Genomic heterogeneity and instability of the AZF locus on the human Y chromosome.
TL;DR: A genetic redundancy of the multi-copy genes in AZFb and AZFc and a causative relationship between the occurrence of first microdeletions then macro deletions in the repetitive structure of Yq11 is suggested where large palindromes are probably promoting multiple gene conversions andAZF rearrangements.
About: This article is published in Molecular and Cellular Endocrinology.The article was published on 2004-09-30. It has received 88 citations till now. The article focuses on the topics: Azoospermia factor.
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TL;DR: The American College of Medical Genetics has developed the following professional guidelines for the interpretation and reporting of copy number variation: evaluation of constitutional copy number variants detected in the postnatal setting.
751 citations
TL;DR: A quantitative, evidence-based scoring framework is introduced; the implementation of the five-tier classification system widely used in sequence variant classification is encouraged; and “uncoupling” the evidence- based classification of a variant from its potential implications for a particular individual is recommended.
673 citations
TL;DR: The genetic causes of male infertility known to date, the genetic polymorphisms possibly associated with male infertility, and novel results of global gene expression profiling of normal human testis by microarray technology are reported.
Abstract: Male infertility represents one of the clearest examples of a complex disease with a substantial genetic basis. Numerous male mouse models, mutation screening and association studies reported over the last few years reveal the high prevalence of genetic causes of spermatogenic impairment, accounting for 10-15% of severe male infertility, including chromosomal aberrations and single gene mutations. Natural selection prevents the transmission of mutations causing infertility, but this protective mechanism may be overcome by assisted reproduction techniques. Consequently, the identification of genetic factors is important for appropriate management of the infertile couple. However, a large proportion of infertile males are diagnosed as idiopathic, reflecting poor understanding of the basic mechanisms regulating spermatogenesis and sperm function. Furthermore, the molecular mechanisms underlying spermatogenic damage in cases of genetic infertility (for example Yq microdeletions) are not known. These problems can be addressed only by large scale association studies and testicular or spermatozoal expression studies in well-defined alterations of spermatogenesis. It is conceivable that these studies will have important diagnostic and therapeutic implications in the future. This review discusses the genetic causes of male infertility known to date, the genetic polymorphisms possibly associated with male infertility, and reports novel results of global gene expression profiling of normal human testis by microarray technology.
418 citations
Cites background from "Genomic heterogeneity and instabili..."
...Therefore, AZF microdeletions can be considered as ‘pre-mutations’ for a subsequent complete loss of the Y chromosome in the AZF-deleted patients’ spermatozoa, increasing the risk of embryonic X0 cells (Vogt, 2004)....
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TL;DR: A systematic search of the nonrecombining region of the human Y chromosome (NRY) identified 12 novel genes or families, 10 with full-length complementary DNA sequences, which may account for infertility among men with Y deletions.
Abstract: A systematic search of the nonrecombining region of the human Y chromosome (NRY) identified 12 novel genes or families, 10 with full-length complementary DNA sequences. All 12 genes, and six of eight NRY genes or families previously isolated by less systematic means, fell into two classes. Genes in the first group were expressed in many organs; these housekeeping genes have X homologs that escape X inactivation. The second group, consisting of Y-chromosomal gene families expressed specifically in testes, may account for infertility among men with Y deletions. The coherence of the NRY's gene content contrasts with the apparently haphazard content of most eukaryotic chromosomes.
412 citations
Journal Article•
TL;DR: The current estimate is that about 30 percent of men seeking help at the infertility clinic are found to have oligozoospermia or azoospermia of unknown aetiology, and there is a need to find the cause of infertility.
Abstract: Infertility is defined as a failure to conceive in a couple trying to reproduce for a period of two years without conception. Approximately 15 percent of couples are infertile, and among these couples, male factor infertility accounts for approximately 50 percent of causes. Male infertility is a multifactorial syndrome encompassing a wide variety of disorders. In more than half of infertile men, the cause of their infertility is unknown (idiopathic) and could be congenital or acquired. Infertility in men can be diagnosed initially by semen analysis. Seminograms of infertile men may reveal many abnormal conditions, which include azoospermia, oligozoospermia, t e r at ozoos p e r mi a , a s t he nozoos p e r mi a , necrospermia and pyospermia. The current estimate is that about 30 percent of men seeking help at the infertility clinic are found to have oligozoospermia or azoospermia of unknown aetiology. Therefore, there is a need to find the cause of infertility. The causes are known in less than half of these cases, out of which genetic or inherited disease and specific abnormalities in the Y chromosome are major factors. About 10–20 percent of males presenting without sperm in the ejaculate carry a deletion of the Y chromosome. This deleted region includes the Azoospermia Factor (AZF) locus, located in the Yq11, which is divided into four recurrently deleted non-overlapping subregions designated as AZFa, AZFb, AZFc and AZFd. Each of these regions may be associated with a particular testicular histology, and several candidate genes have been found within these regions. The Deleted in Azoospermia (DAZ) gene family is reported to be the most frequently deleted AZF candidate gene and is located in the AZFc region. Recently, a partial, novel Y chromosome 1.6-Mb deletion, designated “gr/gr” deletion, has been described specifically in infertile men with varying degrees of spermatogenic failure. The DAZ gene has an autosomal homologue, DAZL (DAZ-Like), on the short arm of the chromosome 3 (3p24) and it is possible that a defective autosomal DAZL may be responsible for the spermatogenic defect. The genetic complexity of the AZF locus on the long arm of the Y chromosome could be revealed only with the development of sequence tagged sites. Random attacks on the naked mitochondrial DNA (mtDNA) of sperm by reactive oxygen species or free radicals will inevitably cause oxidative damage or mutation to the mitochondrial genome with pathological consequences and lead to infertility in males. The key nuclear enzyme involved in the elongation and repair of mtDNA strands is DNA polymerase gamma, mapped to the long arm of chromosome 15 (15q25), and includes a CAG repeat region. Its mutation affects the adenosine triphosphate production. The introduction of molecular techniques has provided great insight into the genetics of infertility. Yet, our understanding of the genetic causes of male infertility remains limited.
328 citations
References
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TL;DR: The results support the relevance of a Y-chromosome effect on BP and suggest that a complex interplay of epistatic and ecogenetic interactions governs its effect on phenotype.
Abstract: Previous studies have revealed conflicting evidence concerning a Y-chromosome effect on blood pressure (BP) in genetic crosses involving different strains of spontaneously hypertensive rats (SHR or SHRSP). We had previously found an approximately 16 mm Hg difference in systolic BP (P < 10(-7)) at baseline but not after dietary salt loading (P = .82) between F2 males derived from an SHRSPHD grandfather and a Wistar-Kyoto (WKYHD-0) grandmother and F2 males from a reciprocal cross (WKYHD-0 grandfather). When we examined F2 animals from reciprocal crosses between SHRSPHD and a congenic strain, WKYHD-1, which carries a 6-centimorgan-long SHRSPHD-homologous genomic fragment on chromosome 10 that contains a quantitative trait locus linked to BP (BP/SP-la), we found no significant differences either at baseline (P = .39) or after salt loading (P = .51) in the two reciprocal F2 cohorts. To test the hypothesis that Y-chromosome-autosomal epistasis accounts for the discrepant Y-chromosome effects on BP, we analyzed the interaction between BP/SP-1a and reciprocal cross status on BP in the two crosses. In the F2 (WKYHD-0xSHRSPHD) cross, no significant interaction was found for basal systolic BP (P = .89), arguing against a major influence of BP/SP-1a on the Y-chromosome effects on basal BP. However, a significant interaction between zygosity at the BP/SP-1a locus and reciprocal cross status for systolic BP after salt loading (P = .022) indicated that the BP/SP-1a-SHRSPHD allele exhibited a significant effect on BP after dietary excess salt only in males that inherited the SHRSP Y chromosome. These results support the relevance of a Y-chromosome effect on BP and suggest that a complex interplay of epistatic and ecogenetic interactions governs its effect on phenotype.
62 citations
Journal Article•
62 citations
"Genomic heterogeneity and instabili..." refers background in this paper
...In different laboratories STS deletions in Yq11 were mapped occasionally to multiple sites and the occurrence of non-contiguous deletion spots in the same Y region suggested a variable location of at least some of them (Najmabadi et al., 1996; Stuppia et al., 1996a; Foresta et al., 1997)....
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...…partial and polymorphic AZF deletions are reported as well, in AZFa (Qureshi et al., 1996; Kamp et al., 2000; Blanco et al., 2000), in AZFb (Ferlin et al., 2003; Prosser et al., 1996) and in AZFc (Stuppia et al., 1996b; Jobling et al., 1996; Repping et al., 2003; Fernandes et al., 2002; 2004)....
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TL;DR: A first blueprint for the putative gene content of the AZFc locus can be given and the gene location compared to the polymorphic DNA domains are compared.
Abstract: Human spermatogenesis is regulated by a network of genes located on autosomes and on sex chromosomes, but especially on the Y chromosome. Most results concerning the germ cell function of the Y genes were obtained by genomic breakpoint mapping studies of the Y chromosome of infertile patients. Although this approach has the benefit of focussing on those Y regions that contain most likely the Y genes of functional importance, its major drawback is the fact that fertile control samples were often missing. In fertile men, molecular and cytogenetic analyses of the Y chromosome has revealed highly polymorphic chromatin domains especially in the distal euchromatic part (Yq11.23) and in the heterochromatic part (Yq12) of the long arm. In sterile patients cytogenetic analyses mapped microscopically visible Y deletions and rearrangements in the same polymorphic Y regions. The presence of a Y chromosomal spermatogenesis locus was postulated to be located in Yq11.23 and designated as AZoospermia Factor (ZF). More recently, molecular deletion mapping in Yq11 has revealed a series of microdeletions that could be mapped to one of three different AZF loci: AZFa in proximal Yq11 (Yq11.21), AZFb and AZFc in two non-overlapping Y-regions in distal Yq11 (Yq11.23). This view was supported by the observation that AZFa and AZFb microdeletions were associated with a specific pathology in the patients' testis tissue. Only AZFc deletions were associated with a variable testicular pathology and in rare cases AZFc deletions were even found inherited from father to son. However, AZFc deletions were found with a frequency of 10-20% only in infertile men and most of them were proved to be "de novo", i.e. the AZFc deletion was restricted to the patient's Y chromosome. Based mainly on positional cloning experiments of testis cDNA clones and on the Y chromosomal sequence now published in GenBank, a first blueprint for the putative gene content of the AZFc locus can now be given and the gene location compared to the polymorphic DNA domains. This artwork of repetitive sequence blocks called AZFc amplicons raised the question whether the AZFc chromatin is still part of the heterochromatic domain of the Y long arm well known for its polymorphic extensions or is decondensed and part of the Yq11.23 euchromatin? We discuss also the polymorphic DAZ gene family and disclose putative origins of its molecular heterogeneity in fertile and infertile men recently identified by the analyses of Single Nucleotide Variants (SNVs) in this AZFc gene locus.
59 citations
TL;DR: A point mutation is found that alters the highly conserved RNP2 motif in one infertile patient and is also found in his father.
Abstract: In order to search for mutations in the multicopy RBM genes that might be associated with male infertility, we have used sequence data from the reported cDNA clone to determine the intron exon boundaries of the YRRM 1 gene. This gene has 12 exons, three of which encode the putative RNA binding domain of the protein. Different copies of the gene contain sequence variations and, additionally, give rise to transcripts with different numbers of copies of the repeated SRGY motif. Since mutations in the RNA binding domain would seem likely to have an effect on the activity of the protein, we have scanned these exons for mutations by SSCP on DNA from normal and infertile men. Sequence differences in the exon encoding the N-terminal part of the RNA binding domain account for at least four different classes of the gene and give rise to different SSCP conformers. Sequence analysis shows that one of these classes is a pseudogene and that the members of another class are nonfunctional. RT-PCR shows that all classes are transcribed and that the A class is most abundant. We have found a point mutation that alters the highly conserved RNP2 motif in one infertile patient. This mutation is also found in his father. We have used PCR followed by SSCP analysis to map RBM on a Y Chromosome (Chr) YAC contig and have demonstrated a distribution that spans a major part of this chromosome's euchromatin.
57 citations
TL;DR: The hypothesis that chromosomal defects may often accompany AZF deletions and cause the lack of a genotype-phenotype correlation in human male idiopathic infertility is proposed and the nature of the spermatogenetic failure associated with isolated AZFc deletions is evaluated.
Abstract: Editor—Over the past 10 years, several authors have reported microdeletions in the long arm of the Y chromosome (Yq) in men with idiopathic, non-obstructive azoospermia or severe oligospermia. These microdeletions were clustered on the Yq fragment previously described as the azoospermia factor region (AZF).1 More recently, a number of genes expressed specifically in the testes and mapping to AZFa, AZFb, or AZFc subregions have been cloned.2-4 One of the approaches to understanding the role of these genes in human spermatogenesis is to look for a correlation between the lack of given AZF genes and the particular spermatogenic defect in the phenotypes of the patients. However, attempts to find such a correlation have failed so far. Instead, a broad spectrum of phenotypes ranging clinically from azoospermia to severe oligospermia and histologically from Sertoli cell only syndrome (SCOS) to hypospermatogenesis has been described in association with AZFc deletions.5 6
A recent study found chromosomal aberrations in 15% of azoospermic patients.7 However, in papers focusing on the analysis of AZF microdeletions in patients with idiopathic infertility,2 3 5 8-30 systematic, bilateral, histological, molecular, and cytogenetic analyses in the same large group of patients was rarely carried out, thus limiting information on the coexistence of AZF deletions and chromosomal aberrations.
In this study, we propose and test the hypothesis that chromosomal defects may often accompany AZF deletions and cause the lack of a genotype-phenotype correlation in human male idiopathic infertility. We also attempt to evaluate the nature of the spermatogenetic failure associated with isolated AZFc deletions. For this purpose, we performed a dual genetic analysis of karyotypes and molecular status of the AZF region along with bilateral testicular histological evaluation in 94 patients with non-obstructive, idiopathic infertility and azoospermia, severe oligospermia, or oligospermia.
Sixty five men with …
46 citations
"Genomic heterogeneity and instabili..." refers background in this paper
...Indeed, it has been shown that X0 cells are assoc ith the occurrence of AZFc microdeletions (Siffroi et al., 000; Jaruzelska et al., 2001) and a man with an AZFc del ion and a 45,X0/46,XY mosaic karyotype has been repo ith ambiguous genitalia (Papadimas et al., 2001)....
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