Nuclear organization in human sperm: preliminary evidence for altered sex chromosome centromere position in infertile males

Finch, Katie A.; Fonseka, K.G.L.; Abogrein, A.; Ioannou, D.E.; Handyside, Alan H.; Thornhill, Alan R.; Hickson, Nicholas; Griffin, Darren K.

doi:10.1093/humrep/den112

Cited by 45 publications

(60 citation statements)

References 44 publications

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“…In contrast, Wiland et al (2008) found inter-individual differences in centromere topology between normal males and reciprocal translocation carriers. Thus far, the only study of which we are aware that examined the radial position for structures expected to reside at the nuclear centre (centromeres of X and 18 and the long arm of the Y) in fertile and infertile males are that of our own laboratory (Finch et al 2008b). We suggested that all three loci occupied interior positions in normal males, but that the sex chromosomes showed altered positions (a more random distribution) in some of the infertile patients.…”

Section: Introductionmentioning

confidence: 84%

“…Given the high levels of chromosome abnormalities in the sperm of infertile men, the association with increased DNA damage, the identification of functional correlates such as mitochondrial dysfunction, the crucial role of nuclear organisation in normal spermatogenesis and the evidence of altered nuclear organisation in other diseases, the hypothesis that nuclear organisation will be altered in males with severely compromised spermatogenesis seems an obvious one to propose (Finch et al 2008b;Ioannou and Griffin 2010;Zalensky and Zalenskaya 2007). Indeed, it is reasonable to suggest that men with measurably altered nuclear organisation in their sperm heads might have fertility problems.…”

Section: Introductionmentioning

confidence: 99%

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Nuclear organisation of sperm remains remarkably unaffected in the presence of defective spermatogenesis

et al. 2011

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Organisation of chromosome territories in interphase nuclei has been studied in many systems and positional alterations have been associated with disease phenotypes (e.g. laminopathies, cancer) in somatic cells. Altered nuclear organisation is also reported in developmental processes such as mammalian spermatogenesis where a "chromocentre" model is proposed with the centromeres and sex chromosomes repositioning to the nuclear centre. The purpose of this study was to test the hypothesis that alterations in nuclear organisation of human spermatozoa are associated with defects upstream in spermatogenesis (as manifest in certain infertility phenotypes). The nuclear address of (peri-) centromeric loci for 18 chromosomes (1-4, 6-12, 15-18, 20, X and Y) was assayed in 20 males using established algorithms for 3D extrapolations of 2D data. The control group comprised 10 fertile sperm donors while the test group was 10 patients with severely compromised semen parameters including high sperm aneuploidy. All loci examined in the control group adopted defined, interior positions thus providing supporting evidence for the presence of a chromocentre and interior sex chromosome territories. In the test group however there were subtle alterations in the nuclear address for certain centromeres in individual patients and, when all patient results were pooled, some different nuclear addresses were observed for chromosomes 3, 6, 12 and 18. Considering the extensive impairment of spermatogenesis in the test group (evidenced by compromised semen parameters and increased chromosome abnormalities), the observed differences in nuclear organisation for centromeric loci compared to the controls were modest. A defined pattern of nuclear reorganisation of centromeric loci in sperm heads therefore appears to be a remarkably robust process, even if spermatogenesis is severely compromised.

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Section: Introductionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Nuclear organisation of sperm remains remarkably unaffected in the presence of defective spermatogenesis

et al. 2011

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“…It should be noted that the nuclear position the chromosome probe occupies and the probe signal size has been suggested to influence the perceived levels of aneuploidy. 65 However, it is clear that certain chromosomes are more prone to non-disjunction (chromosomes 21, 22, X and Y); with a two-to threefold increase in aneuploidy levels for these chromosomes compared to other chromosomes. Indirect evidence of the requirement for meiotic recombination for correct chromosome segregation has been provided by the observation that achiasmate bivalents predominantly involve chromosomes 21, 22, X and Y; mirroring the observation that these are most commonly observed chromosome aneuploidies in sperm.…”

Section: The Relationship Between Chromosome Aneuploidy and Male Infementioning

confidence: 99%

Meiotic recombination and male infertility: from basic science to clinical reality?

Hann¹,

Lau²,

Tempest³

2011

Asian J Androl

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Infertility is a common problem that affects approximately 15% of the population. Although many advances have been made in the treatment of infertility, the molecular and genetic causes of male infertility remain largely elusive. This review will present a summary of our current knowledge on the genetic origin of male infertility and the key events of male meiosis. It focuses on chromosome synapsis and meiotic recombination and the problems that arise when errors in these processes occur, specifically meiotic arrest and chromosome aneuploidy, the leading cause of pregnancy loss in humans. In addition, meiosis-specific candidate genes will be discussed, including a discussion on why we have been largely unsuccessful at identifying disease-causing mutations in infertile men. Finally clinical applications of sperm aneuploidy screening will be touched upon along with future prospective clinical tests to better characterize male infertility in a move towards personalized medicine.

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“…Repositioning of genes, small chromatin regions, or CTs is also seen in other diseases, such as facioscapulohumeral muscular dystrophy (FSHD) (Masny et al 2004), immunodeficiency centromeric instability facial anomalities (ICF) (Matarazzo et al 2007), epilepsy (Borden and Manuelidis 1988), or in male factor infertility (Finch et al 2008). ICF syndrome is caused by mutations in DNA methyltransferase 3B (DNMT3B) and is associated with DNA hypomethylation at specific genomic sites, such as the SYBL1 gene promoter which becomes derepressed.…”

Section: Altered Gene Positioning In Diseasementioning

confidence: 99%

Gene Positioning

Ferrai¹,

Castro²,

Lavitas³

et al. 2010

Cold Spring Harbor Perspectives in Biology

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Eukaryotic gene expression is an intricate multistep process, regulated within the cell nucleus through the activation or repression of RNA synthesis, processing, cytoplasmic export, and translation into protein. The major regulators of gene expression are chromatin remodeling and transcription machineries that are locally recruited to genes. However, enzymatic activities that act on genes are not ubiquitously distributed throughout the nucleoplasm, but limited to specific and spatially defined foci that promote preferred higher-order chromatin arrangements. The positioning of genes within the nuclear landscape relative to specific functional landmarks plays an important role in gene regulation and disease.

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Nuclear organization in human sperm: preliminary evidence for altered sex chromosome centromere position in infertile males

Abstract: Our findings cast doubt on the reliability of centromeric probes for aneuploidy screening. The analysis of chromosome position in sperm heads should be further investigated for the screening of infertile men.

Cited by 45 publications

References 44 publications

Nuclear organisation of sperm remains remarkably unaffected in the presence of defective spermatogenesis

Nuclear organisation of sperm remains remarkably unaffected in the presence of defective spermatogenesis

Meiotic recombination and male infertility: from basic science to clinical reality?

Gene Positioning

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