In therian mammals, with some exceptions, whether an embryo will develop into a male or a female is defined by the presence or absence of a Y chromosome (Capel, 2017). Males bear an X and a Y, whereas females carry two X chromosomes. This is the most fundamental genetic difference between the two sexes and has been the subject of numerous studies.

Historically, the Y chromosome’s biological function has been misunderstood. From the 1950s, it was considered to be a genetic wasteland as studies of human pedigrees were only uncovering traits with autosomal or X-linked inheritance (Stern, 1957). In 1959, it was shown that the male-determining gene is Y-linked, but this was considered an exception on an otherwise functionally inert chromosome (Ford et al., 1959; Jacobs and Strong, 1959). When transcription units were first discovered on the Y chromosome (Agulnik et al., 1994; Arnemann et al., 1991; Page et al., 1987; Reijo et al., 1995; Salido et al., 1992; Sinclair et al., 1990), they were thought to be inactive vestiges of their former autosomal ancestors (Marshall Graves, 1995). More recently, the ‘impending demise’ theory hypothesised a continuous loss of Y-protein-coding genes predicting the eventual loss of the Y chromosome (Aitken and Marshall Graves, 2002; Marshall Graves, 2004). We now know that the view of the Y as a disappearing genetic desert is incorrect. Decades of research have proved that besides controlling male gonadal sex determination, the Y chromosome is crucial for initialisation, maintenance, and completion of spermatogenesis.

In this review, we first describe the evolutionary history of the X-Y chromosome pair, then use it as a paradigm with which to understand how the Y chromosome has become functionally specialised across mammals. Focusing on humans and mice, we discuss the early evidence that the Y chromosome is more than just a sex switch, and the subsequent efforts to discover the Y genes involved in spermatogenesis. We then highlight how experimental limitations have impacted progress in the field and propose approaches to enrich our understanding of Y-chromosome function.

Evolution of the mammalian sex chromosomes

The mammalian heteromorphic X and Y chromosomes have evolved from an ancestral pair of autosomes (Figure 1). This seminal concept, like many principles governing sex chromosome evolution, was hypothesised by Ohno, 1967. Henceforth, breakthroughs in Y-chromosome sequencing and assembly, which were long hindered by the Y’s repeat-rich nature and homology to the X chromosome, have been crucial to understand sex-chromosome evolution (Bellott et al., 2014; Hughes et al., 2012; Hughes et al., 2010; Li et al., 2013; Skaletsky et al., 2003; Soh et al., 2014). We now know that divergence into a ‘proto-Y’ started following mutations of Sox3, creating the sex-determining region Sry gene (Foster and Graves, 1994; Marshall Graves, 1998). The evolution of Sry-specific sex determination is thought to have happened around 160–166 million years ago after the split between therians and monotremes (egg-laying mammals) (Potrzebowski et al., 2008; Veyrunes et al., 2008), and prior to the split between marsupials (metatherians) and eutherians (Luo et al., 2011).

Figure 1

Download asset Open asset

The male-specific inheritance of the proto-Y exposed it to unique evolutionary forces (Larson et al., 2018). Notably, it facilitated selection and accumulation of male-beneficial mutations in the vicinity of Sry (Figure 1). The linkage between Sry and male-beneficial loci in turn created selective pressure to supress X-Y crossing over. Eventually, multiple discrete inversions on the Y supported and amplified meiotic-recombination arrest in specific regions, or strata (Figure 1; Bellott et al., 2014; Cortez et al., 2014; Lahn and Page, 1999). Stratification expanded the non-recombining male-specific region at the expense of the recombining portion of the chromosome known as the pseudoautosomal region (PAR) (Figure 1). In addition to these strata, (retro)transpositions/translocations from autosomes have occurred more recently in various mammalian lineages (Bellott et al., 2014; Cortez et al., 2014; Hughes et al., 2012).

Importantly, the loss of recombination associated with stratification allowed accumulation of Y-linked loss-of-function mutations, triggering chromosome-wide gene decay and amplification of repetitive DNA (Bachtrog, 2013). As a mechanism to maintain male fitness, large deletions of deleterious and non-functional DNA regions occurred within each non-recombining stratum (Bachtrog, 2013; Hughes and Page, 2015). Although 98% of the ancestral human X-genes survived (Mueller et al., 2013), only 3% persisted on the human Y (Bellott et al., 2014; Skaletsky et al., 2003). However, although the Y experienced rapid decay early in evolution, degeneration then dramatically slowed down, with genes having survived this ‘purge’ showing stability (Bellott et al., 2014; Cortez et al., 2014; Hughes et al., 2012; Hughes et al., 2010; Hughes et al., 2005). For instance, of the 18 ancestral genes present in the ~97 million year old eutherian ancestor (Bellott et al., 2014), humans retain 14, bull 13, chimp 11, and mouse 9. In humans, no Y genes appear to have been lost in the last 44 million years.

In addition, the longevity of certain X-Y gene pairs has been convergent between eutherians and marsupials. Indeed, one stratum independently evolved in both therian lineages (Figure 1). Two genes on this stratum have convergently survived, suggesting that Y gene decay is not stochastic (Bellott et al., 2014). Altogether, it is likely that X-Y gene-pair retention did not occur at random. Generally, it is thought that two evolutionary strategies have protected a specific set of Y genes: maintenance of ancestral X-Y gene pairs which are sensitive to transcriptional dosage; or retention and amplification of testis-biased gene families.

Evolutionary forces and functional specialisation of the Y chromosome

Whereas X-chromosome content has remained mostly unchanged over evolutionary time, the Y chromosome has experienced extensive genetic decay. As a result, females carry two copies of the numerous X-linked genes, whereas males carry a single copy. This creates an imbalance between X and autosome transcriptional dosage (X:A ratio) in males as well as between sexes (Table 1). This led to the evolution of dosage-compensation mechanisms, as hypothesised by Ohno, 1967. Firstly, twofold X-chromosome upregulation in both males and females re-established X:A equilibrium in males (Table 1; Deng et al., 2014). However, without other mechanisms, the X:A ratio in females would be two. This was prevented by the evolution of X-chromosome inactivation, a process by which one X is transcriptionally silenced in females, bringing the overall X-output level to that of the autosomes (Table 1; Brockdorff et al., 2020; Loda and Heard, 2019; Lyon, 1961).

Table 1

	No compensation	XCU	XCI
female	AA = 1XX = 1	AA = 1 XX = 2	AA = 1XX = 1
male	AA = 1XY = 0.5	AA = 1XY = 1	AA = 1XY = 1

X-upregulation and X-inactivation can ultimately compensate for genes lost on the Y. However, as an X-Y gene pair loses its Y-copy due to decay, it goes through a transition period during which there will be gene-dosage imbalance. During that intermediate state, the pair has a non-functional Y gene and a non-compensated X gene. For haploinsufficient genes, with function sensitive to their expression dosage, this transition state would be disadvantageous and selected against. As such, dosage-sensitive Y genes have been under strong selective pressure to survive. For instance, studies indicate that Y ancestral genes that share ubiquitous housekeeping regulatory functions with their X homologue, which would be very sensitive to change in expression levels, have preferentially survived on the Y (Bellott et al., 2014; Cortez et al., 2014; Jegalian and Page, 1998; Lahn and Page, 1997). Indeed, the annotations of remaining X-Y pairs link them to the sensitive regulation of histone lysine demethylation, stem-cell self-renewal, splicing, translation initiation and deubiquitylation (Bellott et al., 2014; Lahn and Page, 1997). A key prediction is that if an X-Y pair survives and maintains ancestral gene expression and function, the X copy should escape X-inactivation in females to avoid dosage imbalance. Indeed, the study of allele-specific expression in human, mouse and opossum has revealed that a higher proportion of X-linked genes with a surviving Y homologue escape X-inactivation, compared to genes with no Y homologues or with those showing signs of functional differentiation (Bellott et al., 2014; Cortez et al., 2014). The strict dosage requirement of sex-linked genes can be further inferred from individuals with Turner syndrome (XO), who only have a single full X chromosome (Gravholt et al., 2019). Indeed, human X monosomy is associated with poor embryonic viability and individuals surviving into adulthood tend to be mosaic for at least part of the second sex chromosome. This illustrates the severity of X-X or X-Y dosage imbalance. Interestingly, Turner syndrome is less severe in mice, even in fully XO animals (Burgoyne et al., 1983b; Burgoyne et al., 1983a; Burgoyne and Baker, 1981). This could be in part because mice have fewer surviving Y-linked ancestral genes (9 vs 17 in humans) (Figure 2).

Figure 2

Download asset Open asset

Another strategy thought to have protected Y-genes from regulatory and structural decay is the specialisation towards functions in male fertility. Indeed, ancestral, single-copy genes have sometimes diverged towards male-specific reproductive functions. The expression of some Y genes became almost exclusively limited to the testis, gradually losing expression in other organs to become testis-biased (Jegalian and Page, 1998; Mitchell, 2000). In parallel, the Y chromosome has gained additional testis-biased genes through (retro)transposition and translocation events from autosomes (Burgoyne, 1998). Importantly, some recently acquired testis-biased X/Y gene homologues have been massively amplified, forming tandem and palindromic repeats (Hughes et al., 2020; Rozen et al., 2003; Skaletsky et al., 2003; Soh et al., 2014; Trombetta and Cruciani, 2017; Figure 2). Following amplification, repeats have been maintained and homogenised through intra-chromosomal recombination (Trombetta and Cruciani, 2017). This recombination within the Y can either remove or fix mutations, beneficial or deleterious, and male-advantageous mutations would have then been selected for over time. Overall, amplification seems to have contributed to the longevity of some testis-biased Y genes and it has occurred independently in many lineages. In mice, bull and likely other mammals, amplification of sex chromosomes is thought to have been driven by the presence of antagonistic meiotic drivers (selfish genes) on the X and Y, each competing for transmission to the next generation (Cocquet et al., 2012; Ellis et al., 2011; Hughes et al., 2020; Soh et al., 2014).

Altogether, evolutionary insights have shown that surviving mammalian Y genes tend to fall into two categories: testis-specialised fertility genes or dosage-sensitive ubiquitous housekeepers (Lahn and Page, 1997). This is unlike mammalian autosomes which harbour genes with highly variable biological functions and expression patterns. However, despite the apparent specialisation of the Y chromosome, its exact somatic and fertility functions remain to be fully dissected. Particularly interesting are the functions of the Y chromosome in the context of spermatogenesis, which will be discussed in the rest of this review.

Mammalian spermatogenesis

Spermatogenesis allows continuous formation of gametes from spermatogonial stem cells (Figure 3). It occurs in cycles and can broadly be divided in three phases: mitosis, meiosis and spermiogenesis (Figure 3). All stages happen in the epithelium of the seminiferous tubules of the testis. As cells progress through development, they migrate away from the basal seminiferous membrane towards the lumen (Figure 3). The spermatogenic cycle has been mostly studied in rodents but the mechanisms are believed to be well-conserved across mammals. A major difference seems to be in developmental tempo. In mouse, one cycle can be dissected into 12 stages occurring over 8.6 days, and four cycles (35 days) are required to complete spermatogenesis, from spermatogonial stem cells to mature spermatozoa (de Rooij, 2017; Oakberg, 1956a; Oakberg, 1956b). In humans, one spermatogenic cycle is completed every 16 days, and ~72 days are needed for full differentiation of spermatogonial stem cells into spermatozoa (Muciaccia et al., 2013).

Figure 3

Download asset Open asset

Early in embryogenesis, at embryonic day (E) 6.25 in mouse and E12 in humans, the primordial germ cells are specified and subsequently migrate to the genital ridge (Kurimoto and Saitou, 2019; Sybirna et al., 2019; Tang et al., 2016). The early bipotent gonad is formed at E10.5–11.5 in mouse and week six in humans. Sry then triggers a signalling cascade resulting in the supporting cell lineage differentiating into Sertoli cells (Capel, 2017; Kurimoto and Saitou, 2019). Sertoli cells then direct adoption of the testicular state within the gonad. Germ cell proliferation will then occur until developmental arrest at E13.5 in mouse and after week 20 in human (Kurimoto and Saitou, 2019; Tam and Snow, 1981).

After birth, at around postnatal day (P) three in mouse and 2 months in humans, germ cells resume cell division, giving rise to undifferentiated spermatogonial cells that are found at the basal compartment of seminiferous tubules. Amongst this cell population lie spermatogonial stem cells that can both self-renew and multiply through mitotic divisions. The spermatogonial differentiation and proliferation through mitosis marks the starting point of spermatogenesis. It is a specific subset of spermatogonial cells, referred as type-B, that are now ready to undergo meiotic DNA replication and differentiate into pre-leptotene spermatocytes (de Rooij, 2017; Wu et al., 2009).

Male meiosis is initiated in a synchronous manner during puberty, at P10 in mouse and ~13 years in humans. Meiosis occurs through two rounds of cell division. During prophase I, which takes 2 weeks in mouse, diploid primary spermatocytes (2 N:4 C) enter leptonema, zygonema, pachynema, and diplonema successively (Figure 3; Baudat et al., 2013; Oakberg, 1956b). At leptonema, meiotic DNA double-strand breaks are formed. At zygonema, homologous chromosomes synapse and form bivalents (Figure 3). This allows crossing over via reciprocal recombination between homologues. Unlike autosomes, the X and Y are transcriptionally silenced at pachynema through the process of meiotic sex chromosome inactivation (MSCI) (Turner, 2015) and compartmentalised into a specialised chromatin domain called the sex body (Figure 3; McKee and Handel, 1993; Solari, 1974). MSCI failure leads to pachytene arrest and apoptosis. MSCI persists throughout diplonema, when homologous chromosomes start to separate (Burgoyne et al., 2009). The molecular mechanisms and roles of MSCI in fertility have been reviewed previously (Turner, 2015).

After prophase I, metaphase I takes place and chromosome homologues are lined up along the metaphase plate. At this stage, the spindle assembly checkpoint (SAC) ensures proper chromosome alignment and spindle attachment (Figure 3; Lane and Kauppi, 2019). Upon satisfaction of the SAC, homologues finally separate to opposite poles of the meiotic cells and the first division occurs with cytokinesis, giving rise to haploid secondary spermatocytes (1 N:2 C). The second meiotic division separates sister chromatids, leading to the formation of round spermatid cells (1 N:1 C) (Figure 3). These haploid cells then undergo a complex post-meiotic differentiation programme called spermiogenesis (Figure 3).

Spermiogenesis is characterised by the emergence of unique sperm-specific morphological features and by dramatic epigenetic reprogramming (Bao and Bedford, 2016; O’Donnell, 2014). Importantly, DNA of differentiating spermatids undergo increasing compaction in the nucleus (O’Donnell, 2014). This is achieved notably through near genome-wide replacement of histones with protamines. Protamines permit an up to 20-fold increase in chromatin condensation (Balhorn, 2007). Structurally, the acrosome starts to form over the anterior part of the spermatid nucleus and the flagellum, the propeller of the sperm, elongates on the posterior side (Figure 3). Additionally, the cytoplasm is transported along the spermatid tail and finally disposed (O’Donnell, 2014). Interestingly, most X/Y-linked genes remain repressed throughout spermiogenesis (Greaves et al., 2006; Namekawa et al., 2006; Sin et al., 2012; Turner et al., 2006), but some are re-activated (Hendriksen, 1999; Hendriksen et al., 1995; Mueller et al., 2013; Mueller et al., 2008; Wang et al., 2005). By the end of this post-meiotic stage, sperm are freed into the lumen of the tubule.

The Y chromosome: more than just a sex switch

The first evidence of the Y chromosome having any biological function arose from studies of mice (Welshons and Russell, 1959) and humans with Turner (XO) or Klinefelter (XXY) syndrome (Ford et al., 1959; Jacobs and Strong, 1959). These reports showed that in eutherian mammals, sex was determined by the presence/absence of the Y, independent of the number of X chromosomes. Later research on sex-reversed men; rare individuals which are phenotypically males but have an XX karyotype, narrowed down the search for the male-determining region to the short arm of the Y chromosome. For instance, using DNA hybridisation with several Y-DNA probes, it was showed that these XX males carried translocated DNA from the Y chromosome on one of their X chromosome (Guellaen et al., 1984; Page, 1986; Page et al., 1987; Page et al., 1985). As additional XX males were studied and the number of markers increased, the candidate region was narrowed to 35 kb containing SRY (Sinclair et al., 1990). In the span of 2 years, the evidence for SRY being the testis-determining factor became undeniable. The mouse orthologue was cloned and found to be expressed in specific somatic cells of the embryonic gonad at the time of testis differentiation (Gubbay et al., 1990; Koopman et al., 1990). It was also shown that both sex-reversed XY mice and women had mutations in Sry (Berta et al., 1990; Jäger et al., 1990; Lovell-Badge and Robertson, 1990). Finally, it was shown that, in mouse, Sry alone is sufficient to induce testicular development (Koopman et al., 1991), as XX mice transgenic for Sry developed as males.

Sry is a transcription factor of the SOX family that encodes a protein with an high mobility group (HMG)-box DNA binding domain (Table 2; Kashimada and Koopman, 2010; Figure 2). Much of what is known about the function of Sry in testis determination result from mouse studies. During murine embryogenesis, Sry upregulates Sox9 in Sertoli cell precursors between E11.5 and E12.5 (Kashimada and Koopman, 2010). SOX9 then activates fibroblast growth factor 9 (Fgf9) in a feedforward loop, which represses Wnt4 and the female pathway that would otherwise trigger ovary development (Capel, 2017; Kashimada and Koopman, 2010). Importantly, it has been shown that precise regulation of levels and onset of Sry expression is key for Sertoli cell differentiation. Indeed, minor alteration in amount and timing of Sry expression leads to sex-reversal phenotypes (Kashimada and Koopman, 2010).

Table 2

Y gene	Sequence class	X-homologue	Y copy number	Conserved in	Reported functions in the testis	Key gene ontology process	Expression pattern
Sry	Ancestral	Sox3	1	Opossum, bull, rat, mouse, marmoset, rhesus, chimp, human	Testis determination	DNA-binding transcription factor activity	Somatic cells in genital ridge, germ cell specific in adult
Rbmy array	Ancestral	Rbmx	~30	Opossum, bull, rat, mouse, marmoset, rhesus, chimp, human	Unknown *	RNA splicing	Testis biased
Zfy1,Zfy2	Ancestral	Zfx	2	Bull, rat, mouse, marmoset, rhesus, chimp, human	Apoptotic elimination of univalent spermatocytes at metaphase I, meiosis II completion, MSCI initiation and maintenance, spermatid head and tail morphogenesis	Transcription activator	Spermatogenic cells specific
Kdm5d	Ancestral	Kdm5c	1	Opossum, rat, mouse, marmoset, rhesus, chimp, human	Unknown	Histone demethylase that specifically demethylates 'Lys-4' of histone H3	Ubiquitous
Uty	Ancestral	Utx	1	Bull, rat, mouse, marmoset, rhesus, chimp, human	Unknown	Histone demethylase activity (H3-K27 specific)	Ubiquitous
Ddx3y	ancestral	Ddx3x	1	Bull, rat, mouse, marmoset, rhesus, chimp, human	Unknown	ATP-dependent RNA helicase	Ubiquitous
Usp9y	Ancestral	Usp9x	1	Bull, rat, mouse, marmoset, rhesus, chimp, human	Unknown	Ubiquitination regulator, peptidase C19	Testis biased
Uba1y	Ancestral	Uba1x	1	Opossum, bull, rat, mouse	Unknown	U1 ubiquitin activator	Testis biased, mostly spermatogonia and round spermatid
Eif2s3y	Ancestral	Eif2s3x	1	Bull, rat, mouse	Spermatogonial proliferation and differentiation	Translation initiation	Ubiquitous
Teyorf	Acquired	–	1	Mouse	Unknown	Claudin transmembrane	Testis specific
Prslly	Acquired	–	1	Mouse	Unknown	Serine-type endopeptidase activity	Testis specific
H2al2b, H2al2c	Acquired	H2al1	2	Mouse	Unknown	DNA packaging, pericentric heterochromatin regulation	Testis specific, expressed from round spermatid stage
Sly	Acquired	Slx,Slxl1	126	Mouse	Interacts with SSTY to recruit SMRT/N-Cor in turn mediating spermatid-specific gene expression	Chromatin remodelling	Testis biased
Srsy	Acquired	Srsx	197	Mouse	Unknown	Unknown	Testis biased
Ssty1&2	Acquired	Sstx	85&221	Mouse	H3K4me3-reader at the promoter of spermatid-specific genes, recruits SLY and SLX/SLX1	Methylated histone binding	Testis biased
Rbm31y	Acquired	Rbm31x	2	Mouse	Unknown	RNA binding	Testis biased

The race to discover the sex-determining region brought spotlight to the Y chromosome. However, the Y chromosome is far from being just a sex switch. It has a clear role in spermatogenesis. Mice with one X chromosome and transgenic expression of Sry (XOSry) develop testis populated with pro-spermatogonia that fail to proliferate, leading to absence of meiotic and post-meiotic cells (Figure 4; Mazeyrat et al., 2001). A similar phenotype can be observed in XO germ cells within XO/XY/XYY male mosaic mice (Levy and Burgoyne, 1986).

Figure 4

Download asset Open asset

Furthermore, it seems that additional Y genes are necessary not only in germ cells, but also in testicular somatic cells that are key to support successful spermatogenesis. Indeed, XY spermatogonia transplanted into XXSry testis cannot complete spermatogenesis, whereas segments of immature XY seminiferous tubule transplanted into XXSry testis display normal spermatogenic development of XY germ cells (Ishii et al., 2007). Altogether this highlights the importance of other Y genes besides Sry for both somatic and germ cell functions in the mouse testis.

In humans, the first sign that the Y chromosome may be involved in gamete production after testis determination came from the study of sub/infertile men with de novo deletions on the Y (Tiepolo and Zuffardi, 1976). The authors proposed the existence of at least one spermatogenesis factor or ‘azoospermia factor’ (AZF) on the Y. With an increasing number of studies finding sub-fertile males with Y deletions, and with the advances of physical and molecular mapping, three recurrently deleted regions of the human Y long arm were encountered: AZFa, AZFb, and AZFc (Vogt et al., 1996).

By the end of the twentieth century, there was undeniable evidence that both human and mouse Y chromosomes are crucial for spermatogenesis. However, the nature and number of Y-linked genes involved was still completely unknown. The importance of identifying such spermatogenesis factors became clear, especially given their clinical relevance for human fertility.

The authors would like to thank members of the Turner lab for providing feedback on the manuscript. This review is dedicated to the memory of Paul Burgoyne.

1. 1. Agulnik AI
   2. Mitchell MJ
   3. Lerner JL
   4. Woods DR
   5. Bishop CE

   (1994) A mouse y chromosome gene encoded by a region essential for spermatogenesis and expression of male-specific minor histocompatibility antigens

   Human Molecular Genetics 3:873–878.

   https://doi.org/10.1093/hmg/3.6.873

   • PubMed
   • Google Scholar
2. 1. Aitken RJ
   2. Marshall Graves JA

   (2002) The future of sex

   Nature 415:963.

   https://doi.org/10.1038/415963a

   • PubMed
   • Google Scholar
3. 1. Arnemann J
   2. Jakubiczka S
   3. Thüring S
   4. Schmidtke J

   (1991) Cloning and sequence analysis of a human y-chromosome-derived, testicular CDNA, TSPY

   Genomics 11:108–114.

   https://doi.org/10.1016/0888-7543(91)90107-P

   • PubMed
   • Google Scholar
4. 1. Bachtrog D

   (2013) Y-chromosome evolution: Emerging insights into processes of y-chromosome degeneration

   Nature Reviews. Genetics 14:113–124.

   https://doi.org/10.1038/nrg3366

   • PubMed
   • Google Scholar
5. 1. Balhorn R

   (2007) The protamine family of sperm nuclear proteins

   Genome Biology 8:227.

   https://doi.org/10.1186/gb-2007-8-9-227

   • PubMed
   • Google Scholar
6. 1. Bao J
   2. Bedford MT

   (2016) Epigenetic regulation of the histone-to-protamine transition during spermiogenesis

   Reproduction 151:R55–R70.

   https://doi.org/10.1530/REP-15-0562

   • PubMed
   • Google Scholar
7. 1. Baudat F
   2. Imai Y
   3. de Massy B

   (2013) Meiotic recombination in mammals: Localization and regulation

   Nature Reviews. Genetics 14:794–806.

   https://doi.org/10.1038/nrg3573

   • PubMed
   • Google Scholar
8. 1. Bellott DW
   2. Hughes JF
   3. Skaletsky H
   4. Brown LG
   5. Pyntikova T
   6. Cho T-J
   7. Koutseva N
   8. Zaghlul S
   9. Graves T
   10. Rock S
   11. Kremitzki C
   12. Fulton RS
   13. Dugan S
   14. Ding Y
   15. Morton D
   16. Khan Z
   17. Lewis L
   18. Buhay C
   19. Wang Q
   20. Watt J
   21. Holder M
   22. Lee S
   23. Nazareth L
   24. Alföldi J
   25. Rozen S
   26. Muzny DM
   27. Warren WC
   28. Gibbs RA
   29. Wilson RK
   30. Page DC

   (2014) Mammalian y chromosomes retain widely expressed dosage-sensitive regulators

   Nature 508:494–499.

   https://doi.org/10.1038/nature13206

   • PubMed
   • Google Scholar
9. 1. Berta P
   2. Hawkins JR
   3. Sinclair AH
   4. Taylor A
   5. Griffiths BL
   6. Goodfellow PN
   7. Fellous M

   (1990) Genetic evidence equating SRY and the testis-determining factor

   Nature 348:448–450.

   https://doi.org/10.1038/348448a0

   • PubMed
   • Google Scholar
10. 1. Brockdorff N
    2. Bowness JS
    3. Wei G

    (2020) Progress toward understanding chromosome silencing by xist RNA

    Genes & Development 34:733–744.

    https://doi.org/10.1101/gad.337196.120

    • PubMed
    • Google Scholar
11. 1. Burgoyne PS
    2. Baker TG

    (1981) Oocyte depletion in XO mice and their XX sibs from 12 to 200 days post partum

    Journal of Reproduction and Fertility 61:207–212.

    https://doi.org/10.1530/jrf.0.0610207

    • PubMed
    • Google Scholar
12. 1. Burgoyne PS
    2. Evans EP
    3. Holland K

    (1983a) XO monosomy is associated with reduced birthweight and lowered weight gain in the mouse

    Journal of Reproduction and Fertility 68:381–385.

    https://doi.org/10.1530/jrf.0.0680381

    • PubMed
    • Google Scholar
13. 1. Burgoyne PS
    2. Tam PP
    3. Evans EP

    (1983b) Retarded development of XO conceptuses during early pregnancy in the mouse

    Journal of Reproduction and Fertility 68:387–393.

    https://doi.org/10.1530/jrf.0.0680387

    • PubMed
    • Google Scholar
14. 1. Burgoyne PS

    (1998) The mammalian y chromosome: A new perspective

    BioEssays 20:363–366.

    https://doi.org/10.1002/(SICI)1521-1878(199805)20:5<363::AID-BIES2>3.0.CO;2-P

    • PubMed
    • Google Scholar
15. 1. Burgoyne PS
    2. Mahadevaiah SK
    3. Turner JMA

    (2009) The consequences of asynapsis for mammalian meiosis

    Nature Reviews. Genetics 10:207–216.

    https://doi.org/10.1038/nrg2505

    • PubMed
    • Google Scholar
16. 1. Capel B

    (2017) Vertebrate sex determination: Evolutionary plasticity of a fundamental switch

    Nature Reviews. Genetics 18:675–689.

    https://doi.org/10.1038/nrg.2017.60

    • PubMed
    • Google Scholar
17. 1. Cocquet J
    2. Ellis PJI
    3. Yamauchi Y
    4. Mahadevaiah SK
    5. Affara NA
    6. Ward MA
    7. Burgoyne PS

    (2009) The multicopy gene sly represses the sex chromosomes in the male mouse germline after meiosis

    PLOS Biology 7:e1000244.

    https://doi.org/10.1371/journal.pbio.1000244

    • PubMed
    • Google Scholar
18. 1. Cocquet J
    2. Ellis PJI
    3. Yamauchi Y
    4. Riel JM
    5. Karacs TPS
    6. Rattigan A
    7. Ojarikre OA
    8. Affara NA
    9. Ward MA
    10. Burgoyne PS

    (2010) Deficiency in the multicopy sycp3-like x-linked genes Slx and slxl1 causes major defects in spermatid differentiation

    Molecular Biology of the Cell 21:3497–3505.

    https://doi.org/10.1091/mbc.E10-07-0601

    • PubMed
    • Google Scholar
19. 1. Cocquet J
    2. Ellis PJI
    3. Mahadevaiah SK
    4. Affara NA
    5. Vaiman D
    6. Burgoyne PS

    (2012) A genetic basis for a postmeiotic x versus y chromosome intragenomic conflict in the mouse

    PLOS Genetics 8:e1002900.

    https://doi.org/10.1371/journal.pgen.1002900

    • PubMed
    • Google Scholar
20. 1. Colaco S
    2. Modi D

    (2018) Genetics of the human Y chromosome and its association with male infertility

    Reproductive Biology and Endocrinology 16:14.

    https://doi.org/10.1186/s12958-018-0330-5

    • PubMed
    • Google Scholar
21. 1. Comptour A
    2. Moretti C
    3. Serrentino ME
    4. Auer J
    5. Ialy-Radio C
    6. Ward MA
    7. Touré A
    8. Vaiman D
    9. Cocquet J

    (2014) SSTY proteins co-localize with the post-meiotic sex chromatin and interact with regulators of its expression

    The FEBS Journal 281:1571–1584.

    https://doi.org/10.1111/febs.12724

    • PubMed
    • Google Scholar
22. 1. Conway SJ
    2. Mahadevaiah SK
    3. Darling SM
    4. Capel B
    5. Rattigan AM
    6. Burgoyne PS

    (1994) Y353/B: A candidate multiple-copy spermiogenesis gene on the mouse Y chromosome

    Mammalian Genome 5:203–210.

    https://doi.org/10.1007/BF00360546

    • PubMed
    • Google Scholar
23. 1. Cortez D
    2. Marin R
    3. Toledo-Flores D
    4. Froidevaux L
    5. Liechti A
    6. Waters PD
    7. Grützner F
    8. Kaessmann H

    (2014) Origins and functional evolution of Y chromosomes across mammals

    Nature 508:488–493.

    https://doi.org/10.1038/nature13151

    • PubMed
    • Google Scholar
24. 1. de Rooij DG

    (2017) The nature and dynamics of spermatogonial stem cells

    Development 144:3022–3030.

    https://doi.org/10.1242/dev.146571

    • Google Scholar
25. 1. Decarpentrie F
    2. Vernet N
    3. Mahadevaiah SK
    4. Longepied G
    5. Streichemberger E
    6. Aknin-Seifer I
    7. Ojarikre OA
    8. Burgoyne PS
    9. Metzler-Guillemain C
    10. Mitchell MJ

    (2012) Human and mouse ZFY genes produce a conserved testis-specific transcript encoding a zinc finger protein with a short acidic domain and modified transactivation potential

    Human Molecular Genetics 21:2631–2645.

    https://doi.org/10.1093/hmg/dds088

    • PubMed
    • Google Scholar
26. 1. Deng X
    2. Berletch JB
    3. Nguyen DK
    4. Disteche CM

    (2014) X chromosome regulation: Diverse patterns in development, tissues and disease

    Nature Reviews. Genetics 15:367–378.

    https://doi.org/10.1038/nrg3687

    • PubMed
    • Google Scholar
27. 1. Ellis PJI
    2. Clemente EJ
    3. Ball P
    4. Touré A
    5. Ferguson L
    6. Turner JMA
    7. Loveland KL
    8. Affara NA
    9. Burgoyne PS

    (2005) Deletions on mouse YQ lead to upregulation of multiple x- and y-linked transcripts in spermatids

    Human Molecular Genetics 14:2705–2715.

    https://doi.org/10.1093/hmg/ddi304

    • PubMed
    • Google Scholar
28. 1. Ellis PJI
    2. Bacon J
    3. Affara NA

    (2011) Association of Sly with sex-linked gene amplification during mouse evolution: a side effect of genomic conflict in spermatids?

    Human Molecular Genetics 20:3010–3021.

    https://doi.org/10.1093/hmg/ddr204

    • PubMed
    • Google Scholar
29. 1. Ford CE
    2. Jones KW
    3. Polani PE
    4. De Almedia JC
    5. Briggs JH

    (1959) A sex-chromosome anomaly in a case of gonadal dysgenesis (Turner’s syndrome

    Lancet 1:711–713.

    https://doi.org/10.1016/s0140-6736(59)91893-8

    • PubMed
    • Google Scholar
30. 1. Foster JW
    2. Graves JA

    (1994) An sry-related sequence on the marsupial x chromosome: Implications for the evolution of the mammalian testis-determining gene

    PNAS 91:1927–1931.

    https://doi.org/10.1073/pnas.91.5.1927

    • PubMed
    • Google Scholar
31. 1. Godfrey AK
    2. Naqvi S
    3. Chmátal L
    4. Chick JM
    5. Mitchell RN
    6. Gygi SP
    7. Skaletsky H
    8. Page DC

    (2020) Quantitative analysis of y-chromosome gene expression across 36 human tissues

    Genome Research 30:860–873.

    https://doi.org/10.1101/gr.261248.120

    • PubMed
    • Google Scholar
32. 1. Gravholt CH
    2. Viuff MH
    3. Brun S
    4. Stochholm K
    5. Andersen NH

    (2019) Turner syndrome: mechanisms and management

    Nature Reviews. Endocrinology 15:601–614.

    https://doi.org/10.1038/s41574-019-0224-4

    • PubMed
    • Google Scholar
33. 1. Greaves IK
    2. Rangasamy D
    3. Devoy M
    4. Marshall Graves JA
    5. Tremethick DJ

    (2006) The X and Y chromosomes assemble into H2A.Z-containing [corrected] facultative heterochromatin [corrected] following meiosis

    Molecular and Cellular Biology 26:5394–5405.

    https://doi.org/10.1128/mcb.00519-06

    • PubMed
    • Google Scholar
34. 1. Gubbay J
    2. Collignon J
    3. Koopman P
    4. Capel B
    5. Economou A
    6. Münsterberg A
    7. Vivian N
    8. Goodfellow P
    9. Lovell-Badge R

    (1990) A gene mapping to the sex-determining region of the mouse y chromosome is a member of a novel family of embryonically expressed genes

    Nature 346:245–250.

    https://doi.org/10.1038/346245a0

    • PubMed
    • Google Scholar
35. 1. Guellaen G
    2. Casanovat M
    3. Geldwerth D
    4. Andre G
    5. Felloust M
    6. Weissenbach J

    (1984) Human XX males with Y single-copy DNA fragments

    Nature 307:30–31.

    https://doi.org/10.1038/307172a0

    • Google Scholar
36. 1. Hendriksen PJM
    2. Hoogerbrugge JW
    3. Themmen APN
    4. Koken MHM
    5. Hoeijmakers JHJ
    6. Oostra BA
    7. van der Lende T
    8. Grootegoed JA

    (1995) Postmeiotic transcription of X and Y chromosomal genes during spermatogenesis in the mouse

    Developmental Biology 170:730–733.

    https://doi.org/10.1006/dbio.1995.1252

    • Google Scholar
37. 1. Hendriksen PJM

    (1999) Do X and Y spermatozoa differ in proteins?

    Theriogenology 52:1295–1307.

    https://doi.org/10.1016/S0093-691X(99)00218-6

    • PubMed
    • Google Scholar
38. 1. Hughes JF
    2. Skaletsky H
    3. Pyntikova T
    4. Minx PJ
    5. Graves T
    6. Rozen S
    7. Wilson RK
    8. Page DC

    (2005) Conservation of y-linked genes during human evolution revealed by comparative sequencing in chimpanzee

    Nature 437:100–103.

    https://doi.org/10.1038/nature04101

    • PubMed
    • Google Scholar
39. 1. Hughes JF
    2. Skaletsky H
    3. Pyntikova T
    4. Graves TA
    5. van Daalen SKM
    6. Minx PJ
    7. Fulton RS
    8. McGrath SD
    9. Locke DP
    10. Friedman C
    11. Trask BJ
    12. Mardis ER
    13. Warren WC
    14. Repping S
    15. Rozen S
    16. Wilson RK
    17. Page DC

    (2010) Chimpanzee and human Y chromosomes are remarkably divergent in structure and gene content

    Nature 463:536–539.

    https://doi.org/10.1038/nature08700

    • PubMed
    • Google Scholar
40. 1. Hughes JF
    2. Skaletsky H
    3. Brown LG
    4. Pyntikova T
    5. Graves T
    6. Fulton RS
    7. Dugan S
    8. Ding Y
    9. Buhay CJ
    10. Kremitzki C
    11. Wang Q
    12. Shen H
    13. Holder M
    14. Villasana D
    15. Nazareth LV
    16. Cree A
    17. Courtney L
    18. Veizer J
    19. Kotkiewicz H
    20. Cho T-J
    21. Koutseva N
    22. Rozen S
    23. Muzny DM
    24. Warren WC
    25. Gibbs RA
    26. Wilson RK
    27. Page DC

    (2012) Strict evolutionary conservation followed rapid gene loss on human and rhesus y chromosomes

    Nature 483:82–86.

    https://doi.org/10.1038/nature10843

    • PubMed
    • Google Scholar
41. 1. Hughes JF
    2. Page DC

    (2015) The biology and evolution of mammalian Y chromosomes

    Annual Review of Genetics 49:507–527.

    https://doi.org/10.1146/annurev-genet-112414-055311

    • PubMed
    • Google Scholar
42. 1. Hughes JF
    2. Skaletsky H
    3. Pyntikova T
    4. Koutseva N
    5. Raudsepp T
    6. Brown LG
    7. Bellott DW
    8. Cho TJ
    9. Dugan-Rocha S
    10. Khan Z
    11. Kremitzki C
    12. Fronick C
    13. Graves-Lindsay TA
    14. Fulton L
    15. Warren WC
    16. Wilson RK
    17. Owens E
    18. Womack JE
    19. Murphy WJ
    20. Muzny DM
    21. Worley KC
    22. Chowdhary BP
    23. Gibbs RA
    24. Page DC

    (2020) Sequence analysis in Bos taurus reveals pervasiveness of X-Y arms races in mammalian lineages

    Genome Research 30:1716–1726.

    https://doi.org/10.1101/gr.269902.120

    • PubMed
    • Google Scholar
43. 1. Ishii M
    2. Tachiwana T
    3. Hoshino A
    4. Tsunekawa N
    5. Hiramatsu R
    6. Matoba S
    7. Kanai-Azuma M
    8. Kawakami H
    9. Kurohmaru M
    10. Kanai Y

    (2007) Potency of testicular somatic environment to support spermatogenesis in XX/SRY transgenic male mice

    Development 134:449–454.

    https://doi.org/10.1242/dev.02751

    • PubMed
    • Google Scholar
44. 1. Jacobs BPA
    2. Strong DJA

    (1959) A case of human intersexuality having possible XXY sex-determining mechanism

    Nature 1:7–8.

    https://doi.org/10.1038/183302a0

    • Google Scholar
45. 1. Jäger RJ
    2. Anvret M
    3. Hall K
    4. Scherer G

    (1990) A human XY female with a frame shift mutation in the candidate testis-determining gene SRY

    Nature 348:452–454.

    https://doi.org/10.1038/348452a0

    • PubMed
    • Google Scholar
46. 1. Jegalian K
    2. Page DC

    (1998) A proposed path by which genes common to mammalian X and Y chromosomes evolve to become x inactivated

    Nature 394:776–780.

    https://doi.org/10.1038/29522

    • PubMed
    • Google Scholar
47. 1. Kashimada K
    2. Koopman P

    (2010) SRY: The master switch in mammalian sex determination

    Development 137:3921–3930.

    https://doi.org/10.1242/dev.048983

    • PubMed
    • Google Scholar
48. 1. Kato T
    2. Miyata K
    3. Sonobe M
    4. Yamashita S
    5. Tamano M
    6. Miura K
    7. Kanai Y
    8. Miyamoto S
    9. Sakuma T
    10. Yamamoto T
    11. Inui M
    12. Kikusui T
    13. Asahara H
    14. Takada S

    (2013) Production of sry knockout mouse using TALEN via oocyte injection

    Scientific Reports 3:3136.

    https://doi.org/10.1038/srep03136

    • PubMed
    • Google Scholar
49. 1. Koopman P
    2. Münsterberg A
    3. Capel B
    4. Vivian N
    5. Lovell-Badge R

    (1990) Expression of a candidate sex-determining gene during mouse testis differentiation

    Nature 348:450–452.

    https://doi.org/10.1038/348450a0

    • PubMed
    • Google Scholar
50. 1. Koopman P
    2. Gubbay J
    3. Vivian N
    4. Goodfellow P
    5. Lovell-Badge R

    (1991) Male development of chromosomally female mice transgenic for sry

    Nature 351:117–121.

    https://doi.org/10.1038/351117a0

    • PubMed
    • Google Scholar
51. 1. Kruger AN
    2. Brogley MA
    3. Huizinga JL
    4. Kidd JM
    5. de Rooij DG
    6. Hu YC
    7. Mueller JL

    (2019) A neofunctionalized x-linked ampliconic gene family is essential for male fertility and equal sex ratio in mice

    Current Biology 29:3699–3706.

    https://doi.org/10.1016/j.cub.2019.08.057

    • PubMed
    • Google Scholar
52. 1. Kurimoto K
    2. Saitou M

    (2019) Germ cell reprogramming

    Current Topics in Developmental Biology 135:91–125.

    https://doi.org/10.1016/bs.ctdb.2019.04.005

    • PubMed
    • Google Scholar
53. 1. Lahn BT
    2. Page DC

    (1997) Functional coherence of the human Y chromosome

    Science 278:675–680.

    https://doi.org/10.1126/science.278.5338.675

    • PubMed
    • Google Scholar
54. 1. Lahn BT
    2. Page DC

    (1999) Four evolutionary strata on the human X chromosome

    Science 286:964–967.

    https://doi.org/10.1126/science.286.5441.964

    • PubMed
    • Google Scholar
55. 1. Lane S
    2. Kauppi L

    (2019) Meiotic spindle assembly checkpoint and aneuploidy in males versus females

    Cellular and Molecular Life Sciences 76:1135–1150.

    https://doi.org/10.1007/s00018-018-2986-6

    • PubMed
    • Google Scholar
56. 1. Larson EL
    2. Kopania EEK
    3. Good JM

    (2018) Spermatogenesis and the evolution of mammalian sex chromosomes

    Trends in Genetics 34:722–732.

    https://doi.org/10.1016/j.tig.2018.06.003

    • PubMed
    • Google Scholar
57. 1. Levy ER
    2. Burgoyne PS

    (1986) The fate of XO germ cells in the testes of xo/xy and xo/xy/xyy mouse mosaics: Evidence for a spermatogenesis gene on the mouse Y chromosome

    Cytogenetic and Genome Research 42:208–213.

    https://doi.org/10.1159/000132280

    • Google Scholar
58. 1. Li G
    2. Davis BW
    3. Raudsepp T
    4. Pearks Wilkerson AJ
    5. Mason VC
    6. Ferguson-Smith M
    7. O’Brien PC
    8. Waters PD
    9. Murphy WJ

    (2013) Comparative analysis of mammalian Y chromosomes illuminates ancestral structure and lineage-specific evolution

    Genome Research 23:1486–1495.

    https://doi.org/10.1101/gr.154286.112

    • PubMed
    • Google Scholar
59. 1. Lindeboom RGH
    2. Supek F
    3. Lehner B

    (2016) The rules and impact of nonsense-mediated mrna decay in human cancers

    Nature Genetics 48:1112–1118.

    https://doi.org/10.1038/ng.3664

    • PubMed
    • Google Scholar
60. 1. Lindeboom RGH
    2. Vermeulen M
    3. Lehner B
    4. Supek F

    (2019) The impact of nonsense-mediated mrna decay on genetic disease, gene editing and cancer immunotherapy

    Nature Genetics 51:1645–1651.

    https://doi.org/10.1038/s41588-019-0517-5

    • PubMed
    • Google Scholar
61. 1. Loda A
    2. Heard E

    (2019) Xist RNA in action: Past, present, and future

    PLOS Genetics 15:e1008333.

    https://doi.org/10.1371/journal.pgen.1008333

    • PubMed
    • Google Scholar
62. 1. Lovell-Badge R
    2. Robertson E

    (1990)

    XY female mice resulting from a heritable mutation in the primary testis-determining gene, Tdy

    Development 109:635–646.

    • PubMed
    • Google Scholar
63. 1. Luo ZX
    2. Yuan CX
    3. Meng QJ
    4. Ji Q

    (2011) A jurassic eutherian mammal and divergence of marsupials and placentals

    Nature 476:442–445.

    https://doi.org/10.1038/nature10291

    • PubMed
    • Google Scholar
64. 1. Lyon MF

    (1961) Gene action in the X-chromosome of the mouse (Mus musculus L

    Nature 190:372–373.

    https://doi.org/10.1038/190372a0

    • PubMed
    • Google Scholar
65. 1. Marshall Graves JA

    (1995) The origin and function of the mammalian y chromosome and y‐borne genes – an evolving understanding

    BioEssays 17:950170407.

    https://doi.org/10.1002/bies.950170407

    • Google Scholar
66. 1. Marshall Graves JA

    (1998) Evolution of the mammalian Y chromosome and sex-determining genes

    The Journal of Experimental Zoology 1:2-B.

    https://doi.org/10.1002/(SICI)1097-010X(19980801)281:53.0.CO;2-B

    • Google Scholar
67. 1. Marshall Graves JA

    (2004) the degenerate y chromosome - can conversion save it?

    Reproduction, Fertility, and Development 1:RD03096.

    https://doi.org/10.1071/RD03096

    • Google Scholar
68. 1. Matsubara Y
    2. Kato T
    3. Kashimada K
    4. Tanaka H
    5. Zhi Z
    6. Ichinose S
    7. Mizutani S
    8. Morio T
    9. Chiba T
    10. Ito Y
    11. Saga Y
    12. Takada S
    13. Asahara H

    (2015) Talen-mediated gene disruption on Y chromosome reveals critical role of EIF2S3Y in mouse spermatogenesis

    Stem Cells and Development 24:1164–1170.

    https://doi.org/10.1089/scd.2014.0466

    • PubMed
    • Google Scholar
69. 1. Matsumura T
    2. Endo T
    3. Isotani A
    4. Ogawa M
    5. Ikawa M

    (2019) An azoospermic factor gene, DDX3Y and its paralog, DDX3X are dispensable in germ cells for male fertility

    The Journal of Reproduction and Development 65:121–128.

    https://doi.org/10.1262/jrd.2018-145

    • PubMed
    • Google Scholar
70. 1. Mazeyrat S
    2. Saut N
    3. Sargent CA
    4. Grimmond S
    5. Longepied G
    6. Ehrmann IE
    7. Ellis PS
    8. Greenfield A
    9. Affara NA
    10. Mitchell MJ

    (1998) The mouse y chromosome interval necessary for spermatogonial proliferation is gene dense with syntenic homology to the human AZFA region

    Human Molecular Genetics 7:1713–1724.

    https://doi.org/10.1093/hmg/7.11.1713

    • PubMed
    • Google Scholar
71. 1. Mazeyrat S
    2. Saut N
    3. Grigoriev V
    4. Mahadevaiah SK
    5. Ojarikre OA
    6. Bishop C
    7. Eicher EM
    8. Mitchell MJ
    9. Burgoyne PS

    (2001) A y-encoded subunit of the translation initiation factor eif2 is essential for mouse spermatogenesis

    Nature Genetics 29:49–53.

    https://doi.org/10.1038/ng717

    • PubMed
    • Google Scholar
72. 1. McKee BD
    2. Handel MA

    (1993) Sex chromosomes, recombination, and chromatin conformation

    Chromosoma 102:71–80.

    https://doi.org/10.1007/BF00356023

    • PubMed
    • Google Scholar
73. 1. Mitchell MJ

    (2000) Spermatogenesis and the mouse y chromosome: Specialisation out of decay

    Results and Problems in Cell Differentiation 28:233–270.

    https://doi.org/10.1007/978-3-540-48461-5_10

    • PubMed
    • Google Scholar
74. 1. Moretti C
    2. Blanco M
    3. Ialy-Radio C
    4. Serrentino M-E
    5. Gobé C
    6. Friedman R
    7. Battail C
    8. Leduc M
    9. Ward MA
    10. Vaiman D
    11. Tores F
    12. Cocquet J

    (2020) Battle of the sex chromosomes: Competition between x and Y chromosome-encoded proteins for partner interaction and chromatin occupancy drives multicopy gene expression and evolution in muroid rodents

    Molecular Biology and Evolution 37:3453–3468.

    https://doi.org/10.1093/molbev/msaa175

    • PubMed
    • Google Scholar
75. 1. Muciaccia B
    2. Boitani C
    3. Berloco BP
    4. Nudo F
    5. Spadetta G
    6. Stefanini M
    7. de Rooij DG
    8. Vicini E

    (2013) Novel stage classification of human spermatogenesis based on acrosome development

    Biology of Reproduction 89:60.

    https://doi.org/10.1095/biolreprod.113.111682

    • PubMed
    • Google Scholar
76. 1. Mueller JL
    2. Mahadevaiah SK
    3. Park PJ
    4. Warburton PE
    5. Page DC
    6. Turner JMA

    (2008) The mouse x chromosome is enriched for multicopy testis genes showing postmeiotic expression

    Nature Genetics 40:794–799.

    https://doi.org/10.1038/ng.126

    • PubMed
    • Google Scholar
77. 1. Mueller JL
    2. Skaletsky H
    3. Brown LG
    4. Zaghlul S
    5. Rock S
    6. Graves T
    7. Auger K
    8. Warren WC
    9. Wilson RK
    10. Page DC

    (2013) Independent specialization of the human and mouse X chromosomes for the male germ line

    Nature Genetics 45:1083–1087.

    https://doi.org/10.1038/ng.2705

    • PubMed
    • Google Scholar
78. 1. Nakasuji T
    2. Ogonuki N
    3. Chiba T
    4. Kato T
    5. Shiozawa K
    6. Yamatoya K
    7. Tanaka H
    8. Kondo T
    9. Miyado K
    10. Miyasaka N
    11. Kubota T
    12. Ogura A
    13. Asahara H

    (2017) Complementary critical functions of zfy1 and Zfy2 in mouse spermatogenesis and reproduction

    PLOS Genetics 13:e1006578.

    https://doi.org/10.1371/journal.pgen.1006578

    • PubMed
    • Google Scholar
79. 1. Namekawa SH
    2. Park PJ
    3. Zhang L-F
    4. Shima JE
    5. McCarrey JR
    6. Griswold MD
    7. Lee JT

    (2006) Postmeiotic sex chromatin in the male germline of mice

    Current Biology 16:660–667.

    https://doi.org/10.1016/j.cub.2006.01.066

    • PubMed
    • Google Scholar
80. 1. Naqvi S
    2. Bellott DW
    3. Lin KS
    4. Page DC

    (2018) Conserved microrna targeting reveals preexisting gene dosage sensitivities that shaped amniote sex chromosome evolution

    Genome Research 28:474–483.

    https://doi.org/10.1101/gr.230433.117

    • PubMed
    • Google Scholar
81. 1. Naqvi S
    2. Godfrey AK
    3. Hughes JF
    4. Goodheart ML
    5. Mitchell RN
    6. Page DC

    (2019) Conservation, acquisition, and functional impact of sex-biased gene expression in mammals

    Science 365:eaaw7317.

    https://doi.org/10.1126/science.aaw7317

    • PubMed
    • Google Scholar
82. 1. Oakberg EF

    (1956a) A description of spermiogenesis in the mouse and its use in analysis of the cycle of the seminiferous epithelium and germ cell renewal

    The American Journal of Anatomy 99:391–413.

    https://doi.org/10.1002/aja.1000990303

    • PubMed
    • Google Scholar
83. 1. Oakberg EF

    (1956b) Duration of spermatogenesis in the mouse and timing of stages of the cycle of the seminiferous epithelium

    The American Journal of Anatomy 99:507–516.

    https://doi.org/10.1002/aja.1000990307

    • PubMed
    • Google Scholar
84. Book

    1. Ohno S

    (1967) Sex Chromosomes and Sex-Linked Genes., Monographs on Endocrinology

    Berlin, Heidelberg, New York: Springer Verlag.

    https://doi.org/10.1007/978-3-642-88178-7

    • Google Scholar
85. 1. O’Donnell L

    (2014) Mechanisms of spermiogenesis and spermiation and how they are disturbed

    Spermatogenesis 4:e979623.

    https://doi.org/10.4161/21565562.2014.979623

    • PubMed
    • Google Scholar
86. 1. Page DC
    2. de la Chapelle A
    3. Weissenbach J

    (1985) Chromosome y-specific DNA in related human xx males

    Nature 315:224–226.

    https://doi.org/10.1038/315224a0

    • PubMed
    • Google Scholar
87. Conference

    1. Page DC

    (1986) Cold Spring Harbor Symposia on Quantitative Biology

    Sex reversal: Deletion mapping the male-determining function of the human Y chromosome. pp. 229–235.

    https://doi.org/10.1101/sqb.1986.051.01.028

    • Google Scholar
88. 1. Page DC
    2. Mosher R
    3. Simpson EM
    4. Fisher EMC
    5. Mardon G
    6. Pollack J
    7. McGillivray B
    8. de la Chapelle A
    9. Brown LG

    (1987) The sex-determining region of the human Y chromosome encodes a finger protein

    Cell 51:1091–1104.

    https://doi.org/10.1016/0092-8674(87)90595-2

    • PubMed
    • Google Scholar
89. 1. Potrzebowski L
    2. Vinckenbosch N
    3. Marques AC
    4. Chalmel F
    5. Jégou B
    6. Kaessmann H

    (2008) Chromosomal gene movements reflect the recent origin and biology of therian sex chromosomes

    PLOS Biology 6:e80.

    https://doi.org/10.1371/journal.pbio.0060080

    • PubMed
    • Google Scholar
90. 1. Rathje CC
    2. Johnson EEP
    3. Drage D
    4. Patinioti C
    5. Silvestri G
    6. Affara NA
    7. Ialy-Radio C
    8. Cocquet J
    9. Skinner BM
    10. Ellis PJI

    (2019) Differential sperm motility mediates the sex ratio drive shaping mouse sex chromosome evolution

    Current Biology 29:3692–3698.

    https://doi.org/10.1016/j.cub.2019.09.031

    • PubMed
    • Google Scholar
91. 1. Reijo R
    2. Lee TY
    3. Salo P
    4. Alagappan R
    5. Brown LG
    6. Rosenberg M
    7. Rozen S
    8. Jaffe T
    9. Straus D
    10. Hovatta O
    11. de la Chapelle A
    12. Silber S
    13. Page DC

    (1995) Diverse spermatogenic defects in humans caused by Y chromosome deletions encompassing a novel RNA-binding protein gene

    Nature Genetics 10:383–393.

    https://doi.org/10.1038/ng0895-383

    • PubMed
    • Google Scholar
92. 1. Riel JM
    2. Yamauchi Y
    3. Sugawara A
    4. Li HYJ
    5. Ruthig V
    6. Stoytcheva Z
    7. Ellis PJI
    8. Cocquet J
    9. Ward MA

    (2013) Deficiency of the multi-copy mouse y gene sly causes sperm dna damage and abnormal chromatin packaging

    Journal of Cell Science 126:803–813.

    https://doi.org/10.1242/jcs.114488

    • PubMed
    • Google Scholar
93. 1. Royo H
    2. Polikiewicz G
    3. Mahadevaiah SK
    4. Prosser H
    5. Mitchell M
    6. Bradley A
    7. de Rooij DG
    8. Burgoyne PS
    9. Turner JMA

    (2010) Evidence that meiotic sex chromosome inactivation is essential for male fertility

    Current Biology 20:2117–2123.

    https://doi.org/10.1016/j.cub.2010.11.010

    • PubMed
    • Google Scholar
94. 1. Rozen S
    2. Skaletsky H
    3. Marszalek JD
    4. Minx PJ
    5. Cordum HS
    6. Waterston RH
    7. Wilson RK
    8. Page DC

    (2003) Abundant gene conversion between arms of palindromes in human and APE y chromosomes

    Nature 423:873–876.

    https://doi.org/10.1038/nature01723

    • PubMed
    • Google Scholar
95. 1. Salido EC
    2. Yen PH
    3. Koprivnikar K
    4. Yu LC
    5. Shapiro LJ

    (1992)

    The human enamel protein gene amelogenin is expressed from both the x and the y chromosomes

    American Journal of Human Genetics 50:303–316.

    • PubMed
    • Google Scholar
96. 1. Sharpe JJ
    2. Cooper TA

    (2017) Unexpected consequences: Exon skipping caused by crispr-generated mutations

    Genome Biology 18:1240–1243.

    https://doi.org/10.1186/s13059-017-1240-0

    • PubMed
    • Google Scholar
97. 1. Shpargel KB
    2. Sengoku T
    3. Yokoyama S
    4. Magnuson T

    (2012) UTX and UTY demonstrate histone demethylase-independent function in mouse embryonic development

    PLOS Genetics 8:e1002964.

    https://doi.org/10.1371/journal.pgen.1002964

    • PubMed
    • Google Scholar
98. 1. Sin HS
    2. Ichijima Y
    3. Koh E
    4. Namiki M
    5. Namekawa SH

    (2012) Human postmeiotic sex chromatin and its impact on sex chromosome evolution

    Genome Research 22:827–836.

    https://doi.org/10.1101/gr.135046.111

    • PubMed
    • Google Scholar
99. 1. Sinclair AH
    2. Berta P
    3. Palmer MS
    4. Hawkins JR
    5. Griffiths BL
    6. Smith MJ
    7. Foster JW
    8. Frischauf AM
    9. Lovell-Badge R
    10. Goodfellow PN

    (1990) A gene from the human sex-determining region encodes a protein with homology to a conserved dna-binding motif

    Nature 346:240–244.

    https://doi.org/10.1038/346240a0

    • PubMed
    • Google Scholar
100. 1. Skaletsky H
     2. Kuroda-Kawaguchi T
     3. Minx PJ
     4. Cordum HS
     5. Hillier L
     6. Brown LG
     7. Repping S
     8. Pyntikova T
     9. Ali J
     10. Bieri T
     11. Chinwalla A
     12. Delehaunty A
     13. Delehaunty K
     14. Du H
     15. Fewell G
     16. Fulton L
     17. Fulton R
     18. Graves T
     19. Hou SF
     20. Latrielle P
     21. Leonard S
     22. Mardis E
     23. Maupin R
     24. McPherson J
     25. Miner T
     26. Nash W
     27. Nguyen C
     28. Ozersky P
     29. Pepin K
     30. Rock S
     31. Rohlfing T
     32. Scott K
     33. Schultz B
     34. Strong C
     35. Tin-Wollam A
     36. Yang SP
     37. Waterston RH
     38. Wilson RK
     39. Rozen S
     40. Page DC

     (2003) The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes

     Nature 423:825–837.

     https://doi.org/10.1038/nature01722

     • PubMed
     • Google Scholar
101. Preprint

     1. Smits AH
     2. Ziebell F
     3. Joberty G
     4. Zinn N
     5. Mueller WF
     6. Clauder-Münster S
     7. Eberhard D
     8. Savitski MF
     9. Grandi P
     10. Jakob P
     11. Michon AM
     12. Sun H
     13. Tessmer K
     14. Bürckstümmer T
     15. Bantscheff M
     16. Steinmetz LM
     17. Drewes G
     18. Huber W

     (2019) Biological Plasticity Rescues Target Activity in CRISPR Knockouts

     bioRxiv.

     https://doi.org/10.1101/716019

     • Google Scholar
102. 1. Snell DM
     2. Turner JMA

     (2018) Sex Chromosome Effects on Male-Female Differences in Mammals

     Current Biology 28:R1313–R1324.

     https://doi.org/10.1016/j.cub.2018.09.018

     • PubMed
     • Google Scholar
103. 1. Soh YQS
     2. Alföldi J
     3. Pyntikova T
     4. Brown LG
     5. Graves T
     6. Minx PJ
     7. Fulton RS
     8. Kremitzki C
     9. Koutseva N
     10. Mueller JL
     11. Rozen S
     12. Hughes JF
     13. Owens E
     14. Womack JE
     15. Murphy WJ
     16. Cao Q
     17. de Jong P
     18. Warren WC
     19. Wilson RK
     20. Skaletsky H
     21. Page DC

     (2014) Sequencing the mouse y chromosome reveals convergent gene acquisition and amplification on both sex chromosomes

     Cell 159:800–813.

     https://doi.org/10.1016/j.cell.2014.09.052

     • PubMed
     • Google Scholar
104. 1. Solari AJ

     (1974) The behavior of the XY pair in mammals

     International Review of Cytology 38:273–317.

     https://doi.org/10.1016/S0074-7696(08)60928-6

     • PubMed
     • Google Scholar
105. 1. Song Y
     2. Liu T
     3. Wang Y
     4. Deng J
     5. Chen M
     6. Yuan L
     7. Lu Y
     8. Xu Y
     9. Yao H
     10. Li Z
     11. Lai L

     (2017) Mutation of the Sp1 binding site in the 5’ flanking region of SRY causes sex reversal in rabbits

     Oncotarget 8:38176–38183.

     https://doi.org/10.18632/oncotarget.16979

     • PubMed
     • Google Scholar
106. 1. Stern C

     (1957)

     The problem of complete y-linkage in man

     American Journal of Human Genetics 9:147–166.

     • PubMed
     • Google Scholar
107. 1. Styrna J
     2. Imai HT
     3. Moriwaki K

     (1991) An increased level of sperm abnormalities in mice with a partial deletion of the y chromosome

     Genetical Research 57:195–199.

     https://doi.org/10.1017/S0016672300029268

     • PubMed
     • Google Scholar
108. 1. Sun C
     2. Skaletsky H
     3. Birren B
     4. Devon K
     5. Tang Z
     6. Silber S
     7. Oates R
     8. Page DC

     (1999) An azoospermic man with a de novo point mutation in the y-chromosomal gene USP9Y

     Nature Genetics 23:429–432.

     https://doi.org/10.1038/70539

     • PubMed
     • Google Scholar
109. 1. Sybirna A
     2. Wong FCK
     3. Surani MA

     (2019) Genetic basis for primordial germ cells specification in mouse and human: Conserved and divergent roles of PRDM and SOX transcription factors

     Current Topics in Developmental Biology 135:35–89.

     https://doi.org/10.1016/bs.ctdb.2019.04.004

     • PubMed
     • Google Scholar
110. 1. Szot M
     2. Grigoriev V
     3. Mahadevaiah SK
     4. Ojarikre OA
     5. Touré A
     6. von Glasenapp E
     7. Rattigan A
     8. Turner JMA
     9. Elliott DJ
     10. Burgoyne PS

     (2003) Does Rbmy have a role in sperm development in mice?

     Cytogenetic and Genome Research 103:330–336.

     https://doi.org/10.1159/000076821

     • PubMed
     • Google Scholar
111. 1. Tam PP
     2. Snow MHL

     (1981)

     Proliferation and migration of primordial germ cells during compensatory growth in mouse embryos

     Journal of Embryology and Experimental Morphology 64:133–147.

     • Google Scholar
112. 1. Tang WWC
     2. Kobayashi T
     3. Irie N
     4. Dietmann S
     5. Surani MA

     (2016) Specification and epigenetic programming of the human germ line

     Nature Reviews. Genetics 17:585–600.

     https://doi.org/10.1038/nrg.2016.88

     • PubMed
     • Google Scholar
113. 1. Tiepolo L
     2. Zuffardi O

     (1976) Localization of factors controlling spermatogenesis in the nonfluorescent portion of the human Y chromosome long arm

     Human Genetics 34:119–124.

     https://doi.org/10.1007/BF00278879

     • PubMed
     • Google Scholar
114. 1. Touré A
     2. Szot M
     3. Mahadevaiah SK
     4. Rattigan A
     5. Ojarikre OA
     6. Burgoyne PS

     (2004) A new deletion of the mouse y chromosome long arm associated with the loss of SSTY expression, abnormal sperm development and sterility

     Genetics 166:901–912.

     https://doi.org/10.1534/genetics.166.2.901

     • PubMed
     • Google Scholar
115. 1. Trombetta B
     2. Cruciani F

     (2017) Y chromosome palindromes and gene conversion

     Human Genetics 136:605–619.

     https://doi.org/10.1007/S00439-017-1777-8

     • PubMed
     • Google Scholar
116. 1. Turner JMA
     2. Mahadevaiah SK
     3. Ellis PJI
     4. Mitchell MJ
     5. Burgoyne PS

     (2006) Pachytene asynapsis drives meiotic sex chromosome inactivation and leads to substantial postmeiotic repression in spermatids

     Developmental Cell 10:521–529.

     https://doi.org/10.1016/j.devcel.2006.02.009

     • PubMed
     • Google Scholar
117. 1. Turner JMA

     (2015) Meiotic silencing in mammals

     Annual Review of Genetics 49:395–412.

     https://doi.org/10.1146/annurev-genet-112414-055145

     • Google Scholar
118. 1. Vernet N
     2. Mahadevaiah SK
     3. Ojarikre OA
     4. Longepied G
     5. Prosser HM
     6. Bradley A
     7. Mitchell MJ
     8. Burgoyne PS

     (2011) The y-encoded gene zfy2 acts to remove cells with unpaired chromosomes at the first meiotic metaphase in male mice

     Current Biology 21:787–793.

     https://doi.org/10.1016/j.cub.2011.03.057

     • PubMed
     • Google Scholar
119. 1. Vernet N
     2. Mahadevaiah SK
     3. Yamauchi Y
     4. Decarpentrie F
     5. Mitchell MJ
     6. Ward MA
     7. Burgoyne PS

     (2014) Mouse y-linked zfy1 and zfy2 are expressed during the male-specific interphase between meiosis I and meiosis ii and promote the 2nd meiotic division

     PLOS Genetics 10:e1004444.

     https://doi.org/10.1371/journal.pgen.1004444

     • PubMed
     • Google Scholar
120. 1. Vernet N
     2. Mahadevaiah SK
     3. de Rooij DG
     4. Burgoyne PS
     5. Ellis PJI

     (2016a) Zfy genes are required for efficient meiotic sex chromosome inactivation (MSCI) in spermatocytes

     Human Molecular Genetics 25:5300–5310.

     https://doi.org/10.1093/hmg/ddw344

     • PubMed
     • Google Scholar
121. 1. Vernet N
     2. Mahadevaiah SK
     3. Decarpentrie F
     4. Longepied G
     5. de Rooij DG
     6. Burgoyne PS
     7. Mitchell MJ

     (2016b) Mouse y-encoded transcription factor Zfy2 is essential for sperm head remodelling and sperm tail development

     PLOS ONE 11:e0145398.

     https://doi.org/10.1371/journal.pone.0145398

     • PubMed
     • Google Scholar
122. 1. Veyrunes F
     2. Waters PD
     3. Miethke P
     4. Rens W
     5. McMillan D
     6. Alsop AE
     7. Grützner F
     8. Deakin JE
     9. Whittington CM
     10. Schatzkamer K
     11. Kremitzki CL
     12. Graves T
     13. Ferguson-Smith MA
     14. Warren W
     15. Marshall Graves JA

     (2008) Bird-like sex chromosomes of platypus imply recent origin of mammal sex chromosomes

     Genome Research 18:965–973.

     https://doi.org/10.1101/gr.7101908

     • PubMed
     • Google Scholar
123. 1. Vogt PH
     2. Edelmann A
     3. Kirsch S
     4. Henegariu O
     5. Hirschmann P
     6. Kiesewetter F
     7. Köhn FM
     8. Schill WB
     9. Farah S
     10. Ramos C
     11. Hartmann M
     12. Hartschuh W
     13. Meschede D
     14. Behre HM
     15. Castel A
     16. Nieschlag E
     17. Weidner W
     18. Gröne HJ
     19. Jung A
     20. Engel W
     21. Haidl G

     (1996) Human y chromosome azoospermia factors (AZF) mapped to different subregions in yq11

     Human Molecular Genetics 5:933–943.

     https://doi.org/10.1093/hmg/5.7.933

     • PubMed
     • Google Scholar
124. 1. Vogt PH
     2. Falcao CL
     3. Hanstein R
     4. Zimmer J

     (2008) The AZF proteins

     International Journal of Andrology 31:383–394.

     https://doi.org/10.1111/j.1365-2605.2008.00890.x

     • PubMed
     • Google Scholar
125. 1. Wang PJ
     2. Page DC
     3. McCarrey JR

     (2005) Differential expression of sex-linked and autosomal germ-cell-specific genes during spermatogenesis in the mouse

     Human Molecular Genetics 14:2911–2918.

     https://doi.org/10.1093/hmg/ddi322

     • PubMed
     • Google Scholar
126. 1. Wang H
     2. Hu YC
     3. Markoulaki S
     4. Welstead GG
     5. Cheng AW
     6. Shivalila CS
     7. Pyntikova T
     8. Dadon DB
     9. Voytas DF
     10. Bogdanove AJ
     11. Page DC
     12. Jaenisch R

     (2013) Talen-mediated editing of the mouse Y chromosome

     Nature Biotechnology 31:530–532.

     https://doi.org/10.1038/nbt.2595

     • PubMed
     • Google Scholar
127. 1. Welshons WJ
     2. Russell LB

     (1959) The y-chromosome as the bearer of male determining factors in the mouse

     PNAS 45:560–566.

     https://doi.org/10.1073/pnas.45.4.560

     • PubMed
     • Google Scholar
128. 1. Wiles V

     (2020) Genes adapt to outsmart gene targeting strategies in mutant mouse strains by skipping exons to reinitiate transcription and translation

     Genome Biology 168:1–26.

     https://doi.org/10.1186/s13059-020-02086-0

     • Google Scholar
129. 1. Wu X
     2. Schmidt JA
     3. Avarbock MR
     4. Tobias JW
     5. Carlson CA
     6. Kolon TF
     7. Ginsberg JP
     8. Brinster RL

     (2009) Prepubertal human spermatogonia and mouse gonocytes share conserved gene expression of germline stem cell regulatory molecules

     PNAS 106:21672–21677.

     https://doi.org/10.1073/pnas.0912432106

     • PubMed
     • Google Scholar
130. 1. Yamauchi Y
     2. Riel JM
     3. Stoytcheva Z
     4. Burgoyne PS
     5. Ward MA

     (2010) Deficiency in mouse y chromosome long arm gene complement is associated with sperm dna damage

     Genome Biology 11:R66.

     https://doi.org/10.1186/gb-2010-11-6-r66

     • PubMed
     • Google Scholar
131. 1. Yamauchi Y
     2. Riel JM
     3. Stoytcheva Z
     4. Ward MA

     (2014) Two Y genes can replace the entire y chromosome for assisted reproduction in the mouse

     Science 343:69–72.

     https://doi.org/10.1126/science.1242544

     • PubMed
     • Google Scholar
132. 1. Yamauchi Y
     2. Riel JM
     3. Ruthig V
     4. Ward MA

     (2015) Mouse y-encoded transcription factor ZFY2 is essential for sperm formation and function in assisted fertilization

     PLOS Genetics 11:e1005476.

     https://doi.org/10.1371/journal.pgen.1005476

     • PubMed
     • Google Scholar
133. 1. Yan BW
     2. Zhao YF
     3. Cao WG
     4. Li N
     5. Gou KM

     (2013) Mechanism of random integration of foreign DNA in transgenic mice

     Transgenic Research 22:983–992.

     https://doi.org/10.1007/s11248-013-9701-z

     • PubMed
     • Google Scholar
134. 1. Zuo E
     2. Cai Y-J
     3. Li K
     4. Wei Y
     5. Wang B-A
     6. Sun Y
     7. Liu Z
     8. Liu J
     9. Hu X
     10. Wei W
     11. Huo X
     12. Shi L
     13. Tang C
     14. Liang D
     15. Wang Y
     16. Nie Y-H
     17. Zhang C-C
     18. Yao X
     19. Wang X
     20. Zhou C
     21. Ying W
     22. Wang Q
     23. Chen R-C
     24. Shen Q
     25. Xu G-L
     26. Li J
     27. Sun Q
     28. Xiong Z-Q
     29. Yang H

     (2017) One-step generation of complete gene knockout mice and monkeys by CRISPR/Cas9-mediated gene editing with multiple sgRNAs

     Cell Research 27:933–945.

     https://doi.org/10.1038/cr.2017.81

     • PubMed
     • Google Scholar

Author details

1. Jeremie Subrini

   Sex Chromosome Biology Laboratory, The Francis Crick Institute, London, United Kingdom

   Contribution

   Conceptualization, Writing - original draft, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-5633-0509

2. James Turner

   Sex Chromosome Biology Laboratory, The Francis Crick Institute, London, United Kingdom

   Contribution

   Conceptualization, Supervision, Writing - review and editing

   For correspondence

   james.turner@crick.ac.uk

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-1722-7677

• 3,715

  views

• 592

  downloads

• 18

  citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.