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 suggested that the existence of this deletion as a polymorphism reflects a balance between haploid selection, which culls gr/gr-deleted Y chromosomes from the population, and homologous recombination, which continues to generate newgr/gr deletions.
Abstract: Many human Y-chromosomal deletions are thought to severely impair reproductive fitness, which precludes their transmission to the next generation and thus ensures their rarity in the population. Here we report a 1.6-Mb deletion that persists over generations and is sufficiently common to be considered a polymorphism. We hypothesized that this deletion might affect spermatogenesis because it removes almost half of the Y chromosome's AZFc region, a gene-rich segment that is critical for sperm production. An association study established that this deletion, called gr/gr, is a significant risk factor for spermatogenic failure. The gr/gr deletion has far lower penetrance with respect to spermatogenic failure than previously characterized Y-chromosomal deletions; it is often transmitted from father to son. By studying the distribution of gr/gr-deleted chromosomes across the branches of the Y chromosome's genealogical tree, we determined that this deletion arose independently at least 14 times in human history. We suggest that the existence of this deletion as a polymorphism reflects a balance between haploid selection, which culls gr/gr-deleted Y chromosomes from the population, and homologous recombination, which continues to generate new gr/gr deletions.
428 citations
"Genomic heterogeneity and instabili..." refers background or methods in this paper
...AZFc haplotype 8 was found in three different Y-lineages all *, R1*, R1a1*, were associated with multiple AZFc haplotypes....
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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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...Real deletions of the underlying genomic DNA fragment would only be detectable on Southern blots or by appropiate Fiber-FISH experiments as demonstrated by visualisation of the gr/gr deletions (Repping et al., 2003) and g1/g2, respectively, g1/g3 deletions (Fernandes et al., 2002; 2004)....
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...The authors observed a high requency of gr/gr deletions in men with some sperm enic failure, suggesting an increased risk for the occurr f infertility in these men (Repping et al., 2003)....
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...Introduction Novel findings concerning the genomic heterogeneity f the human Y chromosome have recently been reported y several research groups to occur in Yq11 (Bosch and obling, 2003; Repping et al., 2003; Vogt and Fernandes, 003; Fernandes et al., 2004)....
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TL;DR: The discovery of breakpoint hotspots suggest that factors in addition to homology underlie these deletions, which are the largest of all human interstitial deletions for which deletion junctions and complete intervening sequence are available.
Abstract: It is widely believed that at least three nonoverlapping regions of the human Y chromosome—AZFa, AZFb, and AZFc (“azoospermia factors” a ,b , and c)—are essential for normal spermatogenesis. These intervals are defined by interstitial Y-chromosome deletions that impair or extinguish spermatogenesis. Deletion breakpoints, mechanisms, and lengths, as well as inventories of affected genes, have been elucidated for deletions of AZFa and of AZFc but not for deletions of AZFb or of AZFb plus AZFc. We studied three deletions of AZFb and eight deletions of AZFb plus AZFc, as assayed by the STSs defining these intervals. Guided by Y-chromosome sequence, we localized breakpoints precisely and were able to sequence nine of the deletion junctions. Homologous recombination can explain seven of these deletions but not the remaining two. This fact and our discovery of breakpoint hotspots suggest that factors in addition to homology underlie these deletions. The deletions previously thought to define AZFb were found to extend from palindrome P5 to the proximal arm of palindrome P1, 1.5 Mb within AZFc. Thus, they do not define a genomic region separate from AZFc. We also found that the deletions of AZFb plus AZFc, as assayed by standard STSs heretofore available, in fact extend from P5 to the distal arm of P1 and spare distal AZFc. Both classes of deletions are massive: P5/proximal-P1 deletions encompass up to 6.2 Mb and remove 32 genes and transcripts; P5/distal-P1 deletions encompass up to 7.7 Mb and remove 42 genes and transcripts. To our knowledge, these are the largest of all human interstitial deletions for which deletion junctions and complete intervening sequence are available. The restriction of the associated phenotype to spermatogenic failure indicates the remarkable functional specialization of the affected regions of the Y chromosome.
427 citations
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
TL;DR: Y microdeletion screening is important, not only to define the aetiology of spermatogenic failure, but also because it gives precious information for a more appropriate clinical management of both the infertile male and his future male child.
Abstract: In many centres, Y chromosome deletion analysis is still not performed routinely and if so, the results are used for genetic counselling but are not considered as having a useful prognostic value. The type of deletion (AZFa, b or c) has been proposed as a potential prognostic factor for sperm retrieval in men undergoing TESE. AZFc deletions and partial AZFb deletions are associated with sperm retrieval in approximately 50% of cases while in the case of a patient with complete AZFb deletion the probability of finding mature spermatozoa is virtually nil. Therefore the extent and position of a Y microdeletion is important (complete or partial). The prognostic value of Y chromosome deletion analysis in cases of oligozoospermia is important when one considers the progressive decrease of sperm number over time in men with AZFc deletions. Cryo-conservation of spermatozoa in these cases could avoid invasive techniques, such as TESE/ICSI, in the future. Male offspring that are conceived by ICSI or IVF techniques from father with oligozoospermia or azoospermia would also benefit from knowledge of their Y status, since the identification of the genetic defect will render future medical or surgical therapies unnecessary. Y microdeletion screening is therefore important, not only to define the aetiology of spermatogenic failure, but also because it gives precious information for a more appropriate clinical management of both the infertile male and his future male child.
286 citations
"Genomic heterogeneity and instabili..." refers background in this paper
...Therefore, if one wants to be sure that the patient’s AZF deletion indeed has caused his testicular pathology an estimation of the extension of his AZF deletion seemed to be strongly recommended (Krausz et al., 2000, 2003)....
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01 Jan 1997
TL;DR: The authors identified anewT-ICtransition on the human Ychromosome and found that C-allele chromosomes have been found only in a subset of the populations from Asia and Northern Europe and reach their highest frequencies inYakut, Buryats, and Finns.
Abstract: Summary Wehaveidentified anewT-ICtransition onthehuman Ychromosome. C-allele chromosomes havebeenfound only inasubset ofthepopulations fromAsia andnorthernEurope andreach their highest frequencies inYakut, Buryats, andFinns. Examination ofthemicrosatellite haplotypes oftheC-allele chromosomes suggests that themutation occurred recently inAsia. TheYchromosomethus provides bothinformation about population relationships inAsiaandevidence forasubstantial paternal genetic contribution ofAsians tonorthern Europeanpopulations suchastheFinns.
279 citations