Hum. Reprod. Advance Access originally published online on June 25, 2008
Human Reproduction 2008 23(9):2167-2172; doi:10.1093/humrep/den229
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Y chromosome haplogroups may confer susceptibility to partial AZFc deletions and deletion effect on spermatogenesis impairment
1 Department of Medical Genetics, West China Hospital, West China Medical School and State Key Laboratory of Biotherapy, Sichuan University, Gaopeng Street, Keyuan Road 4, Chengdu, Sichuan 610041, People’s Republic of China 2 Reproductive Medicine Center, West China Second Hospital, Sichuan University, Chengdu, People’s Republic of China
3 Correspondence address. E-mail: szzhang{at}mcwcums.com
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Abstract |
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BACKGROUND: Partial AZFc deletions related to testis-specific gene families are common mutations of the Y chromosome, but their contribution to spermatogenic impairment is still unresolved, and the risk factors for the formation of the deletions remain unknown. With this in mind, we investigated the possible association between Y chromosome haplogroups and predisposition to partial AZFc deletions and their effect on spermatogenesis in a Chinese population.
METHODS: The haplogrouping was carried out using 12 polymorphic loci on the Y chromosome in 269 non-AZFc-deleted controls with an unknown spermatogenic status and 214 men with a partial AZFc deletion defined by the absence of the sequence-tagged site and sequence family variant loss of the DAZ and CDY1 genes. In the latter group, 57 men had normozoospermia and 157 men had azoo/oligozoospermia. Among these, 122 had a de novo partial AZFc deletion.
RESULTS: Y haplogroup distribution differed significantly between men with a de novo partial AZFc deletion and the control group, and between men with a specific subtype of the partial AZFc deletions and the control group. Further, partial AZFc deletions gave rise to spermatogenesis impairment in some Y haplogroups.
CONCLUSIONS: The findings indicate that some monophyletic Y chromosomes may be associated with predisposition to specific subtypes of partial AZFc deletion and adverse effect on spermatogenesis. Although these deletions were not confirmed with gene dosage analysis, the results suggest that Y chromosome background is an important factor that affects partial AZFc deletion formation and its contribution to spermatogenic failure.
Key words: Y chromosome/haplogroup/AZFc/partial deletion
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Introduction |
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Complete AZFc deletion in the Y chromosome is a dominant cause of AZF-linked spermatogenic failure (Ferlin et al., 2006
; Krausz and Degl’Innocenti, 2006). In recent studies, susceptibility to the deletion has been associated with Y chromosome haplogroups in Italian and Chinese populations (Arredi et al., 2007; Yang et al., 2008). In the AZFc region there are also smaller deletions that are perhaps 40 times as common as the complete AZFc deletion (Page, 2004; Repping et al., 2003, 2004; Krausz and Degl’Innocenti, 2006). In this light, it is reasonable to investigate the effect of the Y background on partial AZFc deletions in order to better understand the correlation between AZFc deletion and spermatogenic failure.
With their observation that 20 of 47 Y chromosomes studied had variant AZFc architectures, Repping et al. (2006) found that the AZFc region presents a high variation rate resulting from frequent intrachromosomal recombination between homologous sequences. Some variations, which diversify the structure of AZFc region and possibly create a specific Y genetic background, may influence predisposition of the Y chromosome to partial AZFc deletions and even contribute towards spermatogenic failure. To prove this, in the present study, 12 monophyletic Y chromosomes were identified in 483 Chinese men of the same geographical origin. This included 269 non-AZFc-deleted controls with unknown spermatogenic status, and 214 men with a partial AZFc deletion. Simultaneously, in individual Y haplogroups, the frequencies of partial AZFc deletions were compared between a group of 634 normozoospermic and a group of 1286 azoo/oligozoospermic men to study the association between the effects of the deletion on spermatogenesis and the Y background. The partial AZFc deletions included gr/gr and b2/b3, which are classified using the absence of sequence-tagged sites, and the sequence family variant loss of the DAZ (deleted in azoospermia) and CDY1 (chromo domain Y1) genes.
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Subjects and Methods |
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Study population
A total of 2189 unrelated Han men ranging in age from 21 to 39 years old with the same geographic origin were recruited from Sichuan Province, Southwest China. The general clinical data and blood samples were obtained from the Department of Urology, West China Hospital, and the Center for Reproductive Medicine, West China Second Hospital, Sichuan University during the period from 2000 to 2007. The study was approved by the Institutional Ethical Review Boards, Sichuan University, and signed informed consent forms were obtained from all subjects studied. The subjects were composed of (i) 269 non-AZFc-deleted men with unknown spermatogenic status as controls; (ii) 634 men with normozoospermia with sperm concentration >20 x 106/ml or total sperm count >40 x 106 in three semen analyses, and normal sperm motility and morphology. This set included 57 men with a partial AZFc deletion confirmed by the absence of sY1191 or sY1291 and the presence of sY1161, sY1125, sY1054, sY1206, sY1201, sY254 and sY255. Of these 57 men, 19 were carriers of a de novo deletion based on the absence of such deletions in their fathers or brothers, while 29 men obtained the deletion from their fathers; no samples from fathers or brothers were obtained for the remaining 9 men; (iii) 1286 men with azoospermia or oligozoospermia (sperm concentration <20 x 106/ml or total sperm count <40 x 106 in three semen analyses), including 157 partial AZFc deleted men, of which 103 deletions were de novo and 43 deletions were transmitted. No samples were obtained from the relatives of the remaining 11 men. All men were subjected to microdeletion and karyotyping analysis to exclude those with AZFa or AZFb deletions alone and chromosomal abnormalities. Other possible causes leading to spermatogenic failure, such as the obstruction of the vas deferens, orchitis, cryptorchidism and varicocele were also excluded.
Gene copy analyses
Genomic DNA was extracted from peripheral blood lymphocytes using DNA-isolation kits (TaKaRa Co, Ostu, Japan). Three SNV (single nucleotide variant) loci, sY587, sY581 and DAZ-SNV II, in the DAZ gene family were used to detect the doublet deletion of DAZ1/DAZ2, DAZ3/DAZ4, DAZ1/DAZ4 or DAZ2/DAZ3 (Fernandes et al., 2002; Ferlin et al., 2004, 2005). Another SNV located at 7705 bp upstream of the 5'-end of CDY1 gene family was used to distinguish the deletion of CDY1a or CDY1b (Machev et al., 2004; Giachini et al., 2005). The PCR products were digested with restriction enzymes DraI, Sau3A, MboI and PvuII, and the digestion fragments were separated on a 2% agarose gel and visualized by ethidium bromide staining. The primer sequences, PCR and RFLP analysis conditions are as described in the above literature.
Y chromosome haplogroup analysis
Y chromosome haplogrouping was carried out using 12 highly informative polymorphic loci for East Asians, from which 12 haplogroups could be distinguished (Su et al., 1999; Jin and Su, 2000; Y Chromosome Consortium, 2002). A total of 10 SNPs, namely M7, M9, M45, M89, M95, M119, M122, M130, M134 and LLY22 g, could be detected with PCR–RFLP. Their restriction products, together with the PCR product of M1, were separated by electrophoresis on a 3% agarose gel and visualized by ethidium bromide staining. The PCR product of M5 was analyzed by denaturing high performance liquid chromatography (DHPLC) on a WAVE System (Transgenomics, Omaha, USA) and by direct sequencing. The primer sequences, PCR, RFLP and DHPLC conditions are described in the literature (Underhill et al., 1997; Su et al., 1999).
Statistical analyses
The comparison of the Y chromosome haplogroup distribution between the groups was performed using an exact test of population differentiation with the software of Arlequin ver.3.11 (Raymond and Rousset, 1995; Excoffier et al., 2005). The intra-group gene diversity was calculated using standard diversity indices and the difference in the genetic structure between the groups was analyzed using the AMOVA approach with the same software (Excoffier et al., 1992). The comparison of individual Y haplogroup distribution between two groups was performed using the chi-square test (SPSS 11.0 software), and the P-value was corrected using the Bonferroni method for multiple significant tests on the condition that the population difference of the two groups was found (Bland and Altman, 1995). The chi-square test was also used to compare the frequencies of partial AZFc deletions between men with normozoospermia and azoo/oligozoospermia in the individual haplogroups. In these tests the values of P < 0.05 were regarded as statistically significant.
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Results |
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In present study, a total of 11 Y chromosome haplogroups were observed in the subjects. A phylogenetic tree of these haplogroups, named by the Y Chromosome Consortium (2002
), and their distribution frequencies in the group with a de novo partial AZFc deletion and the control group are shown in Fig. 1. As shown in the figure, the Y haplogroup distribution in the deletion and control groups was significantly differentiated (P < 0.001), although the gene diversity of the two groups was similar (0.865 ± 0.010 versus 0.788 ± 0.015). The reliability of such a population difference was improved by the presence of genetic structural differences between the two groups (FST = 3.47%, P < 0.001). Further, a significant frequency difference of the single haplogroup C, DE* or O3* was observed between the groups (corrected P = 0.011, 0.011 and 0.022, respectively), in which haplogroups C and DE* showed a higher frequency and O3* showed a lower frequency in the partial AZFc deletion group compared with the control group.
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Using combined gene copy analysis according to Machev et al. (2004
) and Giachini et al. (2005), we distinguished five partial AZFc deletions (Supplementary materials, Table S1). Since the sY1291/DAZ1/DAZ2/CDY1a and sY1291/DAZ1/DAZ2/CDY1b deletions were two dominating de novo mutations with a total proportion of 77.9% (95/122), we compared their haplogroup distributions with that of the control group (Fig. 1). A significant difference was observed between the groups (both P < 0.001). This result was consistent with the difference in genetic structure between the groups (control group versus sY1291/DAZ1/DAZ2/CDY1a deletion group, FST = 6.41%, P < 0.001; control group versus sY1291/DAZ1/DAZ2/CDY1b deletion group, FST = 20.47% and P < 0.001). A comparison of the individual haplogroup distribution between the group with a partial AZFc deletion and the control group showed that the frequencies of haplogroup DE* and O3e were significantly higher (both corrected P < 0.001) and that of O3* and O1* were lower (corrected P < 0.001 and P = 0.022, respectively) in the group with the sY1291/DAZ1/DAZ2/CDY1a deletion compared with the control group. In addition, haplogroup C was more common (corrected P < 0.001) in the group with the sY1291/DAZ1/DAZ2/CDY1b deletion than in the control group. Further, we compared the frequencies of partial AZFc deletions including gr/gr and b2/b3 between the normozoospermia and azoo/oligozoospermia groups. As shown in Table I, higher frequencies of gr/gr deleted Y chromosome C and DE* were observed in the infertile men than in the control group with the deleted Y haplogroups. Meanwhile, a frequency difference of the b2/b3 deletion was not found between the two groups with the same deleted haplogroup (Table II). Additional analysis on the frequency of five subtypes of the partial AZFc deletion between men with azoo/oligozoospermia and normozoospermia was performed (Table III). The data show that the gr/gr deletion was more common in men with azoo/oligozoospermia (P < 0.001, OR = 2.098, 95% CI: 1.407–3.127). Similar results were observed when comparing the frequencies of two deletions of sY1291/DAZ1/DAZ2/CDY1a and sY1291/DAZ1/DAZ2/CDY1b between the two groups (corrected P < 0.001 and P = 0.035, respectively), whereas the b2/b3 deletion showed a similar frequency in the groups of infertile and normozoospermic men after the P-value was adjusted using the Bonferroni method (corrected P = 0.130).
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Discussion |
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The integrity of the AZF region in the Y chromosome is absolutely necessary for normal spermatogenesis since numerous genes responsible for the process are located in this region. This has been confirmed by the observation of a much higher deletion rate in men with spermatogenic failure than in men with normozoospermia (Krausz and Degl’Innocenti, 2006
). Of the three AZF subregions, AZFc is remarkable due to its frequent structural mutation and the presence of severe spermatogenic impairment in almost all men with the complete AZFc deletion. In recent studies, Y haplogroup E and O3* have been suggested to be susceptible to the b2/b4 deletion in North Italian and Chinese populations, respectively (Arredi et al., 2007; Yang et al., 2008), indicating that the deletion is a non-stochastic event dependent on Y chromosome background, although a similar result has not been obtained in other populations (Paracchini et al., 2000; Quintana-Murci et al., 2001; Carvalho et al., 2003; Krausz et al., 2004). Meanwhile, partial AZFc deletions, resulting from homologous recombination between the amplicons in the region, have been found to be more common in men with certain spermatogenic phenotypes (Repping et al., 2003, 2004; Page, 2004; Krausz and Degl’Innocenti, 2006). However, little data have been accumulated on the association between susceptibility to the deletion and Y background, and its effect on spermatogenesis is still subject to debate due to the different inclusion criteria of controls and patients, lack of ethnic and geographic matching or the lack of gene dosage analysis (Krausz and Degl’Innocenti, 2006; Krausz and Giachini, 2007). In a recent study, we observed a significant difference in Y haplogroup distribution between normozoospermic and azoo/oligozoospermic men without the AZFc deletion, suggesting that not only the AZFc mutation, but also other Y variations linked to the Y haplogroups, affect the risk for spermatogenic failure (Yang et al., 2008). In this light, it is better to analyze the effect of partial AZFc deletions on spermatogenesis in a similar Y background to minimize the effect of other variables.
To avoid possible selection bias, we compared the haplogroup distribution in 269 controls with that in 341 randomly chosen Sichuan men with unknown spermatogenic status (Ma et al., 2007). No population difference was observed (P > 0.050), suggesting that the control group is representative of the Sichuan population.
In the present study, we investigated 12 Y haplogroups in 483 subjects from the same geographical origin. A significant difference in haplogroup distribution was observed between men with a de novo partial AZFc deletion and controls without the AZFc deletion, suggesting that the susceptibility to this deletion may be affected by Y chromosome background. More interestingly, our findings indicated that haplogroups C and DE* may present a predisposition to partial AZFc deletions, whereas O3* may protect against the deletions. Combining the relatively low frequencies of C and DE* and the high frequency of O3* in controls, together with the possible negative effect of the deletions on spermatogenesis (Giachini et al., 2005; Wu et al., 2007), all of this suggests that the distinct susceptibility to the deletions may be a potential factor that causes the differentiation in Y haplogroup frequency in the population (Vogt, 2005).
More evidence for the association between Y background and partial AZFc deletions comes from the difference in haplogroup distribution between controls and men with the deletion of sY1291/DAZ1/DAZ2/CDY1a or sY1291/DAZ1/DAZ2/CDY1b. The frequencies of the two deletions were significantly different in some haplogroups. The results suggest that Y haplogroups DE* and O3e might be susceptible to the deletion of sY1291/DAZ1/DAZ2/CDY1a, whereas O3* and O1* might protect against the deletion. Men with haplogroup C might be prone to the deletion of sY1291/DAZ1/DAZ2/CDY1b. The findings further suggest that a partial AZFc deletion may not be a stochastic event independent of Y background. It is very possible that there are distinct AZFc structural variations among Y haplogroups that affect the susceptibility to specific partial AZFc deletions, which may be similar to a reported Y haplogroup predisposed to X/Y exchange and the L1PA4 deletion in AZFa (Jobling et al., 1998; Kamp et al., 2000). In the present study, the total frequency of partial AZFc deletions, including gr/gr and b2/b3, was 9.0% and 12.2% in normozoospermia and azoo/oligozoospermia groups, respectively. This is higher than that reported in the literature, which shows that 3–5% of men with the phenotype from normozoospermia to azoospermia carried the deletions (Ferlin, et al., 2007). However, in two other studies of Chinese populations, 10.9% of normozoospermic and 16.1% of azoo/oligozoospermic men (Wu et al., 2007) and 9.5% of men with unknown spermatogenesis status (Lin et al., 2007) were found to carry the deletions. We assume that the frequency difference might arise from the different inclusion criteria of subjects, ethnic factor and the lack of gene dosage analysis. Furthermore, the gr/gr deletion was more common in men with azoo/oligozoospermia than in men with normozoospermia, suggesting that the deletion may be a risk factor for spermatogenic failure (Giachini et al., 2005). Interestingly, the gr/gr deleted Y chromosomes C and DE* were found only in the infertile group, whereas similar frequencies of other deleted Y haplogroups were observed between the two groups, suggesting that the relationship between the deletion and spermatogenic failure might be associated with Y background.
Furthermore, similar to the Giachini's study (2005), our data supported the negative effect of the sY1291/DAZ1/DAZ2/CDY1a deletion on spermatogenesis, although it was observed in both the normozoospermia and azoo/oligozoospermia group. In addition, the sY1291/DAZ1/DAZ2/CDY1b deletion was also more common in the infertile group than the control group, suggesting that the deletion might be a second important risk factor for spermatogenic failure. Moreover, the results suggest that the CDY1a deletion presents a strong association with impaired spermatogenesis due to the higher frequency in the infertile group than in the control group (P < 0.001, OR = 0.270, 95% CI: 0.134–0.547). This is consistent with the findings reported in the literature (Machev et al., 2004; Giachini et al., 2005). Surprisingly, the deletion of sY1191/DAZ3/DAZ4/CDY1b, which was the only pattern of b2/b3 deletion found in the study, seemed to be more frequent in men with normozoospermia than in the infertile men, although the frequency difference was not observed after the correction of the P-value using the Bonferroni method. Since 81.1% (43/53) of the deletions presented in Y chromosome N*, we speculated that there might be certain subsequent variations linked to deleted chromosome N* that decreased the risk for spermatogenic failure in men with the haplogroup. Recently, a study of a Chinese population of 580 men with unknown fertility identified 30 men with sY1191-deleted Y chromosome N* of whom 33.3% (10/30) were observed to have four DAZ gene copies, which suggested that the Y chromosome N* might undergo a b3/b4 duplication in b2/b3-deleted AZFc structure (Lin et al., 2007). If so, it is possible that the duplication variation may compensate for the negative effect of the partial deletion on spermatogenesis, so that it is preserved by genetic drift and transmitted in the population.
In conclusion, the present study obtained, for the first time, evidence for the association between susceptibility to partial AZFc deletions and Y chromosome haplogroup, suggesting that Y chromosome background influences the risk for partial AZFc deletion. Furthermore, our results suggest that the Y chromosome background also influences the effect of the partial AZFc deletion on spermatogenesis. Although we cannot exclude that false deletions or deletions/duplications might bias the study’s results due to the lack of gene dosage confirmation, we believe that the findings are an important step towards the better understanding of spermatogenesis pathology.
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Supplementary material |
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Supplementary material is available at HUMREP Journal online.
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Funding |
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This work was supported by National High Technology Research and Development Program, grant number: 2004AA216090; National Basic Research Program, grant number: 2004CB518805; National Key Technologies R&D Program, grant number: 2006BAL05A08, People's Republic of China.
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Footnotes |
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These two authors contributed equally to this work. 
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Submitted on January 11, 2008; resubmitted on May 8, 2008; accepted on May 15, 2008.
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