“Micro-deletions” of the human Y chromosome and their relationship with male infertility

JOURNAL OF

GENETICS AND GENOMICS J. Genet. Genomics 35 (2008) 193−199 www.jgenetgenomics.org

“Micro-deletions” of the human Y chromosome and their relationship with male infertility Zheng Li a, Christopher J Haines b, Yibing Han b, * a

b

Renji Hospital, School of Medicine, Shanghai Jiaotong University; Shanghai Institute of Andrology, Shanghai 200001, China Department of Obstetrics and Gynaecology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, China Received for publication 2 April 2007; revised 30 April 2007; accepted 30 April 2007

Abstract The Y chromosome evolves from an autochromosome and accumulates male-related genes including sex-determining region of Y-chromosome (SRY) and several spermatogenesis-related genes. The human Y chromosome (60 Mb long) is largely composed of repetitive sequences that give it a heterochromatic appearance, and it consists of pseudoautosomal, euchromatic, and heterochromatic regions. Located on the two extremities of the Y chromosome, pseudoautosomal regions 1 and 2 (PAR1 and PAR2, 2.6 Mb and 320 bp long, respectively) are homologs with the termini of the X chromosome. The euchromatic region and some of the repeat-rich heterochromatic parts of the Y chromosome are called “male-specific Y” (MSY), which occupy more than 95% of the whole Y chromosome. After evolution, the Y chromosome becomes the smallest in size with the least number of genes but with the most number of copies of genes that are mostly spermatogenesis-related. The Y chromosome is characterized by highly repetitive sequences (including direct repeats, inverted repeats, and palindromes) and high polymorphism. Several gene rearrangements on the Y chromosome occur during evolution owing to its specific gene structure. The consequences of such rearrangements are not only loss but also gain of specific genes. One hundred and fifty three haplotypes have been discovered in the human Y chromosome. The structure of the Y chromosome in the GenBank belongs to haplotype R1. There are 220 genes (104 coding genes, 111 pseudogenes, and 5 other uncategorized genes) according to the most recent count. The 104 coding genes encode a total of about 48 proteins/protein families (including putative proteins/protein families). Among them, 16 gene products have been discovered in the azoospermia factor region (AZF) and are related to spermatogenesis. It has been discovered that one subset of gene rearrangements on the Y chromosome, “micro-deletions”, is a major cause of male infertility in some populations. However, controversies exist about different Y chromosome haplotypes. Six AZFs of the Y chromosome have been discovered including AZFa, AZFb, AZFc, and their combinations AZFbc, AZFabc, and partial AZFc called AZFc/gr/gr. Different deletions in AZF lead to different content spermatogenesis loss from teratozoospermia to infertility in different populations depending on their Y haplotypes. This article describes the structure of the human Y chromosome and investigates the causes of micro-deletions and their relationship with male infertility from the view of chromosome evolution. After analysis of the relationship between AZFc and male infertility, we concluded that spermatogenesis is controlled by a network of genes, which may locate on the Y chromosome, the autochromosomes, or even on the X chromosome. Further investigation of the molecular mechanisms underlying male fertility/infertility will facilitate our knowledge of functional genomics. Keywords: human Y-chromosome; micro-deletion; male infertility

Introduction The human Y chromosome (60 Mb long) is composed of pseudoautosomal, euchromatic, and heterochromatic regions. Located on the two extremities of the Y chromo* Corresponding author. E-mail address: [email protected]

some, pseudoautosomal regions 1 and 2 (PAR1 and PAR2, 2.6 Mb, and 320 bp long, respectively) are homologs with the termini of the X chromosome and are paired with the chromosome X during meiosis. The euchromatic region is rich in genes whereas the remaining heterochromatic region lacks genes. The euchromatic DNA sequences include a total of approximately 23 Mb, including 8 Mb on the short arm and 14.5 Mb on the long arm of the Y chromo-

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some. All euchromatic sequences fall into three classes: the ampliconic, X-degenerate, and X-transposed regions. The euchromatic region and some of the repeat-rich heterochromatic part of the Y chromosome are called “male-specific Y” (MSY) in contrast to the pseudoautosomal part of the Y, which is essentially the same as the corresponding part of the X and is common to both males and females. Male-specific Y differentiates the sexes and comprises of 95% of the chromosome’s length. Male-specific Y is actually a mosaic of heterochromatic sequences and the three classes of euchromatic sequences (Fig. 1). The MSY was previously known as NRY (non-recombinating region of the human Y chromosome) because it was believed that no recombining event occurred between the X and Y chromosomes during meiosis in this region. However, as MSY is actually flanked on both sides by pseudoautosomal regions, X-Y crossing over is a normal and frequent event during male meiosis. Recent studies have shown that the human Y chromosome also undergoes a type of recombination (Skaletsky et al., 2003; Rozen et al., 2003). Compared with autochromosomes, the Y chromosome has the least number of genes but the highest copy number of the repetitive sequences (Rozen et al., 2003). There are 220 genes (104 coding genes, 111 pseudogenes, and 5 other uncategorized genes) according to the most recent count (http://www.gdb.org/hugo/chrY/geneMaps.html, accessed April 2007). The 104 coding genes encode a total of about 48 proteins/protein families (including putative proteins/protein families). Among them, 16 proteins have been discovered in the azoospermia factor region (AZF) and are related to spermatogenesis (Skaletsky et al., 2003; Vogt, 2005). The most outstanding character of the human Y chromosome is the existence of repetitive sequences (palindromes). The ampliconic euchromatic segments are scattered across the euchromatic long arm and proximal short arm in 7 fragments whose combined length is 10.2 Mb. The ampliconic sequences exhibit by far the highest density of genes (from 2−35 copies per gene). The most pronounced

structural features of the ampliconic regions are massive palindromes. Eight palindromes comprise of one-quarter of the euchromatic DNA of the human Y chromosome and contain 15 genes and transcript families, all of which are expressed predominantly in the testis (Skaletsky et al., 2003). The vast majority (57 of 60 Mb) of the Y chromosome is less-recombining and transmitted as a single block from generation to generation with most functional variants and neutral polymorphisms being linked. A Y chromosome lineage or haplotype is a monophyletic group of the Y chromosome defined by slowly mutating binary markers, such as single nucleotide variant or insertion/deletion events (McElreavey et al., 2006). Highly mutating Y chromosome markers, such as microsatellites, are variable in all populations and a particular combination of allelic states can be used to define a haplotype. Using denaturing high performance liquid chromatography (DHPLC), 153 haplotypes have been discovered in the human Y chromosome by analyzing the 245 mutational events that occurred in the 74 male Y Chromosome Consortium (YCC) cell lines (Under hill et al., 2000; Jobling and Tyler-Smith, 2003). The current nomenclature of haplotypes and YCC can be checked from the website at http://ycc.biosci.arizona.edu. The structure of Y chromosome in the GenBank belongs to haplotype R1. Among different populations, Y chromosome variations may also exist which make the Y chromosome have higher polymorphism, like what have happened in Chinese populations (Yu et al., 2002; Chen et al., 2006). People with different Y haplotype may have a different phenotype (from normal to different content oligozoospermia) when certain mutations such as micro-deletions occur on the Y chromosome. This will be discussed further in this review.

The origin, evolution, and future of the Y chromosome The X and Y chromosomes are thought to have evolved from an ordinary pair of autochromosomes that stopped

Fig. 1. A: Schematic representation of the whole chromosome including the long arm (Yq), the short arm (Yp), and the centromere (Cen). The Y chromosome is composed of euchromatic, pseudoautosomal (PAR1 and PAR2), and heterochromatic regions. MSY comprises of 95% of the chromosome’s length including the euchromatic region and some of the heterochromatic regions. B: Enlarged view of the euchromatic region extending from the proximal boundary of the Yp pseudochromosomal region to the proximal boundary of the large heretochromatic region of Yq. The ampliconic, X-degenerate, and X-transposed regions are the main components of the euchromatic region. Each chromosomal fragment size in the illustration is not proportional to its real size.

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Fig. 2. Process involved in the Y chromosome evolution (the chromosomal size change in the illustration is not proportional to the real change as the Y chromosome was enlarged to facilitate explanation). A: The differentiation of autochromosome toward Y chromosome is initiated when one homologue acquires a male-determining gene. B: Several female antagonistic alleles (or male-beneficial genes) begin to accumulate around the sex determining gene, and a male-specific region on the Y chromosome (MSY) is created. C: The lack of recombination within the MSY causes genes in this region to degenerate (appearance of pseudogenes and decrease in volume). Genes with a net male-benefit can accumulate and amplify on the Y chromosome through functional specialization of genes originally present on the Y chromosome or through the preferential retention of genes transposed from autochromosomes with a male benefit. Gene conversion between members of a gene family can help to maintain functional copies of that family on the Y chromosome. D: Multiple expansions of the non-recombining region can result in the incorporation of new autochromosomal (Neo-Y) or pseudoautosomal region (PAR) into the Y chromosome, which resets the differentiation process in these regions. E: The result is a pair of hetermorphic sex chromosomes that consists of multiple strata with different evolutionary ages and varying degrees of differentiation.

recombining with each other after acquiring a sex-determining role in reptiles 300 million years ago. The accumulation of sexually antagonistic (beneficial) genes linked to the sex determining genes favors the evolution of suppression of recombination between the nascent sex chromosomes. In the absence of recombination, these originally homologous chromosomes continue to differentiate (Lahn et al, 1999; Rice 1996; Charlesworth 1996). Several female antagonistic alleles (or male-beneficial gene) began to accumulate around the sex determining gene and MSY was created. In this region, there is very little X-Y crossing over and the lack of recombination within the MSY causes genes in this region to degenerate (appearance of pseudogenes and decrease in volume), whereas their homologs on the X chromosome may evolve dosage compensation. Genes with a net male-benefit can accumulate and can be amplified on the Y chromosome through functional specialization of genes originally present on the Y chromosome or through the preferential retention of genes transposed from autosomes with a male benefit. The X chromosome can accumulate genes with female benefits either by functional specialization of ancestral X-linked genes or by transpositions from autosomes similarly. Multiple expansions of the non-recombining region can result in the incorporation of new autosomes or PARS into the sex chromosomes, which resets the differentiation process in these re-

gions. The result is a pair of hetermorphic sex chromosomes that consists of multiple strata with different evolutionary ages and varying degrees of differentiation (Fig. 2, Bachtrog 2006). The Y chromosome has lost 1,393 of its original 1,438 genes in the last 300 million years. If evolution continues at this rate, the last 45 genes will be lost in the next 10 million years (Aitken and Marshal, 2002; Graves, 2004). Will the Y chromosome, with only one third the volume of the X chromosome, eventually disappear in the future? From the point of view of its evolution, the most important cause for Y chromosome degrading is suppression of homologous recombination, which is detrimental to any chromosome region. Once a region is genetically isolated, it can no longer repair itself by piecing together the good bits of two damaged chromosomes. In the Y chromosome, the less-recombining MSY region therefore undergoes mutation, deletion, insertion of retroposons, amplification of repetitive sequences, and rapidly degrades and loses active genes (Charlesworth 1996). A second powerful force driving the Y to degrade is genetic hitchhiking. This occurs when a new allele with a major effect on male health arises on a particular Y chromosome. It sweeps through the population, regardless of what other damaged genes are carried on the same Y. These mechanisms nullify selection for undamaged Y chromosome that carries a full comple-

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ment of functional genes. From the view of its structure, the MSY encodes about 27 distinct proteins/protein families. Within the MSY, the X-transposed sequences (3.4 Mb) are 99% identical to the DNA sequences in Xq21, which is the result of a massive X-to-Y transposition that occurred about 3−4 million years ago (Mumm et al., 1997; Page et al., 1984). The X-transposed segments encode only 2 genes, both of which have homologues in Xq21. The X-degenerate segment of the MSY is dotted with single-copy gene or psudogene homologues of X-linked genes that seem to be surviving relics of ancient autosomes from which the X and Y chromosomes co-evolved. The X-degenerate sequences encode 16 of the MSY’s 27 distinct proteins. The ampliconic segments are composed largely of sequences that exhibit marked similarity (>99.9%) to other sequences in the MSY. Most importantly, genes in the ampliconic segments may be replicated by recombination between the repetitive sequences. The ampliconic sequences encode 9 of the MSY’s 27 distinct proteins that are exclusively expressed in the testis, which is an indication of their importance for the Y chromosome. In contrast to undergoing degeneration, the copy numbers of these genes are increasing during evolution (Bachtrog 2006). As for the 2 genes on the X-transposed fragment, their disappearance may not influence the function of the Y chromosome very much as both of them have homologues in the X chromosome. The 16 genes in the X-degenerate fragment cannot be replicated by recombination like that in the ampliconic region, and thus ongoing gene loss may be expected there. It should also be noted that most genes located in the X-degenerated region were ubiquitously expressed and were interrupted at several points by large blocks of ampliconic, heterochromatic, or other sequences. By comparing the X-degenerate sequences between Chimpanzees and humans that diverged about 6 million years ago, it was found that no X-degenerate gene loss or decay has occurred during the last 6 million years of human evolution (Hughes et al., 2005). This supports a slowing down of the rate of gene decay as the Y chromosome has evolved (Charlesworth and Charlesworth, 2000). We anticipate here that the Y chromosome will be characterized not only by a loss of genes relative to the X chromosome but also by recurrent gains of individual genes or genomic regions that will be beneficial to males in the future.

Micro-deletions in the Y chromosome and male infertility The Y chromosome is essential for human sex determination and male germ cell development and maintenance (Mcelreavey et al., 2000). The association between the Y chromosome and male fertility is apparent from two observations: micro-deletions of the long arm of the Y chromosome are associated with spermatogenic failure and some paternal lineages of the Y chromosome appear to be

associated with reduced sperm counts (Mcelreavey et al., 2000; Kuroki et al., 1999; Krausz et al., 2001). Heterochromatin deletions of the Y chromosome are also linked to morphophysiological variability (Nazareko et al., 1991). In 1976, Tiepolo and Zuffardi published the chromosome pictures of six men with a monocentric Yq11 chromosome who suffered from a severe impairment of spermatogenesis diagnosed in their testicular tissue sections (Tiepolo et al., 1976). Since these Y chromosomal abnormalities were “de novo” mutations, the authors suggested that there must be a genetically functional azoospermia factor (AZF) on the long arm of the human Y chromosome. It has been assumed that these deletions remove Y chromosomal genes required for spermatogenesis. Six AZFs of the Y chromosome, i.e., AZFa, AZFb, AZFc, and their combinations AZFbc, AZFabc, and partial AZFc called AZFc/gr/gr, have been discovered. The percentage of non-obstructive azoospermia with deletions in AZFa, AZFb, AZFc, AZFbc, and AZFabc are 4.9%, 15.8%, 59.6%, 13.6%, and <1%, respectively, and about 6% of severe oligozoospermia cases occur with deletions outside the AZFs (Foresta et al., 2001). Some smaller deletions within the AZF region such as AZFc/gr/gr have been discovered recently, which indicate that micro-deletions of the Y chromosome are relatively common. As we have discussed above, in the evolution process, homologous recombination, involving elimination of one repetitive sequence at the expense of another, is believed to account for the random appearance of de novo AZF micro-deletions in men (Repping et al., 2002). As the fathers and brothers of men with Yq micro-deletions usually have non-deleted Y chromosomes and normal sperm counts, these deletions are spontaneous events. Male infertility affects one in 20 men, which accounts for a third of all infertility, is a cofactor in over half of the assisted reproductive technology treatment worldwide at present. Primary spermatogenic failure (SgF, also termed as idiopathic infertility) accounts for more than one half of the cases (Baker, 1989). Although the pathogenesis of SgF is not clear, recent research has determined that up to 15% of SgF patients and subfertile patients (with sperm counts less than 5 million/mL) are related to at least six known Y chromosomal deletions. It is speculated that these deletion events occur during gametogenesis or early preimplantation development and may involve a deficiency in enzymes responsible for normal DNA repair; thus NAHRs (non-allelic homologous recombinations) may occur with a consequence of micro-deletion on the Y chromosome (Cram et al., 2006). Role(s) of Y Chromosome genes in spermatogenesis and how they work in different Y haplotypes: implications from intensive studies of AZFc micro-deletion and male infertility With the benefit of the Y chromosome sequence, more

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rearrangements (deletions, duplications, and inversions) of DNA fragments both inside and outside the classical AZF deletions have been elucidated. Complicated Y chromosome haplotypes of the Y chromosome result from such rearrangements during evolution. However, these rearrangements are present with similar frequencies in fertile and infertile men, which suggests a functional redundancy of the Y chromosomal multi-copy genes. Alternatively, the functional contribution(s) of these genes to human spermatogenesis may be different in men bearing different Y haplotypes (Repping et al., 2004). For example, a complex of three palindromes, the largest spanning 3 Mb with 99.97% identity between its arms, encompasses the commonly found AZFc deletion. With a total length of 4.5 Mb, it is comprised of six distinct families of near-identical amplicons (massive repeat units; Kuroda et al., 2001). Amplicon b, g, u, r, and t have 4, 3, 3, 4, and 2 repeats, respectively, in the haplotype R1. Repetitive sequences include direct repeats, inverted repeats, and palindromes. AZFc contains 12 families of transcription units, all expressed in the testis such as BPY2, DAZ, CDY1, CSPG4LY, GOLGA2LY, TTTY3, and TTTY4 etc. (Fig. 3; Table 1). AZFc micro-deletions can be divided into several subtypes, complete deletion b2/b4, partial deletion g1/g2, r1/r3, and r2/r4 (Fig. 3 D, E, G, and G). Normally, deletions

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of the AZFc region of the Y chromosome are identified as significant risk factors for spermatogenic impairment in Dutch, Spanish, Chinese, and Italians. However, the presence of this deletion in healthy French, Germans, and Han Chinese questions its importance in male infertility. It has been suggested that the functional difference between AZFc gene copies across populations is a likely cause of inconsistent association of the gr/gr deletion with spermatogenic impairment (Zhang et al., 2005; Lepretre et al., 2005; A et al., 2006). AZFb includes 4 families of genes including RBMY1, PRY, TTTY5, and TTTY6. The mechanisms for AZFb micro-deletion may be similar to that of AZFc. Interestingly, vertical transmission of both AZFb and AZFc has been discovered clinically. In the 2 cases of vertically transmitted AZFc micro-deletions, each of two brothers had the deletion. One brother was infertile, whereas the other was normal. This indicates that in same/similar Y haplotypes, reactions for AZFb/AZFc micro-deletion are different (Samli et al., 2006; Li et al., unpublished data). We postulate that micro-deletion is not an independent activity but is accompanied by the activation of other genes by gene replication or dosage compensation. Therefore, the influence of micro-deletion on spermatogenesis can be neutralized. Deletions on the mouse Y-chromosome long arm (MSYq) lead to different content

Fig. 3. Illustration of AZFs in human Y chromosome (the chromosomal size in the illustration is not proportional to the real size). A: Normal Y chromosome showing the three known AZF regions known as AZFa, AZFb, and AZFc. B: Amplicons and palindromes in the 4.5 Mb portion of the human Y chromosome that includes AZFc. Arrows indicate the amplicons, the direction of arrows indicates transcription direction, the colors of arrows indicate the origins of amplicons, and the notes below are names of amplicons. Palindromes P1, P2, and P3 are indicated. Within P1, there are two smaller palindromes, P1.1 and P1.2. C: Genes in AZFc region. Filled triangles indicate protein coding genes; empty triangles indicate non-coding genes. D: Complete AZF micro-deletion (b2/b4 deletion). Triangles with dashed lines indicate fragments being deleted. E, F, and G: Partial AZF micro-deletions g1/g2, r1/r3, and r2/r4. Triangles with dashed lines indicate fragments being deleted.

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Table 1 Human Y genes with putative spermatogenesis function mapped to the AZFa, AZFb, and AZFc deletion intervals Gene symbol Name of gene

No. of copies and code

Protein homologs

BPY2

Basic protein Y 2

BPY2.1–3

Novel

Only testis

AZFc

CDY1

Chromo domain Y1/2

CDY1.1–2

Chromatin-protein and histone-acetyltransferases

Only testis only testis

AZFb+Yq11-D11 (CDY2) AZFc (CDY1)

Only testis

AZFc

CDY2 CSPG4LY DAZ DBY aka DDX3Y EIF1AY

CDY2.1–2 Chondroitin sulfate proteoglycan 4 like Y Deleted in azoospermia

DAZ1, DAZ2, DAZ3, DAZ4 RNA binding RRM proteins

Only testis

AZFc

DEAD box Y

1

DEAD box RNA helicases

Multiple

AZFa

1

Translation initiation factor

Multiple

AZFb

GOLGA2LY.1 GOLGA2LY.2 HSFY.1–2

CIS GOLGI matrix protein GM130 HSP-2 like

Only testis

AZFc

Testis, kidney

AZFb

PRY.1–2

Protein tyrosine phosphatase

Only testis

AZFb AZFc: pseudogenes

Essential initiation translat. Factor 1A Y GOLGA2LY Golgi autoantigen, golgin subfamiliy a2 like Y HSFY Heat-shock transcription Factor Y linked PRY PTP-BL related Y

CSPG4LY.1 CSPG4LY.2

Cadherins

Tissue expression Location in Yq11

RBMY

RNA binding motif Y-linked

RBMY1.1–6

RNA binding RRM-proteins

Only testis

AZFb AZFc: pseudogenes

RPS4Y2

Ribosomal protein S4 Y linked 2

1

S4 ribosomal protein

Multiple

AZFb

SMCY

Selected mouse C DNA Y

1

H-Y antigen HLA B7

Multiple

AZFb

USP9Y

Ubiquitin specific proteaase 9 Y

1

Ubiquitin-specific protease

Multiple

AZFa

XKRY

X-Kell blood group precursor related Y

XKRY.1–2

Putative membrane transport protein

Only testis

AZFb +Yq11-D11

spermatogenesis losses from teratozoospermia to infertility. Studies have shown that the downstream transcriptional changes in the testis resulting from the loss of MSYqencoded transcript involve up-regulation of multiple X- and Y-linked spermatid-expressed genes. This indicates that in normal males, there is a specific repression of X and Y transcription in post-meiotic cells, which depends on MSYq-encoded transcripts (Ellis et al., 2005). As a highly specialized sex chromosome, the Y chromosome has high polymorphism. As knowledge of human Y chromosome characters, evolution, and the relationship between micro-deletions and male infertility increases, we now realize that the same micro-deletion on the Y chromosome may or may not cause male infertility depending on the individual’s haplotype. There is a pressing urge for large-scale studies on well-characterized normospermic and oligo/azoospermic individuals of different ethnic origins with multiple informative AZF markers if the correlation between these deletions and the phenotype is finally to be resolved.

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