Gene copy number alterations in the azoospermia-associated AZFc region and their effect on spermatogenic impairment

Abstract

abstract:The azoospermia factor c (AZFc) region in the long arm of human Y chromosome is characterized by massive palindromes. It harbors eight multi-copy gene families that are expressed exclusively or predominantly in testis. To assess systematically the role of the AZFc region and these eight gene families in spermatogenesis, we conducted a comprehensive molecular analysis (including Y chromosome haplogrouping, AZFc deletion typing and gene copy quantification) in 654 idiopathic infertile men and 781 healthy controls in a Han Chinese population. The b2/b3 partial deletion (including both deletion-only and deletion-duplication) was consistently associated with spermatogenic impairment. In the subjects without partial AZFc deletions, a notable finding was that the frequency of DAZ and/or BPY2 copy number alterations in the infertile group was significantly higher than in the controls. Combined patterns of DAZ and/or BPY2 copy number abnormality were associated with spermatogenic impairment when compared with the pattern of all AZFc genes with common level copies. In addition, in Y chromosome haplogroup O1 (Y-hg O1), the frequency of copy number alterations of all eight gene families was significantly higher in the case group than that in the control group. Our findings indicate that the DAZ, BPY2 genes may be prominent players in spermatogenesis, and genomic rearrangements may be enriched in individuals belonging to Y-hg O1. Our findings emphasize the necessity of routine molecular analysis of AZFc structural variation during the workup of azoospermia and/or oligozoospermia, which may diminish the genetic risk of assisted reproduction.

Reproductive outcomes and Y chromosome instability in radiation‐exposed male workers in cardiac catheterization laboratory

“…The epidemiological evidence is corroborated by molecular genetic data indicating a higher prevalence of genomic instability (microdeletions and/or duplications) in specific “hot‐spots” of the AZF sex‐coding region of Y chromosome, which is a genetic marker of impaired spermatogenesis (Lu et al ), can be transmitted to the offspring (Jungwirth et al ) and may predispose to severe congenital abnormality when spermatozoa are formed (Diemer and Desjardins ).…”

“…The AZFc region contains eight multicopy gene families, which are believed to be the crucial determinants of spermatogenesis (Navarro-Costa et al 2010;Lu et al 2014;Nailwal and Chauhan 2017). Because AZFc region contains long repeat DNA units, it is particularly prone to recombination events and, hence, to structural and deleterious variation in men (Navarro-Costa et al 2010;Lu et al 2014;Nailwal and Chauhan 2017), especially when exposed to genotoxic insult (Premi et al 2007(Premi et al , 2009Arruda et al 2008;Moghbeli-Nejad et al 2012).…”

The Biology and Evolution of Mammalian Y Chromosomes

“…Much ongoing work in this field focuses on possible associations between spermatogenesis phenotypes and copy number variation in specific testis-expressed gene families (35,36,74,75,84).…”

Susceptibility of gr/gr rearrangements to azoospermia or oligozoospermia is dependent on DAZ and CDY1 gene copy deletions

“…Corroborating these observations further, copy number variations of DAZ and CDY1 genes were found to be associated with reduction in total motile sperm count in men harbouring AZFc subdeletions [37]. Recently, Lu et al also reported that loss of individual copies of genes within AZFc also lead to impaired spermatogenesis [38]. Thus it is possible that copy number variations of the DAZ and CDY1 genes may influence the sperm concentration and clinical manifestation of the men with AZFc subdeletions.…”