Detection of AZF rearrangement among different Iranian ethnic groups through Y chromosome sequencing read depth analysis

The ampliconic region of human Y chromosome is composed of large duplicated sequences that may undergo non-allelic homologous recombination (NAHR) leading to structural rearrangements that may cause infertility, especially when they occur in the Azoospermia Factor b/c region (AZFb/c). Although AZF duplications have long been neglected in human molecular reproduction studies, mainly due to technical limitations of the commonly used STS-based approach, evidence of their relevance on fertility is increasing by Next Generation Sequencing (NGS) studies. In this study, for the first time, we analysed copy number variants in the ampliconic region of the Y chromosome through an NGS-based read depth approach in Iran, a country which is characterised by high primary infertility rates. We identified 21 out of 87 males belonging to eight different ethnic groups, with at least one amplicon having a different copy number with respect to the reference sequence. We identified one individual with a large duplication (approximately 8.0 Mb) resulting in a fourfold increase in copy number for AZFc genes. To our knowledge, this is the largest duplication in the AZFc region ever reported. Notably, the incidence of Y chromosome duplications in the Iranian population is twice as high as in the worldwide “1000 Genomes” dataset. Interestingly, most of the duplications were found in ethnic groups organised into patrilineal clans (Bakhtiari, Turkmen and Qashqai). Overall, our results suggest that it is important to consider not only AZF deletions but also duplications to investigate for the causes of male infertility, especially in patrilineal clan-based populations.