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: It is shown that duplication chromosomes exist in population samples by detecting Y-chromosomal short tandem repeat (YSTR) allele duplications within the AZFa region, and by showing that two chromosomes carrying these duplicated alleles contain a third junction-specific HERV sequence.
Abstract: Deletions of the AZFa region on the long arm of the human Y chromosome cause male infertility. Previous work has shown that this is an example of a genomic disorder, since most deletions are caused by non-allelic homologous recombination between endogenous retroviral elements (HERVs) flanking the 780 kb region. The reciprocal products of these deletion events, AZFa duplications, have not been reported to date. Here we show that duplication chromosomes exist in population samples by detecting Y-chromosomal short tandem repeat (YSTR) allele duplications within the AZFa region, and by showing that two chromosomes carrying these duplicated alleles contain a third junction-specific HERV sequence. Sequence analysis of these cases, which most likely represent independent duplication events, shows that breakpoints lie in the same region of inter-HERV sequence identity as do deletion breakpoints, and thus that the mechanism of duplication is indeed the reciprocal of deletion. Consideration of the accumulated Y-STR allele diversity between duplicated copies of the AZFa region indicates that one of the duplication chromosomes has been in the population for at least 17 generations, and therefore must be compatible with male fertility.
93 citations
TL;DR: Patients with azoospermic factor (AZF)c microdeletions seem to have IVF/ICSI outcomes comparable to those of controls with normal Y chromosomes, according to a retrospective case-control study.
87 citations
TL;DR: The recent construction of a highly resolved tree of the nonrecombining portion of the Y chromosome (NRY), and the development of a cladistic nomenclatural system to name the resulting haplogroups support the hypothesis of an African origin of human NRY diversity.
Abstract: ▪ Abstract In this review we discuss the recent construction of a highly resolved tree of the nonrecombining portion of the Y chromosome (NRY), and the development of a cladistic nomenclatural system to name the resulting haplogroups. This phylogenetic gene tree comprises 18 major haplogroups that are defined by 48 binary polymorphisms. We also present results from a phylogeographic analysis of NRY haplogroups in a global sample of 2007 males, as well as from a regional study focusing on Siberia (n = 902). We use the following statistical techniques to explicate our presentation: analysis of molecular variance, multidimensional scaling, comparative measures of genetic diversity, and phylogeography-based frequency distributions. Our global results, based on the 18 major haplogroups, are similar to those from previous analyses employing additional markers and support the hypothesis of an African origin of human NRY diversity. Although Africa exhibits greater divergence among haplogroups, Asia contains the l...
87 citations
"Genomic heterogeneity and instabili..." refers methods in this paper
...Probably novel and other methods than Southern blots and Fiber- 6,000 years ago (Hammer and Zegura, 2002) and can there ore be considered both to have no detrimental effec en’s fertility....
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TL;DR: Three preliminary trials have given a state-of-the-art picture of the diagnostic performance in various European laboratories, showing an overall rate of misdiagnosis of approximately 5% for both AZFb and AZFc regions, and providing data useful in the generation of guidelines for the molecular diagnosis of Y chromosome microdeletions.
Abstract: The polymerase chain reaction (PCR) screening of microdeletions of the Y chromosome has become an important diagnostic step in the work-up of male infertility. However, there is no agreement about how this diagnosis should be performed. There are suggestions that the large variation in deletion frequency reported in the literature could be due to the various selection criteria of the patients analysed, although methodological aspects may play a role as well. As for other genetic diseases, molecular diagnosis of Y chromosome microdeletions should be controlled by adopting strict internal quality control measures and by participating in external quality assessment schemes. Such an external quality assessment project is presently being organized jointly by the European Academy of Andrology and the European Molecular Genetics Quality Network. Three preliminary trials have given a state-of-the-art picture of the diagnostic performance in various European laboratories, showing an overall rate of misdiagnosis of approximately 5% for both AZFb and AZFc regions, and providing data useful in the generation of guidelines for the molecular diagnosis of Y chromosome microdeletions.
69 citations
"Genomic heterogeneity and instabili..." refers methods in this paper
...…the fi aboratory guidelines suggesting the use of a common r et of six non-repetitive and non-polymorphic STS loci ppropriate controls to provide quality control of the AZ icrodeletion analysis in different laboratories, and als ptimise the PCR multiplex protocol (Simoni et al., 1999 imoni, 2001)....
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TL;DR: Among apparently healthy men who nonetheless produce few or no sperm, about ten percent have microdeletions on their Y chromosome, most of which occur in the AZFc region on the long arm of the chromosome.
Abstract: Among apparently healthy men who nonetheless produce few or no sperm, about ten percent have microdeletions on their Y chromosome. Most of these de novo mutations occur in the AZFc region on the long arm of the chromosome. The high frequency of deletion is explained by the extraordinary structure of the region, which consists almost entirely of very long repeat units.
65 citations