Gr/gr deletions on Y-chromosome correlate with male infertility: an original study, meta-analyses and trial sequential analyses

Bansal, Sandeep; Jaiswal, Deepika; Gupta, Nishi; Singh, Kiran; Dada, Rima; Sankhwar, Satya Narayan; Gupta, Gopal; Rajender, Singh

doi:10.1038/srep19798

Cited by 71 publications

(79 citation statements)

References 77 publications

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“…Klinefelter syndrome) or Y chromosome microdeletions. However, a large proportion of infertile men (~30%) remain diagnosed with idiopathic infertility, i.e., no known underlying cause (1)(2)(3). The X chromosome is of considerable interest to search for mutations that cause male infertility and subfertility, as this chromosome is enriched in testis-specific genes (4-7).…”

Section: Introductionmentioning

confidence: 99%

The humanRHOXgene cluster: target genes and functional analysis of gene variants in infertile men

Borgmann

Tüttelmann²,

Dworniczak³

et al. 2016

Hum. Mol. Genet.

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The X-linked reproductive homeobox (RHOX) gene cluster encodes transcription factors preferentially expressed in reproductive tissues. This gene cluster has important roles in male fertility based on phenotypic defects of Rhox-mutant mice and the finding that aberrant RHOX promoter methylation is strongly associated with abnormal human sperm parameters. However, little is known about the molecular mechanism of RHOX function in humans. Using gene expression profiling, we identified genes regulated by members of the human RHOX gene cluster. Some genes were uniquely regulated by RHOXF1 or RHOXF2/2B, while others were regulated by both of these transcription factors. Several of these regulated genes encode we demonstrate how the X-linked RHOX gene cluster may function in normal human spermatogenesis and we provide evidence that it is impaired in human male fertility.

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Section: Introductionmentioning

confidence: 99%

The humanRHOXgene cluster: target genes and functional analysis of gene variants in infertile men

Borgmann

Tüttelmann²,

Dworniczak³

et al. 2016

Hum. Mol. Genet.

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“…The AZFc region is highly repetitive, harbors palindromes (Kuroda-Kawaguchi et al 2001) and thus is more prone to deletions than the other AZF regions (Navarro-Costa et al 2010;Knebel et al 2011) . Indeed, AZFc deletions constitute 80% of all AZF deletions (Bansal et al 2016) . Ampliconic gene families outside of AZF regions are also implicated in reproductive diseases.…”

Section: Introductionmentioning

confidence: 99%

“…Ampliconic gene families outside of AZF regions are also implicated in reproductive diseases. For example, copy number reductions in DAZ , BPY , and CDY gene families have been associated with lower total motile sperm counts in men (Noordam et al 2011;Bansal et al 2016) . Contradictory results have been reported on the association between TSPY and fertility (Krausz et al 2010) .…”

Section: Introductionmentioning

confidence: 99%

High levels of copy number variation of ampliconic genes across major human Y haplogroups

Zaidi

Tomaszkiewicz

et al. 2017

Preprint

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Due to its highly repetitive nature, the human male-specific Y chromosome remains understudied. It is important to investigate variation on the Y chromosome to understand its evolution and contribution to phenotypic variation, including infertility. Approximately 20% of the human Y chromosome consists of ampliconic regions which include nine multi-copy gene families. These gene families are expressed exclusively in testes and usually implicated in spermatogenesis . Here, to gain a better understanding of the role of the Y chromosome in human evolution and in determining sexually dimorphic traits, we studied ampliconic gene copy number variation in 100 males representing ten major Y haplogroups world-wide. Copy number was estimated with droplet digital PCR. In contrast to low nucleotide diversity observed on the Y in previous studies, here we show that ampliconic gene copy number diversity is very high. A total of 98 copy-number-based haplotypes were observed among 100 individuals, and haplotypes were sometimes shared by males from very different haplogroups, suggesting homoplasies. The resulting haplotypes did not cluster according to major Y haplogroups.Overall, only three gene families ( DAZ , RBMY , TSPY ) showed significant differences in copy number among major Y haplogroups, and the haplogroup of an individual could not be predicted based on his ampliconic gene copy numbers. Finally, we found a significant correlation between copy number variation and individual's height (for three gene families), but not between the former and facial masculinity/femininity. Our results suggest rapid evolution of ampliconic gene copy numbers on the human Y, and we discuss its causes.

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“…21 The outcome of b2/b3 and b1/b3 deletions is similar, leading to the retention of two DAZ gene copies and one or two BPY2 gene copies. Several studies have associated this deletion as a risk factor for the loss of spermatogenesis, 30,35,36 while others have failed to find a correlation. 37 A study in the Han population in China reported that duplication of the gr/gr region is detrimental to fertility, further contributing to uncertainty about the role that this region plays in determining a male's fertility status.…”

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confidence: 99%

“…36 There is wide variation in the prevalence of Y chromosome microdeletions world over. A report from the Middle East indicates a high prevalence of Y chromosome microdeletions (7.5%), 39 and a study from Iran in azoospermic infertile males has reported a prevalence of 12%.…”

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confidence: 99%

Role of Y Chromosome Microdeletions in the Clinical Evaluation of Infertile Males

Modi¹,

Colaco²,

Lakdawala³

2017

MGM Journal of Medical Sciences

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Infertility is a multifaceted condition, which is on the rise in the last few decades. A stage of great importance in the development of human male gametes is spermatogenesis, which is governed by a set of genes located on the q arm of the Y chromosome. Loss of these genes can cause disruptions in spermatogenesis and, thus, lead to male infertility. Studies have identified several deletions on the long arm of the Y chromosome, called Yq microdeletions, which occur in three distinct loci termed AZFa, AZFb, and AZFc. In addition to these, there exist small subdeletions in the AZFc locus, called gr/gr, b1/b2, or b2/b3 subdeletions. Such deletions can lead to azoospermia or oligozoospermia by causing Sertoli cell-only syndrome, impairment in spermatogenesis, or maturation arrest. Testing for Y chromosome microdeletions is clinically significant for several reasons, since these deletions are exclusively associated with male infertility and their detection can help identify the cause of infertility. Knowing the presence or absence of Y chromosome microdeletion also aids in predicting the prognosis of oligozoospermic males, who are usually known to progress to azoospermia over time. The occurrence and type of Yq microdeletion are correlated with testicular phenotype in infertile males and, thus, serve as a good predictor of sperm retrieval. Vertical transmission of Y chromosome microdeletions from father to the male offspring is common in pregnancies achieved via assisted reproductive technologies; hence, the diagnosis of these deletions becomes imperative in such couples to prevent perpetuation of infertility in the next generation. Screening for Yq microdeletions is, thus, clinically significant and must be offered to all infertile males.

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Gr/gr deletions on Y-chromosome correlate with male infertility: an original study, meta-analyses and trial sequential analyses

Cited by 71 publications

References 77 publications

The humanRHOXgene cluster: target genes and functional analysis of gene variants in infertile men

The humanRHOXgene cluster: target genes and functional analysis of gene variants in infertile men

High levels of copy number variation of ampliconic genes across major human Y haplogroups

Role of Y Chromosome Microdeletions in the Clinical Evaluation of Infertile Males

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