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

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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

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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

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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

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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.

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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

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