Discrimination of Deletion and Duplication Subtypes of the Deleted in Azoospermia Gene Family in the Context of Frequent Interloci Gene Conversion

Abstract

Due to its palindromic setup, AZFc (Azoospermia Factor c) region of chromosome Y is one of the most unstable regions of the human genome. It contains eight gene families expressed mainly in the testes. Several types of rearrangement resulting in changes in the cumulative copy number of the gene families were reported to be associated with diseases such as male infertility and testicular germ cell tumors. The best studied AZFc rearrangement is gr/gr deletion. Its carriers show widespread phenotypic variation from azoospermia to normospermia. This phenomenon was initially attributed to different gr/gr subtypes that would eliminate distinct members of the affected gene families. However, studies conducted to confirm this hypothesis have brought controversial results, perhaps, in part, due to the shortcomings of the utilized subtyping methodology. This proof-of-concept paper is meant to introduce here a novel method aimed at subtyping AZFc rearrangements. It is able to differentiate the partial deletion and partial duplication subtypes of the Deleted in Azoospermia (DAZ) gene family. The keystone of the method is the determination of the copy number of the gene family member-specific variant(s) in a series of sequence family variant (SFV) positions. Most importantly, we present a novel approach for the correct interpretation of the variant copy number data to determine the copy number of the individual DAZ family members in the context of frequent interloci gene conversion.Besides DAZ1/DAZ2 and DAZ3/DAZ4 deletions, not yet described rearrangements such as DAZ2/DAZ4 deletion and three duplication subtypes were also found by the utilization of the novel approach. A striking feature is the extremely high concordance among the individual data pointing to a certain type of rearrangement. In addition to being able to identify DAZ deletion subtypes more reliably than the methods used previously, this approach is the first that can discriminate DAZ duplication subtypes as well.

Új korszak a daganatos betegséghajlam genetikai hátterének megismerésében

“…Munkatársaimmal "variant ratio analysis"nek nevezett új módszert fej lesztettünk ki az Ykromoszóma AZFc régiójának genetikai vizsgálatára, ami NGSre adaptálva alkalmas lehet az Ykromoszómához köthető rákhajlam ta nulmányozására (Vaszkó et al 2016).…”

Copy number variants within AZF region of Y chromosome and their association with idiopathic male infertility in Serbian population

“…Amplicons are assembled in eight highly symmetrical palindromes, and, due to its structure, this region of the Y chromosome represents a hotspot for non‐allelic homologous recombination leading to structural rearrangements (Kuroda‐Kawaguchi et al, 2001). Palindromes containing amplicon sequences located within the AZFc region enable partial deletions and/or duplications to occur, which affect gene dosage of multiple copy number genes resulting in copy number variants (CNVs) (Vaszkó et al, 2016). Deletion CNVs that occur within the AZFc region of the Y chromosome are named after the amplicons involved in the structural rearrangements.…”