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Journal ArticleDOI

Localization of factors controlling spermatogenesis in the nonfluorescent portion of the human Y chromosome long arm.

28 Oct 1976-Human Genetics (Springer-Verlag)-Vol. 34, Iss: 2, pp 119-124
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.
Citations
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Journal ArticleDOI
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

Journal ArticleDOI
TL;DR: The region contains a single–copy gene, DAZ (Deleted in AZoospermia), which is transcribed in the adult testis and appears to encode an RNA binding protein, and the possibility that DAZ is AZF should now be explored.
Abstract: We have detected deletions of portions of the Y chromosome long arm in 12 of 89 men with azoospermia (no sperm in semen). No Y deletions were detected in their male relatives or in 90 other fertile males. The 12 deletions overlap, defining a region likely to contain one or more genes required for spermatogenesis (the Azoospermia Factor, AZF). Deletion of the AZF region is associated with highly variable testicular defects, ranging from complete absence of germ cells to spermatogenic arrest with occasional production of condensed spermatids. We find no evidence of YRRM genes, recently proposed as AZF candidates, in the AZF region. The region contains a single–copy gene, DAZ (Deleted in AZoospermia), which is transcribed in the adult testis and appears to encode an RNA binding protein. The possibility that DAZ is AZF should now be explored.

1,133 citations

Journal ArticleDOI
TL;DR: The factors responsible for Y chromosome deletions in spermatozoa remain unresolved but may be one facet of a central reproductive problem: controlling the amount of oxidative stress experienced by germ cells during their differentiation and maturation in the male reproductive tract.
Abstract: Recent advances in understanding of male infertility have implicated two major causative factors, oxidative stress and Y chromosome deletions. A major cause of oxidative stress appears to be the high rate of reactive oxygen species generation associated with the retention of excess residual cytoplasm in the sperm midpiece. Other possible causes include the redox cycling of xenobiotics, and antioxidant depletion or apoptosis. Oxidative stress induces peroxidative damage in the sperm plasma membrane and DNA damage in both the mitochondrial and nuclear genomes. Nuclear DNA damage in the germ line of the father may be associated with pathology in the offspring, including childhood cancer and infertility. Gene deletions on the non-recombining region of the Y chromosome account for the infertility observed in about 15% of patients with azoospermia and 5-10% of subjects with severe oligozoospermia. The Y chromosome is particularly susceptible to gene deletions because of the inability of the haploid genome to deploy recombination repair in retrieving lost genetic information. Aberrant recombination, defective chromatin packaging, abortive apoptosis and oxidative stress may all be involved in the aetiology of DNA damage in the germ line. The factors responsible for Y chromosome deletions in spermatozoa remain unresolved but may be one facet of a central reproductive problem: controlling the amount of oxidative stress experienced by germ cells during their differentiation and maturation in the male reproductive tract.

699 citations

Journal ArticleDOI
TL;DR: Men and women will continue to be confronted with difficult decisions on whether or not to use state-of-the-art technology and hormonal treatments to propagate their germline, despite the risks of transmitting mutant genes to their offspring.
Abstract: The world's population is increasing at an alarming rate and is projected to reach nine billion by 2050. Despite this, 15% of couples world-wide remain childless because of infertility. Few genetic causes of infertility have been identified in humans; nevertheless, genetic aetiologies are thought to underlie many cases of idiopathic infertility. Mouse models with reproductive defects as a major phenotype are being rapidly created and discovered and now total over 200. These models are helping to define mechanisms of reproductive function, as well as identify potential new contraceptive targets and genes involved in the pathophysiology of reproductive disorders. With this new information, men and women will continue to be confronted with difficult decisions on whether or not to use state-of-the-art technology and hormonal treatments to propagate their germline, despite the risks of transmitting mutant genes to their offspring.

595 citations

Journal ArticleDOI
TL;DR: Y-chromosome deletions in leucocyte DNA similar in location to those previously reported in azoospermic individuals are detected and are therefore the cause of their severe oligozoospermia.

519 citations

References
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Journal ArticleDOI
TL;DR: Data from a chromosome examination of 14,069 consecutive newborn infants is presented, finding 294 babies with a major chromosome abnormality or distinctive marker chromosomes.
Abstract: Data from a chromosome examination of 14,069 consecutive newborn infants is presented. Successful karyotypes were obtained on 13,939 babies using short-term blood cultures and conventional staining methods. Of those, 13,645 babies had normal chromosomes; 64 (0.46%) had a major chromosome abnormality; and 230 (1.65%) had a marker chromosome; giving a total of 294 (2.11%) babies with a major chromosome abnormality or distinctive marker chromosomes. Six male babies with sex chromosome abnormalities had a 47,XXY and four a 47,XYY karyotype, and three were mixoploids. Five female babies had a 47,XXX karytotype and two were mixoploids. There were three babies with ambiguous external genitalia, all with normal karyotypes. Fourteen babies had 21-trisomy; there were three 18-trisomics and one 13-trisomic. The mother of one 18-trisomy baby had a balanced (18;21) translocation. Twenty-four infants had a balanced chromosome rearrangement. Eleven of these were reciprocal and thirteen were Robertsonian translocations. One baby had an unbalanced derivative chromosome resulting from an 18;11 insertion. Two infants with additional unidentified fragments were detected. Two hundred and thirty babies (1:60) carying distinctive chromosome variants were detected. The commonest variant was the Yq+ among males (0.89%). Other common variants involved the short arms of the D and G groups (0.32% and 0.57%, respectively) 16q+ (0.09%), and 1q+ (0.04%). The results of the present study when combined with five other comparable studies, thus comprising a total of 46,150 newborn infants, indicates that the frequency of major chromosome abnormalities is between 1:150 and 1:200 live-born babies. This represents a small proportion of all conceptuses with chromosome abnormalities, which has been estimated as being approximately 1:20. It is thus clear that chromosome abnormalities form a major part of the genetic load carried by the human population. The development of chromosome banding techniques already has increased, and with further increase, the complexities of human cytogenetics and may reveal many additional rearrangements undetectable by conventional methods.

508 citations

Journal ArticleDOI
18 Sep 1975-Nature
TL;DR: The part that the X chromosome plays in male sexual differentiation has been clarified at the level of an individual gene situated on this chromosome.
Abstract: IN mammals, the genetic basis of sex determination and differentiation seems to be simple1,2. A gene or set of genes on the Y chromosome causes the indifferent embryonic gonad to develop as a testis3. Thus an ovary develops in the absence of the Y and a testis in its presence. The testis then secretes testosterone which induces male development of the accessory glands and ducts4,5. The masculinising action of testosterone on its target cells is mediated by the product of a gene on the X chromosome. This product activates all the genes required for manifestation of the male phenotype in response to circulating testosterone1. Evidence for this crucial involvement of the X chromosome in male sexual differentiation comes from a mutation of the relevant gene in the mouse (Tfm), resulting in failure to respond to testosterone. A chromosomally XY animal with this mutant gene develops testes, because the Y chromosome is present, but shows no further male differentiation, thus exhibiting the syndrome known as ‘testicular feminisation’6. This insensitivity to androgen is caused by a mutational deficiency of the nuclear–cytosol androgen-receptor protein not only in mice7–9 but also in man10. Thus the part that the X chromosome plays in male sexual differentiation has been clarified at the level of an individual gene situated on this chromosome.

356 citations

Journal ArticleDOI
TL;DR: The results of the present study when combined with five other comparable studies, thus comprising a total of 46,150 newborn infants, indicates that the frequency of major chromosome abnormalities is between 1:150 and 1:200 live-born babies.
Abstract: Data from a chromosome examination of 14,069 consecutive newborn infants is presented. Successful karyotypes were obtained on 13,939 babies using short-term blood cultures and conventional staining methods. Of those, 13,645 babies had normal chromosomes; 64 (0.46%) had a major chromosome abnormality; and 230 (1.65%) had a marker chromosome; giving a total of 294 (2.11%) babies with a major chromosome abnormality or distinctive marker chromosomes. Six male babies with sex chromosome abnormalities had a 47,XXY and four a 47,XYY karyotype, and three were mixoploids. Five female babies had a 47,XXX karytotype and two were mixoploids. There were three babies with ambiguous external genitalia, all with normal karyotypes. Fourteen babies had 21-trisomy; there were three 18-trisomics and one 13-trisomic. The mother of one 18-trisomy baby had a balanced (18;21) translocation. Twenty-four infants had a balanced chromosome rearrangement. Eleven of these were reciprocal and thirteen were Robertsonian translocations. One baby had an unbalanced derivative chromosome resulting from an 18;11 insertion. Two infants with additional unidentified fragments were detected. Two hundred and thirty babies (1:60) carying distinctive chromosome variants were detected. The commonest variant was the Yq+ among males (0.89%). Other common variants involved the short arms of the D and G groups (0.32% and 0.57%, respectively) 16q+ (0.09%), and 1q+ (0.04%). The results of the present study when combined with five other comparable studies, thus comprising a total of 46,150 newborn infants, indicates that the frequency of major chromosome abnormalities is between 1:150 and 1:200 live-born babies. This represents a small proportion of all conceptuses with chromosome abnormalities, which has been estimated as being approximately 1:20. It is thus clear that chromosome abnormalities form a major part of the genetic load carried by the human population. The development of chromosome banding techniques already has increased, and with further increase, the complexities of human cytogenetics and may reveal many additional rearrangements undetectable by conventional methods.

233 citations


"Localization of factors controlling..." refers background in this paper

  • ...This variation is due to differences in the extension of the bright fluorescent portion of the long arm and does not have obvious phenotypie effects (Bobrow et M., 1971 ; Borgaonkar and Hollander, 1971; Hamerton et al., 1975)....

    [...]

Journal ArticleDOI
23 Apr 1966-Nature

178 citations

Journal ArticleDOI
TL;DR: The baseline data presented here reinforce the view that polymorphic chromosome characteristics are very useful markers for characterizing the karyotype of an infant born at the Albert Einstein College Hospital, Bronx, New York, and are consistent with the expectations of the Hardy-Weinberg law.
Abstract: Replicate chromosome preparations of umbilical-cord-blood leukocytes from 376 neonates born at the Albert Einstein College Hospital, Bronx, New York, were stained with C-, Q-, and G-banding methods to determine the frequencies and distributions of the variable chromosome bands. The C-band variants of primarily chromosomes 1, 9, and 16, as well as those of the remaining C, E, and F-group chromosomes, and the brightly fluorescing Q-band variants of chromosomes 3 and 4 and all of the acrocentrics, including the Y, were similarly analyzed. Polymorphism of these chromosome regions was so extensive that the idiogram of each of the 376 newborns of this study had a unique variant pattern, even when only the C- or only the Q-band patterns were compared. The distribution of polymorphic Q-bands in the population sampled was consistent with the expectations of the Hardy-Weinberg law, with the exception of chromosomes 3 and 22, where some deficiency of individuals with "homozygous" Q-band patterns was found. The baseline data presented here reinforce the view that polymorphic chromosome characteristics are very useful markers for characterizing the karyotype of an individual, for pedigree studies, for prenatal chromosome analyses, for population studies, for attempts at gene localizations, and for identifying specific cells or their chromosomes in somatic cell genetic studies.

131 citations

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