Differential effect of specific gr/gr deletion subtypes on spermatogenesis in the Chinese Han population

Abstract

As a common variation in the azoospermia factor c (AZFc) region of Y chromosome, the gr/gr deletion is regarded as a significant risk factor for spermatogenic impairment, whereas the association of the deletion's phenotypic expression with Y-chromosomal background is still a subject of debate. To further investigate the contribution of the deletion to spermatogenic impairment in different Y-chromosomal haplogroups, the partial AZFc deletion was detected with AZFc-specific sequence tagged sites, gene dosage and gene copy analyses of deleted in azoospermia (DAZ), chromodomain Y1 (CDY1) and basic protein Y2 (BPY2) in 1426 azoo/oligozoospermic and 672 normozoospermic men from a Chinese population. The haplogrouping was performed in 231 deletion carriers with 12 polymorphic loci of Y chromosome. As a result, five gr/gr rearrangement types in eight Y haplogroups were observed, in which the simple gr/gr deletion was the most common type, and its frequency was significantly higher in men with azoo/oligozoospermia relative to normozoospermia. Also the distribution of gr/gr-rearranged Y haplogroups was significantly different between the two groups, in which gr/gr-deleted haplogroups C and DE were more common in men with azoo/oligozoospermia. In the 6 gr/gr copy deletion haplotypes, the frequencies of DAZ1/DAZ2+CDY1a or CDY1b deletion were significantly higher in men with azoo/oligozoospermia, while all DAZ3/DAZ4+CDY1b+BPY2.2 or 2.3 deletions were found only in haplogroup Q1 without any distribution difference between the azoo/oligozoospermic and normozoospermic groups. This study provided further evidence for the existence of multiple subtypes of gr/gr deletion and indicates that gr/gr-DAZ1/DAZ2 deletion is a significant risk factor. However, the association of the phenotypic variation of gr/gr deletion with Y-chromosomal haplogroups is not definite yet, because of the limited amounts of the deletions observed in each of the haplogroups and the lack of the quantitative trait analyses such as sperm density analysis. The fact that a common gr/gr copy deletion haplotype was found exclusively in the Y hgr Q1, without pathogenic consequences, implies the importance of haplogrouping and of copy deletion typing prior to genetic counselling of deletion carriers of Chinese descent.

Characterization of the AZF region of the Y chromosome in Native American haplogroup Q

“…The developed technique become part of a manuscript that is already submitted (Greve et al) and was the trigger for this Master Thesis work on human Y chromosomes belonging to haplogroup Q1a3a1, which has not been studied in deep until the present. The hypothesis of this work was based on the fact that in primates and in humans the MSY was described to suffer microdeletions and copy number variants that are not always related to male infertility and this variation can be found also in normal fertile males (Fernandes, Paracchini et al 2004;Yang, Ma et al 2010).…”

“…However, the association of the phenotypic variation of gr/gr deletion with Y-chromosomal haplogroups is not definite yet, because of the limited amounts of deletions observed in each haplogroup and the lack of quantitative trait such as sperm density analysis. The fact that a common gr/gr copy deletion haplotype was found exclusively in the Y haplogroup Q1, without pathogenic consequences, underscore the importance of haplogrouping and copy number typing (Yang, Ma et al 2010). …”

“…Furthermore, as a common variation in the AZFc region, the gr/gr deletion is regarded as a significant risk factor for spermatogenic impairment, whereas the association of the deletion's phenotypic expression with Y-chromosomal background was studied in several haplogroups but is still a subject of debate (Repping, Skaletsky et al 2003;Fernandes, Paracchini et al 2004;Repping, van Daalen et al 2004;Repping, van Daalen et al 2006;Yang, Ma et al 2008;Yang, Ma et al 2010;Shahid, Dhillon et al 2011). In a previous study regarding haplogroup E, it was found that its particular background seems to be more prone to rearrangements, in particular to b2/b4 microdeletions, than other haplogroups.…”

“…As previously discussed, AZFc deletions account for approximately 60% of all recorded AZF deletions and, therefore, the genetic disruption of AZFc is generally perceived as a key concern for male reproductive health (Navarro-Costa, Goncalves et al 2010). From the most frequently found deletions on AZFc (Figure 1.8), the gr/gr deletion (sY1291 deletion) and b2/b3 or g1/g3 deletion (sY1191 deletion) have been identified in men with impaired as well as normal espermatogenesis and these deletions have been found to predispose to spermatogenic failure in some populations but not in others (Repping, van Daalen et al 2004;Yang, Ma et al 2010). (Lin, Hsu et al 2006) In clinical terms, the importance of the AZF regions is paramount as deletions in these domains are one of the most frequent genetic causes of spermatogenic failure.…”

“…As Argentina has an admixed population, with European and Native American genetic To continue with the present research, it is needed to identify SFVs (sequence family variants) of DAZ and CDY genes in order to clarify which of the copies of DAZ/CDY has been deleted or duplicated (Machev, Saut et al 2004;Yang, Ma et al 2010). For this purpose, a molecular genetics approach, using Real Time PCR and High Resolution Melting (HRM) analysis, aiming to identify the SNPs in these genes can be easily set up.…”