Y Chromosome Microdeletions and Male Infertility

The human Y chromosome carries genes indispensable for testis development and spermatogenesis. Within its long arm lie the azoospermia factor regions—AZFa, AZFb and AZFc—prone to intra-chromosomal rearrangements owing to extensive palindromic and ampliconic sequences. Microdeletions affecting these regions remove one or more spermatogenic genes, leading to oligozoospermia or azoospermia and accounting for a significant proportion of non-obstructive male infertility worldwide. Prevalence varies by ethnicity and geographic region, with overall rates of Y chromosome microdeletions approaching 5–10% in infertile men. Detection of these deletions is integral to clinical assessment, guiding patient counselling, informing the likelihood of sperm retrieval through microdissection testicular sperm extraction, and shaping assisted reproduction strategies such as intracytoplasmic sperm injection. As these deletions are transmitted to male offspring conceived by assisted fertilisation, genetic screening enables informed reproductive decision-making and may have broader implications for men’s health beyond fertility.

Research from Nature Portfolio

Recent large-scale sequencing in an Icelandic cohort has quantified de novo copy number variation across palindromic regions of the Y chromosome, revealing mutation rates substantially higher than phylogenetic estimates and indicating rapid purging of non-reference alleles under weak negative selection. Despite extensive structural diversity, no direct correlations with fertility measures were detected, underscoring the resilience of spermatogenesis against many large-scale rearrangements. In parallel, next-generation read-depth analysis of Iranian patrilineal clans uncovered a high incidence of duplications within the AZFb/c region, including an unprecedented 8 Mb amplification, suggesting that both deletions and duplications contribute to spermatogenic impairment in populations with constrained male effective population sizes. Foundational meta-analysis of partial AZFc gr/gr deletions has further refined risk estimates, confirming a moderate but significant association with reduced sperm count and increased infertility odds, particularly among Caucasian cohorts. Together, these studies highlight the spectrum of structural variation on the Y chromosome and its nuanced impact on male reproductive potential.

Y Chromosome Microdeletions and Male Infertility publication trend

The graph below shows the total number of articles in y chromosome microdeletions and male infertility across all publications each year (not limited to Nature Index journals).

Technical terms

Y chromosome microdeletion: The loss of small genomic segments from the male-specific region of the Y chromosome, often encompassing genes essential for sperm production.

Azoospermia factor (AZF) regions: Three gene-rich domains (AZFa, AZFb, AZFc) on the long arm of the Y chromosome whose loss leads to spermatogenic failure.

Copy number variation (CNV): Alterations in the number of copies of specific DNA segments that can include deletions or duplications affecting gene dosage.

Azoospermia: Complete absence of spermatozoa in the ejaculate, a severe form of male infertility.

Intracytoplasmic sperm injection (ICSI): An assisted reproduction technique in which a single sperm is injected directly into an oocyte to achieve fertilisation.

References

1. Genetics of the human Y chromosome and its association with male infertility. Reproductive Biology and Endocrinology (2018).
2. Genetic Dissection of the AZF Regions of the Human Y Chromosome: Thriller or Filler for Male (In)fertility?. BioMed Research International (2010).
3. Characterizing the evolution and phenotypic impact of ampliconic Y chromosome regions. Nature Communications (2023).
4. High incidence of AZF duplications in clan-structured Iranian populations detected through Y chromosome sequencing read depth analysis. Scientific Reports (2023).
5. Gr/gr deletions on Y-chromosome correlate with male infertility: an original study, meta-analyses and trial sequential analyses. Scientific Reports (2016).
6. Y chromosome microdeletions in Chinese men with infertility: prevalence, phenotypes, and intracytoplasmic sperm injection outcomes. Reproductive Biology and Endocrinology (2023).
7. Clinical outcomes of microdissection testicular sperm extraction and intracytoplasmic sperm injection in Japanese men with Y chromosome microdeletions. Reproductive Medicine and Biology (2020).