Structural variation on the short arm of the human Y chromosome: Recurrent multigene deletions encompassing Amelogenin Y

Leiden University, Leyden, South Holland, Netherlands
Human Molecular Genetics (Impact Factor: 6.39). 03/2007; 16(3):307-16. DOI: 10.1093/hmg/ddl465
Source: PubMed


Structural polymorphism is increasingly recognized as a major form of human genome variation, and is particularly prevalent on the Y chromosome. Assay of the Amelogenin Y gene (AMELY) on Yp is widely used in DNA-based sex testing, and sometimes reveals males who have interstitial deletions. In a collection of 45 deletion males from 12 populations, we used a combination of sequence-tagged site mapping, and binary-marker and Y-short tandem repeat haplotyping to understand the structural basis of this variation. Of the 45 deletion males, 41 carry indistinguishable deletions, 3.0-3.8 Mb in size. Breakpoint mapping strongly implicates a mechanism of non-allelic homologous recombination between the proximal major array of TSPY gene-containing repeats, and a single distal copy of TSPY; this is supported by the estimation of TSPY copy number in deleted and non-deleted males. The remaining four males carry three distinct non-recurrent deletions (2.5-4.0 Mb), which may be due to non-homologous mechanisms. Haplotyping shows that TSPY-mediated deletions have arisen seven times independently in the sample. One instance, represented by 30 chromosomes mostly of Indian origin within haplogroup J2e1*/M241, has a time-to-most-recent-common-ancestor of approximately 7700+/-1300 years. In addition to AMELY, deletion males all lack the genes PRKY and TBL1Y, and the rarer deletion classes also lack PCDH11Y. The persistence and expansion of deletion lineages, together with direct phenotypic evidence, suggests that absence of these genes has no major deleterious effects.

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    • "The oligozoospermic patient with karyotype 46,XY, delY(q12-qter) seen in the present study had no microdeletion in any of the three regions analyzed, perhaps because the region Yq12-qter, in which had occurred this deletion, is a region of the Y chromosome rich in heterochromatin without any active gene.64 Although it seems not to be clinically relevant for male infertility, the severe oligozoospermia found in a patient with karyotype 46,XY(8p+) without any other cause identifiable indicates that some genes added to this autosome chromosome may affect spermatogenesis. "
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    ABSTRACT: OBJECTIVE To determine the prevalence of chromosomal abnormalities and microdeletions on Y chromosome in infertile patients with oligozoospermia or azoospermia in Mato Grosso state, Brazil. METHODS This cross-sectional study enrolled 94 men from infertile couples. Karyotype analysis was performed by lymphocyte culture technique. DNA from each sample was extracted using non-enzymatic method. Microdeletions were investigated by polymerase chain reaction (PCR). RESULTS With the use of cytogenetic analysis, five patients (5.3%) had abnormal karyotype, one azoospermic patient (1.1%) had karyotype 46,XY,t(7;1) (qter-p35), one (1.1%) with mild oligozoospermia had karyotype 46,XY,delY(q), and two other azoospermic patients had karyotype 47,XXY, consistent with Klinefelter syndrome (KS). One of them (1.1%) with severe oligozoospermia had karyotype 46,XY,8p+. Microdeletion on Y chromosome was found in the azoospermia factor c (AZFc) region in only one azoospermic patient (1.1%). CONCLUSIONS The prevalence of genetic abnormalities in oligo/azoospermic Brazilian men from infertile couple was 5.3%, and microdeletion on Y chromosome was not a common finding in this population (1.1%).
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    • "There are known deletion patterns observed in different clinical conditions e.g. AZFa, P5- proximal P1, P5- distal P1, AZFc, gr/gr, b1/b2 and b2/b3 and TSPY-TSPY deletion [29-36]. We have screened STSs encompassing these regions which were found to remain intact in DU145 of LNCaP cells (Figure 3). "
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    ABSTRACT: Background Prostate cancer is a known cause of mortality in men worldwide although the risk factor varies among different ethnic groups. Loss of the Y chromosome is a common chromosomal abnormality observed in the human prostate cancer. Results We screened 51 standard sequence tagged sites (STSs) corresponding to a male-specific region of the Y chromosome (MSY), sequenced the coding region of the SRY gene and assessed the status of the DYZ1 arrays in the human prostate cancer cell lines DU145 and LNCaP. The MSY was found to be intact and coding region of SRY showed no sequence variation in both the cell lines. However, DYZ1 arrays showed sequence and copy number variations. DU145 and LNCaP cells were found to carry 742 and 1945 copies of the DYZ1, respectively per 3.3 pg of genomic DNA. The DYZ1 copies detected in these cell lines are much below the average of that reported in normal human males. Similarly, the number of “TTCCA” repeat and its derivatives within the DYZ1 arrays showed variation compared to those of the normal males. Conclusions Clearly, the DYZ1 is maximally affected in both the cell lines. Work on additional cell lines and biopsied samples would augment our understanding about the susceptibility of this region. Based on the present work, we construe that copy number status of the DYZ1 may be exploited as a supplementary prognostic tool to monitor the occurrence of prostate cancer using biopsied samples.
    Full-text · Article · May 2013 · BMC Genomics
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    • "In one of these orientations, recombination can occur between DNA including the genes AMELY, TBL1Y and PRKY as well as some TSPY copies. Deletion carriers show no overt phenotypic effects, and the deletion is present at a frequency of ∼2% in the Indian subcontinent [14,15]. "
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    ABSTRACT: The TSPY gene stands out from all other human protein-coding genes because of its high copy number and tandemly-repeated organization. Here, we review its evolutionary history in great apes in order to assess whether these unusual properties are more likely to result from a relaxation of constraint or an unusual functional role. Detailed comparisons with chimpanzee are possible because a finished sequence of the chimpanzee Y chromosome is available, together with more limited data from other apes. These comparisons suggest that the human-chimpanzee ancestral Y chromosome carried a tandem array of TSPY genes which expanded on the human lineage while undergoing multiple duplication events followed by pseudogene formation on the chimpanzee lineage. The protein coding region is the most highly conserved of the multi-copy Y genes in human-chimpanzee comparisons, and the analysis of the dN/dS ratio indicates that TSPY is evolutionarily highly constrained, but may have experienced positive selection after the human-chimpanzee split. We therefore conclude that the exceptionally high copy number in humans is most likely due to a human-specific but unknown functional role, possibly involving rapid production of a large amount of TSPY protein at some stage during spermatogenesis.
    Full-text · Article · Dec 2011 · Genes
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