Mol. Hum. Reprod. Advance Access originally published online on July 22, 2005
Molecular Human Reproduction 2005 11(7):507-512; doi:10.1093/molehr/gah191
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The Y chromosome gr/gr subdeletion is associated with male infertility
1Prince Henry’s Institute of Medical Research, 2Monash Immunology and Stem Cell Laboratories, Monash University, 3Monash IVF, 4Monash Institute of Medical Research, Monash University, 5ARC Centre of Excellence in Biotechnology and Development, 6University of Melbourne, Department of Obstetrics and Gynaecology, Royal Women’s Hospital, Carlton and 7Department of Obstetrics and Gynaecology, Monash University, Monash Medical Centre, Clayton, Victoria, Australia
8 To whom correspondence should be addressed at: Prince Henry’s Institute of Medical Research, P.O.Box 5152, Clayton, 3168, Victoria, Australia. E-mail: rob.mclachlan{at}phimr.monash.edu.au
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Abstract |
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Men with Y chromosome (Yq) AZFc deletions lack all copies of the DAZ gene and have severe spermatogenic failure. A recently described gr/gr subdeletion of AZFc removes two of four copies of DAZ. To better understand the relative frequencies of AZFc and gr/gr deletions and their associated phenotypes, we analysed two large groups of infertile men. A total of 788 men from the Monash Male Infertility (MMI) database with a range of fertility disorders showed similar overall prevalences of AZFc (2.5%) and gr/gr deletions (3.4%). There was no association of gr/gr deletions with sperm density. In 234 control men of known or presumed fertility, only one gr/gr deletion was found. In a further 599 consecutive men presenting for assisted reproductive technologies, we detected 13 (2.2%) AZFc deletions and 28 (4.7%) gr/gr deletions. All AZFc deletions were seen with sperm densities <5 million/ml but again the gr/gr deletion occurred with similar frequency across all sperm density categories. These data show that gr/gr deletions are significantly associated with infertility in the Australian population (P = 0.0015) but not exclusively with reduced sperm density suggesting a complex interaction with other factors important for male fertility. Vertical transmission of gr/gr deletions from father to son by ICSI was demonstrated in four cases. Analysis of 130 ICSI-conceived sons revealed no de novo gr/gr deletions indicating that ICSI is not a risk factor. The data suggest that testing for gr/gr deletions should be considered in the routine genetic assessment of men with idiopathic infertility.
Key words: deletion/male infertility/spermatogenic failure/Y chromosome
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Introduction |
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Spermatogenic disorders are the leading cause of male infertility and are increasingly recognized as being of genetic origin. Deletions of the long arm of the Y chromosome (Yq) are the most frequently recognized genetic cause of male infertility with a prevalence of approximately 5% (range 1–20%) in azoo- or severely oligospermic men (reviewed in Vogt, 1998
; Foresta et al., 2001). Three AZF regions of Yq (termed AZFa, b and c) have been defined by molecular analysis of conserved sequence tagged sites (STS; Vollrath et al., 1992; Vogt et al., 1996; Vogt, 1998). Deletions involving the AZFc region account for up to 90% of all Yq deletions with phenotypes varying from azoospermia to severe oligospermia (Reijo et al., 1995; Najmabadi et al., 1996; Vogt et al., 1996; Pryor et al., 1997; Simoni et al., 1997; Kleiman et al., 1999; Krausz et al., 1999) and occasionally, milder oligozoospermia (Oliva et al., 1998). Large Yq deletions extending proximal to AZFc commonly involve the AZFb and AZFa regions and are always associated with azoospermia and a testis pathology of germ cell arrest or Sertoli cell-only syndrome (Vogt et al., 1996; Brandell et al., 1998; Kamp et al., 2001). Men with AZFa, AZFb or large AZFabc deletions have a poor outlook for sperm recovery at testicular sperm extraction (Brandell et al., 1998; Krausz et al., 2000). Yq deletions carried by infertile men are transmitted to male offspring by assisted reproduction technologies (ART) such as ICSI and are likely to cause similar fertility problems (Kent-First et al., 1996; Cram et al., 2000).
Recent molecular analysis and sequencing of the Yq have revealed eight large palindromic regions containing an array of different ampliconic sequences (Kuroda-Kawaguchi et al., 2001; Skaletsky et al., 2003). Homologous recombination between specific palindromic sequences is believed to be the mechanism for the formation of various Yq deletions (Kamp et al., 2000; Sun et al., 2000; Repping et al., 2002). For example, generation of AZFc deletions is caused by recombination involving b2 and b4 sequences (Kuroda-Kawaguchi et al., 2001) and removes all four copies of the DAZ gene and all three copies of the BPY2 gene. DNA sequence alignments within AZFc also revealed the possibility for the formation of smaller subdeletions. Detailed analysis of the AZFc region using new molecular markers has confirmed the existence of three such deletions; namely, gr/gr, b1/b3 and b2/b3 (also known as g1/g3) (Repping et al., 2003; Fernandes et al., 2004; Repping et al., 2004a). The most prevalent deletion, gr/gr (Repping et al., 2003), is caused by recombination between repeat sequences g and r, resulting in the loss of two of the four copies of the DAZ gene and one of three copies of the BPY2 gene. The outcome of b2/b3 and b1/b3 deletions is similar leading to the retention of two DAZ gene copies and one or two BPY2 gene copies. An initial association of the gr/gr deletion with spermatogenic failure (Repping et al., 2003) has been substantiated in a Spanish cohort of men undergoing ICSI treatment (de Llanos et al., 2005) but not in a German cohort of men with nonobstructive oligo-/azoospermia or in a French group of infertile men (Machev et al., 2004; Hucklenbroich et al., 2005).
Yq assessment for AZFa, b and c deletions using PCR-based approaches is a standardized practice (Simoni et al., 1999) and widely recommended for men with idiopathic spermatogenic disorders and sperm densities <5 million/ml prior to fertility treatments. To establish the contribution of these newly defined AZFc subdeletions to male infertility, we have assessed their prevalence and associated phenotype in a large cohort of infertile men represented in the Monash Male Infertility (MMI) database, in consecutive infertile men presenting for assisted reproductive treatment and in a cohort of male children conceived by ICSI. Such data are essential to determine whether the scope of Yq testing in ART should be broadened to include other subgroups of men with idiopathic infertility. Our results indicate that gr/gr deletions are found in infertile men over a wide range of sperm densities but are essentially absent from men of known or presumed fertility.
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Materials and methods |
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Study subjects
Two populations of infertile men presenting to the Monash IVF and Melbourne IVF programmes and control fertile men were identified for the study.
MMI database
Since 1995, men presenting for fertility assessment have been invited to participate in a study of the genetic basis of male infertility. This data set of men does not represent a consecutive series of infertile men but rather a collection focussing on phenotypes of particular interest for genetic studies including spermatogenic failure, disorders of sperm motility and morphology. For this study, men with Klinefelter’s syndrome or other karyotypic abnormalities were excluded. In total, 788 infertile men were assessed.
Participation involved the collection of clinical information relevant to reproduction: (i) physical examination, including testicular volumes; (ii) serum hormone levels of testosterone, FSH and luteinizing hormone; (iii) semen analysis as assessed by the WHO criteria (World Health Organisation, 1999); (iv) testicular histology when clinically indicated as assessed in 5 µm sections of Bouin’s fixed paraffin-embedded sections stained with Mason’s trichrome and (v) genetic assessments for karyotype and Yq chromosome microdeletions (encompassing AZFa, b and c regions). All patients gave their informed consent, and the study was approved by the Human Research and Ethics Committees of Southern Health, Monash Medical Centre and the Royal Women’s Hospital, Melbourne.
In a related study, cord or peripheral venous blood or buccal scrapings were obtained from offspring conceived by ICSI from several of the men in the MMI database. This DNA resource has been reported previously in the demonstration of the vertical transmission of AZFc deletions (Cram et al., 2000). This study screened 134 of the male children for gr/gr deletions. The study was approved by the Human Ethics and Research Committees of the Epworth Medical Centre, the Monash Day Surgery Hospital and Monash University, and both parents gave informed consent.
Monash IVF clinical patients
As part of routine assessment prior to assisted reproduction treatment, 448 consecutive severely infertile men with idiopathic spermatogenic failure and sperm densities of 
5 million/ml underwent assessment for Yq chromosome microdeletions. DNA samples referred to the Monash reproductive pathology and genetics laboratory were assessed for the gr/gr AZFc subdeletion. The laboratory also received samples from a further 114 men with sperm densities of 5–19 million/ml and 37 samples from men with normal sperm densities. Although all these men were undergoing fertility assessment, the basis of the couple’s infertility was unclear. The assessment for Yq subdeletions was considered as a laboratory service quality assurance activity covered by the original consent for genetic testing as outlined in the National Health and Medical Research Council (NHMRC) ethical guidelines. No further information other than their semen quality at the same laboratory was accessed.
Control subjects
The following groups of men were enrolled as controls (i) men of proven fertility (fathers) who have not undergone physical examination (n = 58), (ii) previously fertile men presenting with obstructive azoospermia after vasectomy (n = 42) and (iii) healthy young men with a normal reproductive history, normal physical examination and normal semen analysis who volunteered for sperm donation programmes or for a study to examine the distribution of reproductive hormone levels (n = 134). All subjects gave their informed consent, and the study was approved by the Human Research and Ethics Committees of Southern Health, Monash Medical Centre and by the Royal Women’s Hospital, Melbourne and the Concord Hospital, Sydney.
Mapping of Yq deletions
Testing of AZFa, b and c deletions in the Monash IVF cohort was performed by multiplex PCR according to established protocols (Cram et al., 2000). Genomic DNA preparation and genetic testing was also performed, as described previously (Cram et al., 2000).
The presence or absence of the AZFc subdeletions was tested by PCR amplification of STS markers essentially as described (Repping et al., 2003, 2004b) with minor modifications (Figure 1). Multiplex PCR of five Yq STS markers (sY1161, sY1191, sY1201, sY1206* and sY1291) was performed. The absence of an sY1291 product was indicative of a gr/gr deletion. The absence of amplification of the STS markers sY1291, sY1206* and sY1191 with the presence of the markers sY1201 and sY1161 indicated a full AZFc deletion. The absence of markers sY1291, sY1191 and sY1161 with the presence of sY1206* and sY1201 was indicative of the b1/b3 deletion. The absence of amplification of sY1191 indicated a b2/b3 (g1/g3) deletion. Primer sequences were as described (Repping et al., 2003 and GenBank) except for sY1206*, which used the primers sY1206* F (5'-ctgggctttctgtggcattt-3') and sY1206* R (5'-gccaatttgaccagtgacttc-3') from within the GenBank sY1206 sequence to allow easier size separation of multiplex PCR products on agarose gels. Multiplex PCR was performed on 50 ng of genomic DNA template using 2–8 pmoles of each primer in 50 mM of KCl, 10 mM of Tris–HCl (pH 8.3), 1.5 mM of MgCl2, 0.1% Triton-X100, 200 µM of each dNTP and 1 unit of Taq polymerase (Fisher Biotech, Perth, Australia) in a final volume of 15 µl. Amplification cycles consisted of an initial denaturation step at 94°C for 4 min, followed by 35 cycles at 94°C for 30 s, 61.5°C for 45 s and 72°C for 45 s, with a final extension of 72°C for 5 min, DNA amplification products were separated in 2% agarose-ethidium bromide gels in 0.5X TBE buffer. DNA amplification profiles used to identify the different AZFc subdeletions are shown in Figure 1
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Yq haplogroups
To determine Y haplogroups, we analysed all gr/gr deleted genomic DNA samples with a panel of markers: SRY1532 (DraIII digest; Santos et al., 1999), YAP (Hammer and Horai, 1995; primer sequences from Underhill et al., 2000), M213 (HpyCH4IV digest; Underhill et al., 2000), M9 (HinfI digest, primers from Underhill et al., 2000), 12f2 (duplex PCR; Rosser et al., 2000), 92R7 (HindIII digest; Hurles et al., 1999) and SRY4064 (Whitfield et al., 1995; BsrBI digest, primers from Y Chromosome Consortium, 2002). Genomic DNA from one gr/gr-deleted control sample was also typed for the markers M174 (BfaI digest; Underhill et al., 2000) and M116 (sequenced, Underhill et al., 2000). All restriction enzymes were supplied by New England Biolabs (Beverly, MA, USA). PCR amplifications (except YAP) were performed as described above using 10 pmoles of each primer and with a touchdown protocol of two cycles at an annealing temperature of 63°C for 30 s stepping down to 59°C then a further 25 cycles with an annealing temperature of 58°C. YAP was amplified with the conditions above except that a final concentration of 1.0 mM of MgCl2 and an annealing temperature of 54°C for 30 s were used.
Statistical analysis
Study and control groups were compared using Fisher’s exact test (one-tailed) on GraphPad (San Diego, CA, USA) with P values <0.05 statistically significant.
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Results |
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Prevalence and distribution of Yq deletions in infertile men
A total of 788 patients from the MMI database was stratified according to sperm density, and their associated clinical features including combined testis volume (CTV), history of cryptorchidism, serum FSH levels and sperm motility and morphology data are summarized in Table I. Declining sperm density was associated with the expected trend towards small testis volumes, higher serum FSH levels and declines in progressive motility and normal morphology.
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The prevalence of AZFc, gr/gr, b1/b3 and b2/b3 deletions in the 788 men was determined by multiplex PCR analysis of genomic DNA (Figure 1). Fifty-seven (7.2%) Yq deletions were detected, comprising 19 (2.4%) AZFc deletions, 27 (3.4%) gr/gr subdeletions, 4 (0.5%) b1/b3 subdeletions and 7 (0.9%) b2/b3 subdeletions (Table II). In contrast, screening of 234 control men revealed no AZFc deletions, one gr/gr subdeletion, one b1/b3 subdeletion and two b2/b3 subdeletions. There was a statistically significant difference in the frequency of gr/gr deletions (Fisher’s exact test, P = 0.0059) and AZFc deletions (P = 0.0068) between control and infertile men. However, there was no significant difference in the frequency of the b2/b3 or b1/b3 subdeletions between the patient and control groups. All 19 AZFc deletions were seen in the 504 men with severe primary spermatogenic failure, and sperm densities of <5 million/ml giving an overall prevalence of 3.8% in this grouping, with the highest being in those with sperm densities of 0.1–0.5 million/ml (11%). The gr/gr deletions were seen across all sperm densities with no significant trends over any of the six categories of sperm density. The clinical characteristics (testis volume, serum FSH, motility and morphology) of both the AZFc and gr/gr-deleted men were similar to that of the whole database population. AZFc-deleted patients had CTVs from 16 to 47 ml and FSH levels from 2 to 33.9 IU/l. Subjects with gr/gr deletions had CTVs from 12 to 50 ml and FSH levels from 3 to 37.8 IU/ml. There were no clinical features such as sperm motility or morphology that were common to the gr/gr-deleted patients. In addition, eight patients (1%) had a deletion of one or more markers in a pattern that did not correspond to the previously described AZFc subdeletions.
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The frequency of AZFc subdeletions in severely infertile men presenting for ICSI/ART was also assessed in 448 consecutive DNA samples from men with sperm densities <5 million/ml. The observed frequencies of AZFc, AZFb, AZFbc and AZFc subdeletions are shown in Table III. Overall, there were 16 AZF deletions (13 AZFc and 3 AZFbc) giving a total prevalence of 3.6%. A total of 21 gr/gr and 4 b2/b3 subdeletions were also detected in this group with a prevalence of 4.7% and 0.9%, respectively. No b1/b3 subdeletions were found. As gr/gr, b2/b3 and b1/b3 subdeletions were also found in men with sperm densities >5 million/ml in the MMI database cohort, we tested a further 151 men referred for Yq testing with sperm densities over 5 million/ml. No b1/b3 subdeletions were detected, but 7 (4.6%) gr/gr subdeletions and 4 (2.6%) b2/b3 subdeletions were found. The prevalence of the gr/gr deletions was significantly different in these patients compared with controls (P = 0.0007).
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Y chromosome haplogroups
The Y chromosomes of all 56 subjects who carried a gr/gr deletion were typed for seven Y chromosome polymorphic markers (Y Chromosome Consortium, 2002) to determine their haplogroup. The patients were characterized into six groups that showed a wide range of sperm density within each group (except haplogroup BC which has a single individual) (Figure 2). The control individual who carried a gr/gr deletion belonged to haplogroup D2b that has already been described as carrying the gr/gr deletion with little effect on fertility (Repping et al., 2003). The D2b haplogroup was not found in the infertile patients. The most common Yq haplogroup in the gr/gr-deleted patients (haplogroup P, in 49% of deleted patients) was found at a similar frequency (48%) in the normal group of control samples.
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Vertical transmission of AZFc subdeletions via ART
There were four instances of the vertical transmission of gr/gr subdeletions from father to ICSI-conceived son (see Figure 1 for example). These fathers had sperm densities of 0.9 x 106, 2 x 106, 12 x 106 and 24 x 106/ml. No de novo gr/gr deletions were seen in the remaining 130 ICSI-conceived sons. We also found two boys who had inherited the b2/b3 deletion from their father.
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Discussion |
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We have determined the frequency of AZFc subdeletions in two large cohorts of infertile men, one selected for a research programme on the genetics of spermatogenic failure, sperm motility and morphology defects, and the other a consecutive clinical cohort of men being assessed prior to ART/ICSI. These data were compared with a control set of proven or presumably fertile men. Of the three types of AZFc subdeletions analysed, only gr/gr deletions were statistically associated with infertility. Within both infertile cohorts, gr/gr deletions were observed at similar frequencies across a wide range of sperm densities and, in contrast to AZF deletions, also occurred in infertile men with moderate oligospermia and normospermia. The overall gr/gr deletion frequencies of 3.4% in the MMI database and 4.7% in the Monash IVF clinical cohort were both higher than their respective AZFc deletion frequency. This was true even when stratifying men in the Monash IVF clinical cohort with sperm densities <5 million/ml (4.7% gr/gr deletions versus 3.6% AZF deletions). Overall, from a cohort of 1387 infertile men, 55 (4.0%) had gr/gr deletions. When compared with a control sample of 234 men with 1 g/gr-deleted subject, there was a highly significant association with infertility (P = 0.0015).
Our gr/gr-deletion prevalence is similar to that originally documented (Repping et al., 2003), where a gr/gr deletion frequency of 3.2% in 246 men with spermatogenic failure was reported with the absence of this deletion in 148 men with normal spermatogenesis. These prevalence figures are similar to those reported in an infertile Spanish population (4.2% of 283 patients) (de Llanos et al., 2005), an infertile German population (4% of 348 patients) (Hucklenbroich et al., 2005) and a French population of infertile men (6% of 300 patients) (Machev et al., 2004). However, only one of these three recent studies found a significant association of gr/gr deletion with spermatogenic failure when the infertile groups were compared with their respective control groups. This may reflect specific population differences or variation between the selected patient and control groups. It is difficult to match control and study groups exactly, but we can attempt to reduce the effects of differences in individual studies by considering these three recent studies with the original description of the gr/gr deletion and our own results. Comparing a total group of 3035 infertile men studied so far with a control group of 1398 men of proven or presumed fertility, 123 subjects had gr/gr deletions in the patient samples compared with 22 men in the control groups. This comparison shows a highly significant association of gr/gr deletions with infertility (Fisher’s exact test, one-tailed P = 0.0001).
The findings reported here indicate that gr/gr deletions are frequently but not exclusively associated with a low sperm count. Further, our observation of a significantly increased prevalence of gr/gr deletions in infertile men with mild oligo- to normospermia indicates that this deletion may also manifest as unidentified defects in sperm function in men with higher sperm counts leading to the observed strong association between gr/gr deletions and the male infertility phenotype. This association of gr/gr deletions with a low but variable sperm count and infertility is difficult to reconcile with our limited knowledge of AZFc gene function and polymorphisms.
There is variation in Yq structure which is not well resolved by STS marker screening. A similar pattern of STS amplification can be observed from different Yq structures (Jobling et al., 1996; Fernandes et al., 2004; Machev et al., 2004). The gr/gr-deleted chromosomes characterized by Machev et al. (2004) are not all equivalent in their structure or in their association with infertility. Duplication of sequences following gr/gr deletion has been observed (Repping et al., 2003), whereas an as yet uncharacterized Yq polymorphism has been postulated to compensate for the gr/gr deletion on D2b chromosomes (Repping et al., 2003). Some of the rarer STS deletions published by Hucklenbroich et al. (2005) cannot be derived from the published reference sequence of Skaletsky et al. (2003) by simple recombination. It should be noted that this reference sequence is from a single individual and represents only one Yq structure. We also observed some less common patterns of deletion but only in individual cases or pairs of cases indicating uncommon deletions or rare Yq structures before deletion. Molecular characterization of the variation in Yq structure at the DNA sequence level will lead to a better understanding of the effects of different subdeletions on sperm parameters and fertility.
The Yq haplogroups of the patients carrying the gr/gr deletion reflect the heterogeneity of the Australian population from which the patients were drawn. The Australian male population is mainly of British origin but with large numbers originating from Mediterranean Europe and Asia. Subdividing the gr/gr-deleted patients by haplogroup does not appreciably alter the observed association seen across the sample as a whole. Within each defined haplogroup category of patients, the gr/gr deletions are accompanied by a low but variable sperm density.
In our study, we identified four cases of vertical transmission to male offspring through the use of ICSI. In the analysis of 134 ICSI-conceived boys, no de novo gr/gr deletions were detected indicating that ICSI is not a risk factor for deletion. In sons inheriting a full AZFc-deleted Yq, it is likely that their fertility phenotype will be similar to that of their father although genetic background could modify the severity of infertility. In the few cases where natural transmission of an AZFc deletion has been observed, the sons are infertile (Vogt et al., 1996; Pryor et al., 1997; Saut et al., 2000; Kuhnert et al., 2004). Fertility in adulthood for children inheriting gr/gr deletions is less clear given the unpredictability of potential compensating factors. When these ICSI-conceived sons reach sexual maturity, it will be interesting to compare their phenotypes with their fathers’, given that each will have the same Y haplotype and presumably an identical gr/gr deletion. Such analyses will begin to identify the genome-wide genetic factors affecting their sperm production.
Regardless of the compensating genetic factors that operate following a gr/gr deletion, the fact remains that overall 1 man in every 25 presenting at Australian clinics with infertility carries a gr/gr deletion which is associated with his infertility. Further molecular characterization of gr/gr deletions together with Yq haplotyping is essential to provide a plausible explanation for the variable spermatogenic phenotype. Until then, consideration should be given to the inclusion of gr/gr deletion probes in the panel used for routine Yq deletion testing given this association with infertility and the certainty of its transmission to male offspring for whom its presence must be considered at least a potential risk for their fertility.
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Acknowledgements |
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The authors thank the patients and control subjects for their participation, L. Swain for technical assistance, Dr J. Stankovic for advice on statistics and Prof. D. Handelsman for assistance with control subjects. This work was supported by funding from the NHMRC (241000 and 334011), ARC (CE0348239), Andrology Australia and Monash IVF.
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References |
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Brandell RA, Mielnik A, Liotta D, Ye Z, Veeck LL, Palermo GD and Schlegel PN (1998) AZFb deletions predict the absence of spermatozoa with testicular sperm extraction: preliminary report of a prognostic genetic test. Hum Reprod 13, 2812–2815.
Cram DS, Ma K, Bhasin S, Arias J, Pandjaitan M, Chu B, Audrins MS, Saunders D, Quinn F and de Kretser D (2000) Y chromosome analysis of infertile men and their sons conceived through intracytoplasmic sperm injection: vertical transmission of deletions and rarity of de novo deletions. Fertil Steril 74, 909–915.[CrossRef][ISI][Medline]
de Llanos M, Luis Ballesca J, Gazquez C, Margarit E and Oliva R (2005) High frequency of gr/gr chromosome Y deletions in consecutive oligospermic ICSI candidates. Hum Reprod 20, 216–220.
Fernandes S, Paracchini S, Meyer LH, Floridia G, Tyler-Smith C and Vogt PH (2004) A large AZFc deletion removes DAZ3/DAZ4 and nearby genes from men in Y haplogroup N. Am J Hum Genet 74, 180–187.[CrossRef][ISI][Medline]
Foresta C, Moro E and Ferlin A (2001) Y chromosome microdeletions and alterations of spermatogenesis. Endocr Rev 22, 226–239.
Hammer MF and Horai S (1995) Y chromosomal DNA variation and the peopling of Japan. Am J Hum Genet 56, 951–962.[ISI][Medline]
Hucklenbroich K, Gromoll J, Heinrich M, Hohoff C, Nieschlag E and Simoni M (2005) Partial deletions in the AZFc region of the Y chromosome occur in men with impaired as well as normal spermatogenesis. Hum Reprod 20, 191–197.
Hurles ME, Veitia R, Arroyo E, Armenteros M, Bertranpetit J, Perez-Lezaun A, Bosch E, Shlumukova M, Cambon-Thomsen A, McElreavey K et al. (1999) Recent male-mediated gene flow over a linguistic barrier in Iberia, suggested by analysis of a Y-chromosomal DNA polymorphism. Am J Hum Genet 65, 1437–1448.[CrossRef][ISI][Medline]
Jobling MA, Samara V, Pandya A, Fretwell N, Bernasconi B, Mitchell RJ, Gerelsaikhan T, Dashnyam B, Sajantila A, Salo PJ et al. (1996) Recurrent duplication and deletion polymorphisms on the long arm of the Y chromosome in normal males. Hum Mol Genet 5, 1767–1775.
Kamp C, Hirschmann P, Voss H, Huellen K and Vogt PH (2000) Two long homologous retroviral sequence blocks in proximal Yq11 cause AZFa microdeletions as a result of intrachromosomal recombination events. Hum Mol Genet 9, 2563–2572.
Kamp C, Huellen K, Fernandes S, Sousa M, Schlegel PN, Mielnik A, Kleiman S, Yavetz H, Krause W, Kupker W et al. (2001) High deletion frequency of the complete AZFa sequence in men with Sertoli–cell–only syndrome. Mol Hum Reprod 7, 987–994.
Kent-First MG, Kol S, Muallem A, Ofir R, Manor D, Blazer S, First N and Itskovitz-Eldor J (1996) The incidence and possible relevance of Y-linked microdeletions in babies born after intracytoplasmic sperm injection and their infertile fathers. Mol Hum Reprod 2, 943–950.
Kleiman SE, Yogev L, Gamzu R, Hauser R, Botchan A, Lessing JB, Paz G and Yavetz H (1999) Genetic evaluation of infertile men. Hum Reprod 14, 33–38.
Krausz C, Bussani-Mastellone C, Granchi S, McElreavey K, Scarselli G and Forti G (1999) Screening for microdeletions of Y chromosome genes in patients undergoing intracytoplasmic sperm injection. Hum Reprod 14, 1717–1721.
Krausz C, Quintana-Murci L and McElreavey K (2000) Prognostic value of Y deletion analysis: what is the clinical prognostic value of Y chromosome microdeletion analysis? Hum Reprod 15, 1431–1434.
Kuhnert B, Gromoll J, Kostova E, Tschanter P, Luetjens CM, Simoni M and Nieschlag E (2004) Case report: natural transmission of an AZFc Y-chromosomal microdeletion from father to his sons. Hum Reprod 19,886–888.
Kuroda-Kawaguchi T, Skaletsky H, Brown LG, Minx PJ, Cordum HS, Waterston RH, Wilson RK, Silber S, Oates R, Rozen S et al. (2001) The AZFc region of the Y chromosome features massive palindromes and uniform recurrent deletions in infertile men. Nat Genet 29, 279–286.[CrossRef][ISI][Medline]
Machev N, Saut N, Longepied G, Terriou P, Navarro A, Levy N, Guichaoua M, Metzler-Guillemain C, Collignon P, Frances AM et al. (2004) Sequence family variant loss from the AZFc interval of the human Y chromosome, but not gene copy loss, is strongly associated with male infertility. J Med Genet 41, 814–825.
Najmabadi H, Huang V, Yen P, Subbarao MN, Bhasin D, Banaag L, Naseeruddin S, de Kretser DM, Baker HW, McLachlan RI et al. (1996) Substantial prevalence of microdeletions of the Y-chromosome in infertile men with idiopathic azoospermia and oligozoospermia detected using a sequence-tagged site-based mapping strategy. J Clin Endocrinol Metab 81, 1347–1352.[Abstract]
Oliva R, Margarit E, Ballesca JL, Carrio A, Sanchez A, Mila M, Jimenez L, Alvarez-Vijande JR and Ballesta F (1998) Prevalence of Y chromosome microdeletions in oligospermic and azoospermic candidates for intracytoplasmic sperm injection. Fertil Steril 70, 506–510.[CrossRef][ISI][Medline]
Pryor JL, Kent-First M, Muallem A, Van Bergen AH, Nolten WE, Meisner L and Roberts KP (1997) Microdeletions in the Y chromosome of infertile men. N Engl J Med 336, 534–539.
Reijo R, Lee TY, Salo P, Alagappan R, Brown LG, Rosenberg M, Rozen S, Jaffe T, Straus D, Hovatta O et al. (1995) Diverse spermatogenic defects in humans caused by Y chromosome deletions encompassing a novel RNA-binding protein gene. Nat Genet 10, 383–393.[CrossRef][ISI][Medline]
Repping S, Skaletsky H, Lange J, Silber S, Van Der Veen F, Oates RD, Page DC and Rozen S (2002) Recombination between palindromes P5 and P1 on the human Y chromosome causes massive deletions and spermatogenic failure. Am J Hum Genet 71, 906–922.[CrossRef][ISI][Medline]
Repping S, Skaletsky H, Brown L, van Daalen SK, Korver CM, Pyntikova T, Kuroda-Kawaguchi T, de Vries JW, Oates RD, Silber S et al. (2003) Polymorphism for a 1.6-Mb deletion of the human Y chromosome persists through balance between recurrent mutation and haploid selection. Nat Genet 35, 247–251.[CrossRef][ISI][Medline]
Repping S, van Daalen SK, Korver CM, Brown LG, Marszalek JD, Gianotten J, Oates RD, Silber S, van der Veen F, Page DC et al. (2004a) A family of human Y chromosomes has dispersed throughout northern Eurasia despite a 1.8-Mb deletion in the azoospermia factor c region. Genomics 83, 1046–1052.[CrossRef][ISI][Medline]
Repping S, Korver CM, Oates RD, Silber S, van der Veen F, Page DC and Rozen S (2004b) Are sequence family variants useful for identifying deletions in the human Y chromosome? Am J Hum Genet 75, 514–517.[CrossRef][ISI][Medline]
Rosser ZH, Zerjal T, Hurles ME, Adojaan M, Alavantic D, Amorim A, Amos W, Armenteros M, Arroyo E, Barbujani G et al. (2000) Y-chromosomal diversity in Europe is clinal and influenced primarily by geography, rather than by language. Am J Hum Genet 67, 1526–1543.[CrossRef][ISI][Medline]
Santos FR, Pandya A, Tyler-Smith C, Pena SDJ, Schanfield M, Leonard WR, Osipova L, Crawford MH and Mitchell RJ (1999) The central Siberian origin for Native American Y chromosomes. Am J Hum Genet 64, 619–628.[CrossRef][ISI][Medline]
Saut N, Terriou P, Navarro A, Levy N and Mitchell MJ (2000) The human Y chromosome genes BPY2, CDY1 and DAZ are not essential for sustained fertility. Mol Hum Reprod 6, 789–793.
Simoni M, Gromoll J, Dworniczak B, Rolf C, Abshagen K, Kamischke A, Carani C, Meschede D, Behre HM, Horst J et al. (1997) Screening for deletions of the Y chromosome involving the DAZ (Deleted in AZoospermia) gene in azoospermia and severe oligozoospermia. Fertil Steril 67, 542–547.[CrossRef][ISI][Medline]
Simoni M, Bakker E, Eurlings MC, Matthijs G, Moro E, Muller CR and Vogt PH (1999) Laboratory guidelines for molecular diagnosis of Y-chromosomal microdeletions. Int J Androl 22, 292–299.[CrossRef][ISI][Medline]
Skaletsky H, Kuroda-Kawaguchi T, Minx PJ, Cordum HS, Hillier L, Brown LG, Repping S, Pyntikova T, Ali J and Bieri T (2003) The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes. Nature 423, 825–837.[CrossRef][Medline]
Sun C, Skaletsky H, Rozen S, Gromoll J, Nieschlag E, Oates R, Page DC (2000) Deletion of azoospermia factor a (AZFa) region of human Y chromosome caused by recombination between HERV15 proviruses. Hum Mol Genet 9, 2291–2296.
Underhill PA, Shen P, Lin AA, Jin L, Passarino G, Yang WH, Kauffman E, Bonne-Tamir B, Bertranpetit J, Francalacci P et al. (2000) Y chromosome sequence variation and the history of human populations. Nat Genet 26, 358–361.[CrossRef][ISI][Medline]
Vogt PH (1998) Human chromosome deletions in Yq11, AZF candidate genes and male infertility: history and update. Mol Hum Reprod 4, 739–744.
Vogt PH, Edelmann A, Kirsch S, Henegariu O, Hirschmann P, Kiesewetter F, Kohn FM, Schill WB, Farah S, Ramos C et al. (1996) Human Y chromosome azoospermia factors (AZF) mapped to different subregions in Yq11. Hum Mol Genet 5, 933–943.
Vollrath D, Foote S, Hilton A, Brown LG, Beer-Romero P, Bogan JS and Page DC (1992) The human Y chromosome: a 43-interval map based on naturally occurring deletions. Science 258, 52–59.
Whitfield LS, Sulston JE and Goodfellow PN (1995) Sequence variation of the human Y chromosome. Nature 378, 379–380.[CrossRef][Medline]
World Health Organisation (1999) Laboratory Manual for the Examination of Human Semen and Sperm–Cervical Mucus Interaction. Cambridge University Press, Cambridge, UK.
YChromosome Consortium (2002) A nomenclature system for the tree of human Y-chromosomal binary haplogroups. Genome Res 12, 339–348. Submitted on January 1, 2005; accepted on May 13, 2005
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