, Zhang L (2015) Meiotic crossover patterns: obligatory article’s Creative Commons license and your intended use is not permitted by statutory crossover, interference and homeostasis in a single process. Cell Cycle 14:305–314 regulation or exceeds the permitted use, you will need to obtain permission directly Waters PD, Duffy B, Frost CJ, Delbridge ML, Graves JAM (2001) The human Y chro- from the copyright holder. To view a copy of this license, visit http://creativecommons. mosome derives largely from a single autosomal region added to the sex org/licenses/by/4.0/. chromosomes 80-130 million years ago. Cytogenetics Cell Genet 92:74–79 Waters PD, Ruiz-Herrera A (2020) Meiotic executioner genes protect the Y from extinction. Trends Genet 36:728–738 © The Author(s) 2022 Heredity (2022) 129:22 – 30