Abstract
Y-chromosomal microdeletion (YCM) serves as an important genetic factor in non-obstructive azoospermia (NOA). Multiplex polymerase chain reaction (PCR) is routinely used to detect YCMs by tracing sequence-tagged sites (STSs) in the Y chromosome. Here we introduce a novel methodology in which we sequence 1,787 (post-filtering) STSs distributed across the entire male-specific Y chromosome (MSY) in parallel to uncover known and novel YCMs. We validated this approach with 766 Chinese men with NOA and 683 ethnically matched healthy individuals and detected 481 and 98 STSs that were deleted in the NOA and control group, representing a substantial portion of novel YCMs which significantly influenced the functions of spermatogenic genes. The NOA patients tended to carry more and rarer deletions that were enriched in nearby intragenic regions. Haplogroup O2* was revealed to be a protective lineage for NOA, in which the enrichment of b1/b3 deletion in haplogroup C was also observed. In summary, our work provides a new high-resolution portrait of deletions in the Y chromosome.
Highlights
The majority of deleterious deletions are dispersed along the ampliconic regions that consist of a total of 5.7 Mb or 25% of the male-specific Y chromosome (MSY) euchromatin, which creates a technological difficulty for Whole genome sequencing (WGS) because this method requires mapping based on short reads, and these regions are usually filtered for further analyses[15]
Increasing the resolution of the current understanding of Y chromosomal microdeletions (YCMs) in different population, the rare/partial deletions that are associated with spermatogenic failure, is highly attractive
Our method combines the low cost/high throughput of the next generation sequencing (NGS) technique with easy to use of STS markers to depict the most comprehensive and highest resolution landscape of YCMs to date, which significantly enhances our understanding of the field
Summary
Focusing on only the numerous STSs within the palindrome rather than the entire sequences provides unique landmarks that can be used to track deletions. This set of STSs in combination with the NGS technique is perfectly suited for the identification of deletions across the Y chromosome. We carefully recruited 766 patients (post-filtering) with NOA and excluded those with complete AZFa, AZFb or AZFc deletions (see the Methods for details) and 683 matched controls (post-filtering) with normal fertility histories from the Chinese population to test all of the STSs. In this study, we first developed a novel algorithm to detect deletions in our dataset and validated its high level of accuracy with various experimental approaches (Fig. 1). A few novel and significant Y deletions were carefully described
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