Molecular screening for Yq microdeletion in men with idiopathic oligozoospermia and azoospermia

Infertility affects 15% couples attempting pregnancy and in 40–50% of these cases the male partner has qualitative or quantitative abnormalities of sperm production. Microdeletions in the azoospermia factor (AZF) region on the long arm of the Y chromosome are known to be associated with spermatogenic failure and have been used to define three regions on Yq (AZFa, AZFb and AZFc) which are critical for spermatogenesis and are recurrently deleted in infertile males. Semen analysis was carried out on one hundred and twenty five infertile males with oligozoospermia and azoospermia. Cytogenetic analysis was done for all the cases and in all cytogenetically normal cases (n = 83) microdeletion analysis was carried out on DNA extracted from peripheral blood using PCR. The sequence tagged sites (STS) primers sY84, sY86 (AZFa); sY127, sY134 (AZFb); sY254, sY255 (AZFc) were used for each case. Eight of the eighty three cases (9.63%) showed deletion of at least one of the STS markers. Correlation of phenotype with microdeletion was done in each case to determine any phenotype association with deletion of particular AZF locus. Based on the present study, the frequency of microdeletion in the Indian population is 9.63%. This study emphasizes the need for PCR analysis for determining genetic aetiology in cases with idiopathic severe testiculopathy.     

Y chromosome--a tool in infertility studies of Latvian population

Human Y chromosome is used as a tool in male infertility and population genetic studies. The aims of this research were to analyse the prevalence of Y chromosome microdeletions among infertile Latvian men, and to identify possible lineages of Y chromosome that may be at increased risk of developing infertility. A study encompassed 105 infertile men with different spermatogenic disturbances. Deletions on Y chromosome were detected in 5 out of 105 (approximately 5%) cases analysed in this study. Three of them carried deletion in AZFc region and two individuals had AZFa + b + c deletion. Study of Y chromosome haplogroups showed that N3a1 and R1a1 lineages were found less frequently in the infertile male group compared to ethnic Latvian group, however K* cluster was predominantly found in infertile male Y chromosomes. Conclusions: 1) Our study advocates running Y chromosome microdeletion analyses only in cases of severe form of infertility; 2) Y chromosome haplogroup analysis showed statistically significant tendencies that some haplogroups are more common in ethnic male group, but others are more common in infertile males.     

Y chromosome—a tool in infertility studies of Latvian population

Human Y chromosome is used as a tool in male infertility and population genetic studies. The aims of this research were to analyse the prevalence of Y chromosome microdeletions among infertile Latvian men, and to identify possible lineages of Y chromosome that may be at increased risk of developing infertility. A study encompassed 105 infertile men with different spermatogenic disturbances. Deletions on Y chromosome were detected in 5 out of 105 (∼5%) cases analysed in this study. Three of them carried deletion in AZFc region and two individuals had AZFa+b+c deletion. Study of Y chromosome haplogroups showed that N3a1 and R1a1 lineages were found less frequently in the infertile male group compared to ethnic Latvian group, however K* cluster was predominantly found in infertile male Y chromosomes. Conclusions: (1) Our study advocates running Y chromosome microdeletion analyses only in cases of severe form of infertility; (2) Ychromosome haplogroup analysis showed statistically significant tendencies that some haplogroups are more common in ethnic male group, but others are more common in infertile males.     

Existe-il, dans la population générale masculine un risque plus fort de développer des délétions du chromosome Y qui entraîneraient une infertilité?

The role of the Y-chromosome in spermatogenesis remains one of the hottest topics in andrology. Three non overlapping recurrently deleted regions on Yq (AZFa, AZFb, AZFc) have been defined, each of them containing several genes that are candidates for male infertility. The causes and mechanisms leading to microdeletion formation on the Y are largely unknown. Theoretically, it could be possible that some groups of Y-chromosomes (haplogroups) currently distributed in the population could confer a selective advantage/disadvantage towards deletion formation. A precedent in the field is the recent identification of a Y-chromosome haplotype that confers a selective advantage against a translocation of Yp leading to another form of male infertility, the Y+XX-male phenotype. In order to test if selection is acting on Y-chromosome haplotype distribution, we have defined and compared Y-chromosome haplotypes in a group of around 60 individuals with Y microdeletions from North-Western Europe using 10 biallelic Y-markers (SRY-2627, SRY-1532, SRY-8299, 92R7, Tat, YAP, sY81, LLY22g, M9, DYS257). The defined heplotypes were compared to a control normospermic population of the same ethnic/geographic origin (in the framework of the European Biodiversity Project). We evaluatte the relationship between different Y-chromosome backgrounds and microdeletions, and to which extent selection on this chromosome could have influenced fifness of certain individuals/populations. We also discuss the selective forces that are acting on this chromosome and speculate on the mechanisms underlying deletion formation.     

Molecular analysis of Y chromosome microdeletions in idiopathic cases of male infertility in Serbia

The aim of this study was to detect frequency of microdeletions of Y chromosome in idiopathic cases of male infertility in Serbian population. Patients were subjected to detailed clinical, endocrinological and cytogenetic examinations. Ninety patients with normal cytogenetic findings with azoospermia and severe oligozoospermia were included in the study. In these patients microdeletion analysis was performed by multiplex polymerase chain reaction (PCR) method on DNA extracted from peripheral blood. In each case 6 markers in azoospermia factor (AZF) regions were tested: sY84, sY86 (AZFa); sY127, sY134 (AZFb); sY254, sY255 (AZFc). Deletions on Y chromosome were detected in 14 of 90 cases (15.6%), 9 with azoospermia and 5 with severe oligozoospermia. Of total number of 17 deletions, 11 (64.7%) were detected in AZFc region, 3 (17.6%) in AZFa region and 3 (17.6%) in AZFb region. Microdeletions in AZF region of Y chromosome, especially AZFc microdeletions, represent common genetic cause of idiopathic azoospermia and severe oligozoospremia in Serbian infertile men. Therefore, testing for Y chromosome microdeletions should be considered as an important element in diagnosis and genetic counseling of infertile men in Serbia and decisions regarding the assisted reproduction should be made based on the presence and type of AZF microdeletions.     

对法医学相关的DYS549、DYS527和DYS459基因座在男性不育症人群中的缺失、重复调查

位于Y染色体无精症因子区域(Azoospermia factor, AZF)的基因座位点DYS549、DYS527和DYS459在法医学鉴定和家系分析中被广泛应用。但是,在男性不育患者中,DYS549、DYS527和DYS459位点很可能会表现出特殊的基因型,对应用Y染色体短串联重复序列(Y chromosome short tandem repeat, Y-STR)进行个体识别的结果产生干扰。因此,文章应用14个Y-STR基因座复合扩增体系和Y染色体AZFc区DAZ、CDY1基因的拷贝数检测等方法,探讨男性不育症中法医学相关的3个Y-STR基因座的异常分型,对个体识别和家系分析中的DNA检验异常结果提供合理的解释。在240例男性非梗阻性无精、严重少精、先天性双侧输精管缺如(CBVAD)患者中,采用改良的多重PCR体系进行AZF区域微缺失的序列标签位点(Sequence tagged sites, STSs)检测,发现AZF微缺失40例(AZFa：2例;AZFb：2例;AZFc：30例;AZFb+c：6例),AZF的总缺失率为16.67%。应用14 Y-STR复合扩增体系对上述AZF微缺失的阳性患者样本进行检测,发现所有AZFb缺失患者存在DYS549等位基因缺失,AZFc缺失患者存在DYS527、DYS459等位基因缺失,AZFb+c缺失患者存在DYS549、DYS527和DYS459等位基因缺失。在AZF微缺失阴性的不育症患者中,通过检测DAZ、CDY1基因拷贝数发现10例AZFc部分复制的患者(1例为先天性输精管缺如,2例非梗阻性无精症,7例严重少精子症),占所调查不育人群的4.17%。男性不育人群AZF区域3个Y-STR基因座多态性会造成等位基因缺失或者重复,这些异常分型是由于临床遗传缺陷造成的而不是实验偏差。阐明Y-STR在男性不育人群中的异质性可以更好地完善Y-STR数据库和解释STR实验结果。     

Molecular analysis of Y chromosome microdeletions in idiopathic cases of male infertility in Serbia

The aim of this study was to detect frequency of microdeletions of Y chromosome in idiopathic cases of male infertility in Serbian population. Patients were subjected to detailed clinical, endocrinological and cytogenetic examinations. Ninety patients with normal cytogenetic findings with azoospermia and severe oligozoospermia were included in the study. In these patients microdeletion analysis was performed by multiplex polymerase chain reaction (PCR) method on DNA extracted from peripheral blood. In each case 6 markers in azoospermia factor (AZF) regions were tested: sY84, sY86 (AZFa); sY127, sY134 (AZFb); sY254, sY255 (AZFc). Deletions on the Y chromosome were detected in 14 of 90 cases (15.6%), nine with azoospermia and five with severe oligozoospermia. Of total number of 17 deletions, 11 (64.7%) were detected in AZFc region, three (17.6%) in AZFa region and three (17.6%) in AZFb region. Microdeletions in AZF region of the Y chromosome, especially AZFc microdeletions, represent common genetic cause of idiopathic azoospermia and severe oligozoospremia in Serbian infertile men. Therefore, testing for Y chromosome microdeletions should be considered as an important element in diagnosis and genetic counseling of infertile men in Serbia and decisions regarding the assisted reproduction should be made based on the presence and type of AZF microdeletions. The text was submitted by the authors in English.     

中国无精症、严重寡精症患者的染色体异常和Y染色体微缺失

染色体异常和Y染色体微缺失被认为是两个白种人群中常见的生精障碍相关遗传因素。为了解中国无精症、严重寡精症患者中的染色体异常和Y染色体微缺失,运用染色体G显带技术,在358个原发无精症（256人）和严重寡精症（102人）不育患者中进行染色体核型分析;同时运用多重PCR技术,在核型正常的患者和100个正常生育男性中,对Y染色体AZF区微缺失进行筛查。在358个患者中,39人（10．9％）发现有染色体异常,Klinefelter（47,XYY）最为常见。无精症患者性染色体异常频率明显高于严重寡精症患者（12．1％VS1％）。在319个核型正常的患者中,46（14．4％）发现有AZF区微缺失,无精症和寡精症患者中Y染色体微缺失频率分别为15％和13．1％,AZFc区的微缺失最为常见,AZFa区的微缺失只见于无精症患者,正常生育男性中未发现AZF区的微缺失。结果显示,在中国无精症、严重寡精症患者中,大约25％的患者有染色体异常或Y染色体AZF区微缺失,提示这两种遗传异常是中国人群生精障碍的重要相关遗传病因,有必要在男性不育的诊断以及利用细胞浆内精子注射技术进行辅助生育时,对患者的这些遗传异常进行筛查。     

Chromosomal Abnormality and Y Chromosome Microdeletion in Chinese Patients with Azoospermia or Severe Oligozoo-spermia

Chromosomal abnormality and Y chromosome microdeletion are regarded as two frequent genetic causes associated with spermatogenic failure in Caucasian population. To investigate the distribution of the two genetic defects in Chinese patients with azoospermia or severe oligozoospermia, karyotype analysis by G-banding was carried out in 358 idiopathic infertile men, including 256 patients with azoospermia and 102 patients with severe oligozoospermia, and screening of AZF region microdeletion of Y chromosome by multiplex PCR was performed in those patients without detectable chromosomal abnormality and 100 fertile controls. Of 358 patients, 39(10.9%) were found to have chromosomal abnormalities in which Klinefelters syndrome (47, XXY) was the most common chromosomal aberration. The incidence of sex chromosomal abnormality in patients with azoospermia was significantly higher than that in patients with severe oligozoospermia (12.1% vs 1%). Among the rest of the 319 patients with normal karyotype, 46 (14.4%) were found to have microdeletions in AZF region. The prevalence rates of AZF microdeletion was 15% and 13.1% in patients with azoospermia and severe oligozoospermia respectively. The microdeletion in AZFc was the most frequent deletion and all the microdeletions in AZFa were found in azoospermic patients. No microdeletion in AZF region was detected in fertile controls. In conclusion, chromosomal abnormality and AZF region microdeletion of Y chromosome might account for about 25% of Chinese infertile patients with azoospermia or severe oligozoospermia, suggesting the two abnormalities are important genetic etiology of spematogenic failure in Chinese population and it is essential to screen them during diagnosis of male infertility before in vitro assisted fertilization by introcytoplasmic sperm injection.     

Idiopathic cases of male infertility from a region in India show low incidence of Y-chromosome microdeletion

Chromosomal and Y-chromosomal microdeletion analysis has been done in cases of idiopathic infertility with the objective of evaluating the frequency of chromosomal and molecular anomaly as the causal factor of infertility. Barring a few cases of Klinefelter syndrome (XXY or XY/XXY mosaics), no chromosomal anomaly was encountered. Y-microdeletion was analysed by PCR-screening of STSs from different regions of the AZF (AZFa, AZFb, AZFc) on the long arm of the Y, as well as by using DNA probes of the genes RBM, DAZ (Yq), DAZLA (an autosomal homologue of DAZ) and SRY (Yp; sex determining gene). Out of 177 cases examined, 9 (azoospermia -8 and oligoasthenospermia -1) showed partial deletion of AZF. The size of deletion varied among patients but AZFc was either totally or partially removed in all of them. In contrast, no deletion was detected in AZFa. Testis biopsy done on a limited number of cases (50) showed diverse stages of spermatogenic arrest with no specific correlation with the genotype. The frequency of Y-chromosome microdeletion in our samples (∼ 5%) is much lower than the frequency (∼ 10%) reported globally and the two previous reports from India. We contend that the frequency may be affected by population structures in different geographical regions.     

Yq microdeletions--azoospermia factor candidate genes and spermatogenic arrest.

In the last few years considerable progress has been made in the study of sperm physiology and the biology of gamete interaction, furthering our understanding of the pathophysiology of male infertility. With the advent of assisted reproductive technology and intracytoplasmic sperm injection, study of the various factors leading to spermatogenic impairment has become a major focus of scientific research. Understanding the genetic factors that lead to infertility has taken on a certain urgency, as we have learned not only of the transmission to male offspring of spermatogenic impairment, but that these offspring may also be born with a secondary, larger deletion with worsening of phenotype and genital ambiguity.Ten to twenty-five percent of couples encounter difficulty procreating. Microdeletions of the long arm of the Y chromosome are associated with spermatogenic failure and have been used to define three regions on Yq (AZFa, AZFb, and AZFc) that are critical for spermatogenesis. This study was conceived in order to identify the frequency of submicroscopic interstitial deletions in azoospermia factor loci in infertile Indian males. One hundred and seventy five males with nonobstructive oligozoospermia and azoospermia were included in this study. Semen analysis was done in each case to determine the spermatogenic status-normospermic, oligozoospermic (< 20 million sperm/mL), or azoospermic (no sperm in the semen). Detailed medical, clinical, reproductive, and family histories were taken of each patient. Thirty G-banded metaphases were analyzed in each case and polymerase chain reaction microdeletion analysis was done in 133 cytogenetically normal cases. For this genomic, DNA was extracted using peripheral blood. The sequence tagged site primers tested in each case were sY84, sY86 (AZFa); sY113, sY116, sY127, sY134 (AZFb); sY254, sY255 (AZFc). Polymerase chain reaction amplifications found to be negative were repeated at least three times to confirm the deletion of a given marker. The polymerase chain reaction products were analyzed on a 1.8% agarose gel. Eight of the 133 cases showed deletion of at least one of the sequence tagged site markers. Review of the literature has shown that the overall frequency of microdeletions varies from 1% to 55%. In the present study the frequency of microdeletion was 6.01%. Deletions were detected in cases with known and unknown etiology with bilateral severe testiculopathy.     

The relationship between Y chromosome DNA haplotypes and Y chromosome deletions leading to male infertility

Microdeletions on the short arm of the Y chromosome have defined three non-overlapping regions (AZFa, b, c) recurrently deleted among infertile males. These regions contain several genes or gene families involved in male germ-cell development and maintenance. Even though a meiotic origin for these microdeletions is assumed, the mechanisms and causes leading to microdeletion formation are largely unknown. In order to assess whether some Y chromosome groups (or haplogroups) are predisposed to, or protected against, deletion formation during male meiosis, we have defined and compared Y chromosome haplogroup distribution in a group of infertile/subfertile males harbouring Yq deletions and in a relevant Northwestern European control population. Our analyses suggest that Y chromosome deletion formation is, at least in the study populations, a stochastic event independent of the Y chromosome background on which they arise and may be caused by other genetic and/or environmental factors.     

Molecular cytogenetic analysis of a ring-Y infertile male patient

In the present study, we report on the case of a 43-year-old male patient seeking for fertility assistance, who showed a seminal analysis and testicular biopsy of complete azoospermia. Peripheral blood culture for chromosome studies revealed a karyotype of 46 chromosomes with a ring-Y-chromosome that lost the long arm heterochromatin. Molecular analysis of genomic DNA from the patient detected the presence of the sex-determining region of the Y-chromosome (SRY) but the complete absence of regions involved in spermatogenesis (AZFa, AZFb, AZFc). Several molecular markers distributed along the Y-chromosome were tested through PCR amplification, and a breakpoint was established close to the centromere, predicting the deletion of the growth control region, in agreement with the short stature observed in this patient. All results obtained through molecular cytogenetic characterization are in accordance with the clinical features observed in this patient.     

Defining regions of the Y-chromosome responsible for male infertility and identification of a fourth AZF region (AZFd) by Y-chromosome microdeletion detection

Cytogenetic and molecular deletion analyses of azoospermic and oligozoospermic males have suggested the existence of AZoospermia Factor(s) (AZF) residing in deletion intervals 5 and 6 of the human Y-chromosome and coinciding with three functional regions associated with spermatogenic failure. Nonpolymorphic microdeletions in AZF are associated with a broad spectrum of testicular phenotypes. Unfortunately, Sequence Tagged Sites (STSs) employed in screening protocols range broadly in number and mapsite and may be polymorphic. To thoroughly analyze the AZF region(s) and any correlations that may be drawn between genotype and phenotype, we describe the design of nine multiplex PCR reactions derived from analysis of 136 loci. Each multiplex contains 4-8 STS primer pairs, amplifying a total of 48 Y-linked STSs. Each multiplex consists of one positive control: either SMCX or MIC2. We screened four populations of males with these STSs. Population I consisted of 278 patients diagnosed as having significant male factor infertility: either azoospermia, severe oligozoospermia associated with hypogonadism and spermatogenic arrest or normal sperm counts associated with abnormal sperm morphology. Population II consisted of 200 unselected infertile patients. Population III consisted of 36 patients who had previously been shown to have aneuploidy, cytological deletions or translocations involving the Y-chromosome or normal karyotypes associated with severe phenotype abnormalities. Population IV consisted of 920 fertile (control) males. The deletion rates in populations I, II and III were 20.5%, 7% and 58.3%, respectively. A total of 92 patients with deletions were detected. The deletion rate in population IV was 0.87% involving 8 fertile individuals and 4 STSs which were avoided in multiplex panel construction. The ability of the nine multiplexes to detect pathology associated microdeletions is equal to or greater than screening protocols used in other studies. Furthermore, the data suggest a fourth AZF region between AZFb and AZFc, which we have termed AZFd. Patients with microdeletions restricted to AZFd may present with mild oligozoospermia or even normal sperm counts associated with abnormal sperm morphology. Though a definitive genotype/phenotype correlation does not exist, large deletions spanning multiple AZF regions or microdeletions restricted to AZFa usually result in patients with Sertoli Cell Only (SCO) or severe oligozoospermia, whereas microdeletions restricted to AZFb or AZFc can result in patients with phenotypes which range from SCO to moderate oligozoospermia. The panel of nine multiplexed reactions, the Y-deletion Detection System (YDDS), provides a fast, efficient and accurate method of assessing the integrity of the Y-chromosome. To date, this study provides the most extensive screening of a proven fertile male population in tandem with 514 infertile males, derived from three different patient selection protocols.     

Y-chromosome microdeletions as a prognostic marker of male infertility

The results of molecular-genetic study of Y-chromosome microdeletions in men with spermatogenesis failure and in patients with cryptorchism are presented. The molecular-genetic studies of regions AZFa, AZFb, AZFc in STS loci - sY84, sY86, sY127, sY134, sY254, sY255 and SRY gene have been performed. Y-chromosome microdeletions were detected in 13,3% infertile men with spermogram failure. The frequency of genetic (cyto- and molecular) abnormalities among boys with isolated cryptorchism was 4%. The results show the necessity of additional study ofgenetic factors ofcryptorchism development.     

Génétique et infertilité masculine: données actuelles

Intracytoplasmic sperm injection (ICSI) and testicular biopsies (TESE) have revolutionized the treatment of male infertility, introducing a risk of an increased frequency of genetic defects in the offspring. These risks and their consequences must therefore be evaluated when proposing ICSI to an infertile man. Karyotype and molecular analysis should be performed to detect any genetic defects responsible for male infertility. Y microdeletion screening is important, not only to define the aetiology of spermatogenic failure, but also to provide information allowing a more appropriate management of both the infertile male and his future male child. Genetic counselling is then advised before deciding to attempt ICSI.     

Cytogenetic and molecular analysis of male infertility

Reduced male fertility and subfertility can be caused by genetic factors that affect both germ cell development, differentiation, and function; in particular, chromosome abnormalities and Yq microdeletions are a possible cause of spermatogenetic impairment in males as shown by their higher frequency in infertile men than in the general male population. Microdeletion of the long arm of the Y chromosome (Yq) are associated with spermatogenic failure and have been used to define three regions on Yq (AZFa, AZFb, and AZFc) that are critical for germ cell development. With the advent of assisted reproductive technology and intracytoplasmic sperm injection, knowledge about the various factors leading to spermatogenic impairment is one of the most important aspects of scientific research. Therefore, this study was designed to identify the frequency of cytogenetic and submicroscopic interstitial deletions in azoospermia factor loci in infertile Indian males. One hundred and eighty males with nonobstructive oligozoospermia and azoospermia were included in this study. Semen analysis was done in each case to determine the spermatogenic status. Individuals were subjected to detailed clinical examination, family history, and endocrinological and cytogenetic study after consent from the patient. Peripheral blood cultures were set up according to standard protocols and 30 G-banded metaphases were analyzed in each case. Numerical and structural chromosomal abnormalities were detected in 40 infertile cases. Fluorescence in situ hybridization analysis was done in some cases to identify the percentage of mosaic cell lines and any cryptic or low-level mosaicism. Polymerase chain reaction microdeletion analysis was done in 140 cytogenetically normal cases. Of the 140 cases, 8 showed deletion of at least one of the sequence-tagged site markers. Review of literature has shown that the overall frequency of microdeletions varies from 1 to 55%. In the present study, the frequency of microdeletion was 5.8%, and deletions were identified in cases with undescended testis and varicocele and cases with bilateral severe testiculopathy.     

Y chromosome micro-deletions in idiopathic infertility from Northern India

Azoospermia factor locus (AZF) is assumed to contain the genes responsible for spermatogenesis. Deletions in these genes are thought to be pathologically involved in some cases of male infertility associated with azoospermia or oligozoospermia. An attempt was made to establish the prevalence of micro-deletions on the Y chromosome in 79 infertile North Indians with azoospermia and oligozoospermia. Detail clinical examinations as well as endocrinological parameters were also done. Polymerase chain reaction (PCR) micro-deletion analysis was done in 79 infertile men. For this, genomic DNA was extracted from the peripheral blood. Seven sets of primers were used encompassing AZFa, AZFb and AZFc regions. Micro-deletions in five of the 79 cases (6.3%) showed deletions of at least one of the STS markers. Deletions were detected with known and unknown aetiology and at least in one of the infertile male with varicocele. AZF micro-deletions seen in idiopathic infertile males suggest the need for molecular screening in non-idiopathic cases.     

Screening of Y chromosome microdeletion which contains AZF regions in 71 Turkish azoospermic men

Screening of Y chromosome microdeletion which contains AZF regions in 71 turkish azoospermic men: In 71 Turkish men Y chromosome microdeletions have been studied before intracytoplasmic sperm injection (ICSI). DNA samples were amplified with 18 STS primers of the azoospermia factor (AZF) region on the Y chromosome by using multiplex polymerase chain reaction (PCR). Microdeletions were detected in 4 azoospermic men (5.6 %); one with a deletion in the AZFb region, while the 3 others had a large deletion extending over multiple chromosomal regions (AZFb+c+d and AZFa+b+c+d). In the patients with microdeletion, no spermatogenetic activity could be detected in testis biopsies. This result confirms the idea that Y chromosome microdeletion analysis is important in investigating the possibility of finding sperm in testicular sperm extraction (TESE). Therefore, we point out the importance of genetic testing and counselling regarding Y chromosome microdeletion for couples requesting ICSI.     

Y chromosome and male infertility: what is a normal Y chromosome?

The human Y chromosome contains a number of genes and gene families that are essential for germ cell development and maintenance. Many of these genes are located in highly repetitive elements that are subject to rearrangements. Deletion of azoospermia factor (AZF) regions AZFa, AZFb, and AZFc are found in approximately 10-15% of men with severe forms of spermatogenic failure. Several partial AZFc deletions have been described. One of these, which removes around half of all the genes within the AZFc region, appears to be present as an inconsequential polymorphism in populations of northern Eurasia. A second deletion, termed gr/gr, also results in the absence of several AZFc genes and it may be a genetic risk factor for spermatogenic failure. However, the link between these partial deletions and fertility is unclear. The gr/gr deletion is not a single deletion but a combination of deletions that vary in size and complexity and result in the absence of different genes. There are also regional or ethnic differences in the frequency of gr/gr deletions. In some Y-chromosome lineages, these deletions appear to be fixed and may have little influence on spermatogenesis. Most of these data (gene content and Y chromosome structure) have been deduced from the reference Y chromosome sequence deposited in NCBI. However, recently there have been attempts to define these types of structural rearrangements in the general population. These have highlighted the considerable degree of structural diversity that exist. Trying to correlate these changes with the phenotypic variability is a major challenge and it is likely that there will not be a single reference (or normal) Y chromosome sequence but many.