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: This study emphasizes the importance of detailed genetic analysis in male infertility evaluation and helps to estimate the outcome of infertility treatment.
Abstract: Blackwell Munksgaard, 2007The success of infertility treatment depends on the underlying cause andseverity of the infertility problem. The current report addresses thecomplex genotype–phenotype interactions in an azoospermic man.Cytogenetic, molecular cytogenetic and molecular genetic studiesindicated the derivative monocentric Y chromosome with duplication ofYp11 (including SRY gene) and partial deletion of Yq11 (includingazoospermia factor – AZFb-c regions) as the most probable cause of thesevere testicular failure. Our study emphasizes the importance of detailedgenetic analysis in male infertility evaluation and helps to estimate theoutcome of infertility treatment.
6 citations
Cites background from "Genomic heterogeneity and instabili..."
...In extreme cases, the presence of 45,X cell line in a 46,XY AZF-microdeleted infertile patient may lead to an ambiguous genitalia phenotype (7)....
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...However, AZF microdeletions are difficult to correlate with different spermatogenic phenotypes because of genomic plasticity in the AZF region and the diverse polymorphic deletions that occur in fertile men (7)....
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TL;DR: A much lower Y chromosome microdeletion frequency than previously thought is suggested, even among a strictly selected group of sub-fertile males in Sri Lanka.
Abstract: Aims: This study was designed to determine the prevalence of azoospermia factor (AZF) microdeletions on the Y chromosome in Sri Lankan Sinhalese infertile men with azoospermia and severe oligozoospermia. Settings and Design: The patient group was 207 karyotypically normal infertile Sinhalese males. Materials and Methods: The presence of 13 sequence-tagged site (STS) markers in the AZF region was tested using multiplex polymerase chain reaction (M-PCR). One hundred and twenty unselected men were also studied as a control group. Results: Three (1.5%) had classic Y chromosome microdeletions in the AZFc sub-region. Conclusions: These results suggest a much lower Y chromosome microdeletion frequency than previously thought, even among a strictly selected group of sub-fertile males in Sri Lanka.
5 citations
Cites background from "Genomic heterogeneity and instabili..."
...[11] Deletions most frequently seen are the AZFc region including DAZ, less frequently the AZFb region including RBMY, and rarely the AZFa interval.[7] In addition to these deletions, several smaller sub‐deletions exist within the AZFc region....
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...[32] Lastly, the general heterogeneity and instability of the human Y chromosome suggests that AZF‐microdeletions can also become “pre‐mutations” for a subsequent complete loss of the Y chromosome in the AZF deleted patients’ sperms, increasing the risk of embryonic X0 cells.[7]...
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...[6] The spermatogenesis locus azoospermia factor (AZF) in Yq11 has been mapped to three microdeletion intervals designated as AZFa, AZFb, and AZFc[7] [Table 1]....
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...All the AZF regions, AZFa, AZFb, and AZFc, were tested for Y chromosome microdeletions in the Yq AZF region in two steps....
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...Patients without the classical AZFa, AZFb, and AZFc deletions underwent assessment for AZFc partial deletions including all 120 control subjects....
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TL;DR: Cytogenetic investigation and screening of the CFTR gene are the only genetics testing suggested in all the couples undergoing ART and other tests should be performed only in selected cases.
Abstract: Background: An increasing number of couples undergo assisted reproduction techniques (ART) to generate a child, with the risk of the transmission to the offspring of a genetic defect underlying the condition of infertility. Objective: To review the most common genetic causes of infertility and identify the appropriate genetic testing to be carried out to reduce the risk of genetic defect in the offspring. Method: Review of the literature in the field. Results/conclusion: Cytogenetic investigation and screening of the CFTR gene are the only genetics testing suggested in all the couples undergoing ART; other tests should be performed only in selected cases.
5 citations
Cites background from "Genomic heterogeneity and instabili..."
...However, a reduced percentage of normal Y-bearing spermatozoa, a concomitant increase in nullisomic spermatozoa and a significant increase of XY-disomic spermatozoa in patients with AZFc deletions have been reported, suggesting that AZF microdeletions could be considered as ‘pre-mutations’ for a subsequent complete loss of the Y chromosome, increasing the risk of embryonic X0 cells [18,65,66]....
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TL;DR: There is a limit in the detection of microdeletion using conventional sequence-tagged sites based on polymerase chain reaction because of the structure of the azoospermia factor region of the ampliconic region, and it is now necessary to update the AZF concept.
Abstract: The completion of a draft sequence of the entire human genome in 2001 was followed by a complete sequencing of the Y chromosome in 2003. It is now possible to refer to a physical map of the Y chromosome. The Y chromosome can be classified into X-transposed, X-degenerate and ampliconic sequences depending on the origins of its sequences. In particular, the ampliconic sequences are complexes of massive palindrome structures in which sequences having higher than 99.9% homology are present symmetrically. Interestingly, palindromic repeats may undergo frequent gene conversion associated with intrachromosomal recombination and play an important role in the maintenance of the genetic materials of the Y chromosome. The azoospermia factor (AZF) region of the ampliconic region is the most probable candidate for spermatogenesis, and forms a palindrome structure. Thus, there is a limit in the detection of microdeletion using conventional sequence-tagged sites based on polymerase chain reaction because of their structure. It is now necessary to update the AZF concept.
4 citations
26 Jun 2014
TL;DR: The aim of this work is to assess the validity in the use of Y-stR multiplex systems in structurally abnormal Y-chromosomes, which may occur in forensic casework analysis.
Abstract: Y-chromosome infertility is usually caused by deletions of genetic material in Azoospermia Factor (AZF) regions, localized in three nonoverlapping Yq regions – AZFa, AZFb and AZFc. However, some of the Y-stRs routinely studied in Forensic Genetics with multiplex kits are localized in these three regions giving rise to microdeletions observed in some loci. Rare alleles were also encountered in these samples with Y-chromosome structural changes. A complete Y-stR profile in a sample from a female individual was detected which may raise ethical implications. the aim of this work is to assess the validity in the use of Y-stR multiplex systems in structurally abnormal Y-chromosomes, which may occur in forensic casework analysis. keywords: AZF regions; Y-stRs; microdeletions.
3 citations
References
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TL;DR: The male-specific region of the Y chromosome, the MSY, differentiates the sexes and comprises 95% of the chromosome's length, and is a mosaic of heterochromatic sequences and three classes of euchromatics sequences: X-transposed, X-degenerate and ampliconic.
Abstract: The male-specific region of the Y chromosome, the MSY, differentiates the sexes and comprises 95% of the chromosome's length. Here, we report that the MSY is a mosaic of heterochromatic sequences and three classes of euchromatic sequences: X-transposed, X-degenerate and ampliconic. These classes contain all 156 known transcription units, which include 78 protein-coding genes that collectively encode 27 distinct proteins. The X-transposed sequences exhibit 99% identity to the X chromosome. The X-degenerate sequences are remnants of ancient autosomes from which the modern X and Y chromosomes evolved. The ampliconic class includes large regions (about 30% of the MSY euchromatin) where sequence pairs show greater than 99.9% identity, which is maintained by frequent gene conversion (non-reciprocal transfer). The most prominent features here are eight massive palindromes, at least six of which contain testis genes.
2,022 citations
TL;DR: The presence of not one but three spermatogenesis loci in Yq11 is proposed and that each locus is active during a different phase of male germ cell development.
Abstract: In a large collaborative screening project, 370 men with idiopathic azoospermia or severe oligozoospermia wereanalysed for deletions of 76 DNA loci in Yq11. In 12 individuals, we observed de novo microdeletions involvingseveral DNA loci, while an additional patient had an inherited deletion. They were mapped to three differentsubregions in Yq11. One subregion coincides to the AZF region defined recently in distal Yq11. The second andthird subregion were mapped proximal to it, in proximal and middle Yq11, respectively. The different deletionsobserved were not overlapping but the extension of the deleted Y DNA in each subregion was similar in eachpatient analysed. In testis tissue sections, disruption of spermatogenesis was shown to be at the same phasewhen the microdeletion occurred in the same Yq11 subregion but at a different phase when the microdeletionoccurred in a different Yq11 subregion. Therefore, we propose the presence of not one but three spermatogenesisloci in Yq11 and that each locus is active during a different phase of male germ cell development. As the mostsevere phenotype after deletion of each locus is azoospermia, we designated them as: AZFa, AZFb and AZFc.Their probable phase of function in human spermatogenesis and candidate genes involved will be discussed. INTRODUCTIONGenes for male germ cell development are present on the Ychromosome in different species groups (1–3). In men, theposition of a spermatogenesis locus was mapped in theeuchromatic part of the long Y arm (Yq11). It was called‘azoospermia factor’ (AZF), as the first six men observed withterminal deletions in Yq were azoospermic (4). Mature spermcells were not detectable in their seminal fluid. In all cases, the Ydeletions included the large heterochromatin block of the long Yarm (Yq12) and an undefined amount of the adjacent euchromatin(Yq11). Subsequently, the presence of AZF in Yq11 wasconfirmed by numerous studies at both cytogenetic (5) andmolecular level (6–8). However, the genetic complexity of AZFcould not be revealed by these analyses.This first became possible by the detection of sterile patientswith small interstitial deletions (i.e. microdeletions) in Yq11. Ina study with 13 sterile men suffering from idiopathic azoospermiatwo different microdeletions in Yq11 were observed (9). Theywere mapped to two non overlapping positions in Yq11 interval6 (10). However, further studies of Yq11 microdeletionsassociated to the phenotype of male sterility, only confirmed theposition of an AZF locus in distal Yq11 (11,12). The mostextensive study was performed by Reijo et al. (13) on 89 sterile
1,246 citations
"Genomic heterogeneity and instabili..." refers background in this paper
...E-mail address:petervogt@med.uni-heidelberg.de. mosomes with a ring structure (ring-Y), or translocation the Y to an autosome or the X chromosome, all characte by a complete absence of the fluorescent Y heterochrom in distal Yq (Yq12) were most often reported (Sandberg 1985; Vogt, 1996)....
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...Infertile men with microscopically visible abberratio n Yq11 usually have a mosaic karyotype such as 46,X 45,X0 or 46,X idicY/45,X0, with a variable number 0 cells (Sandberg, 1985; Vogt, 1996; Vogt and Fernan 003)....
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Stanford University1, University of Texas Health Science Center at Houston2, Tel Aviv University3, Pompeu Fabra University4, University of Sassari5, University of Khartoum6, University of the Witwatersrand7, Yale University8, Harvard University9, Wellcome Trust Centre for Human Genetics10, University of Turin11
TL;DR: Binary polymorphisms associated with the non-recombining region of the human Y chromosome (NRY) preserve the paternal genetic legacy of the authors' species that has persisted to the present, permitting inference of human evolution, population affinity and demographic history.
Abstract: Binary polymorphisms associated with the non-recombining region of the human Y chromosome (NRY) preserve the paternal genetic legacy of our species that has persisted to the present, permitting inference of human evolution, population affinity and demographic history 1 . We used denaturing highperformance liquid chromatography (DHPLC; ref. 2) to identify 160 of the 166 bi-allelic and 1 tri-allelic site that formed a parsimonious genealogy of 116 haplotypes, several of which display distinct population affinities based on the analysis of 1062 globally representative individuals. A minority of contemporary East Africans and Khoisan represent the descendants of the most ancestral patrilineages of anatomically modern humans that left Africa between 35,000 and 89,000 years ago.
959 citations
TL;DR: It is suggested that on the distal portion of the nonfluorescent segment of the long arm of the Y, factors are located controlling spermatogenesis.
Abstract: A deletion of the Y chromosome at the distal portion of band q11 was found in 6 men with normal male habitus but with azoospermia. Five of them were found during a survey of 1170 subfertile males while the sixth was karyotyped because of slight bone abnormalities. These findings, together with a review of the literature, suggest that on the distal portion of the nonfluorescent segment of the long arm of the Y, factors are located controlling spermatogenesis.
926 citations
TL;DR: The availability of the near-complete chromosome sequence, plus many new polymorphisms, a highly resolved phylogeny and insights into its mutation processes, now provide new avenues for investigating human evolution.
Abstract: Until recently, the Y chromosome seemed to fulfil the role of juvenile delinquent among human chromosomes — rich in junk, poor in useful attributes, reluctant to socialize with its neighbours and with an inescapable tendency to degenerate. The availability of the near-complete chromosome sequence, plus many new polymorphisms, a highly resolved phylogeny and insights into its mutation processes, now provide new avenues for investigating human evolution. Y-chromosome research is growing up.
917 citations
"Genomic heterogeneity and instabili..." refers background in this paper
...They have inevitably led o new speculations about the evolutionary future of this ale-specific chromosome (Jobling and Tyler-Smith, 2003) ut also to an increased understanding of the azoospermia actor (AZF) locus in Yq11 concerning its function in uman spermatogenesis....
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...It might be found in men of Y lineage O; a sister clade to N in the current Y phylogeny (Jobling and Tyler-Smith, 2003)....
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