Rotte, N. | Search bioRxiv

bioRxiv2026

A single-nucleus multiomic and spatial atlas of gene regulation in human spermatogenesis

Gametogenesis, the production of oocytes and sperm, ensures the faithful transmission of genetic material to the next generation. In males, spermatogenesis occurs within the testis, where germ cells progress through a highly ordered developmental programme in close association with supporting somatic cells. Defects in this process cause infertility, yet the gene regulatory mechanisms coordinating normal and dysfunctional human spermatogenesis remain incompletely defined. Here we generate a single-nucleus multiomic and spatial atlas of human spermatogenesis by profiling chromatin accessibility and gene expression in the same nuclei and integrating these data with spatial transcriptomics of intact testicular tissue. We infer high-confidence gene regulatory networks that resolve stage-specific activity of known and novel candidate regulators across germline and somatic compartments, and map spatially restricted signalling interactions within the seminiferous tubule niche. Integration with infertility-associated genetic variation links non-coding risk loci to candidate enhancers and target genes in cell-type-specific regulatory contexts. Finally, profiling clinical cryptozoospermia samples as in vivo perturbations supports the ability of this network to capture downstream transcriptional consequences of disease-associated regulatory disruption. Together, these data provide a spatially resolved regulatory framework for human spermatogenesis and a foundation for interpreting the molecular basis of male infertility.

genomics↗

bioRxiv2019

Biallelic mutations in M1AP are a frequent cause of meiotic arrest leading to male infertility

Male infertility affects [~]7% of men in Western societies, but its causes remain poorly understood. The most clinically severe form of male infertility is non-obstructive azoospermia (NOA), which is, in part, caused by an arrest at meiosis, but so far only few genes have been reported to cause germ cell arrest in males. To address this gap, whole exome sequencing was performed in 60 German men with complete meiotic arrest, and we identified in three unrelated men the same homozygous frameshift variant c.676dup (p.Trp226LeufsTer4) in M1AP, encoding meiosis 1 arresting protein. Then, with collaborators from the International Male Infertility Genomics Consortium (IMIGC), we screened a Dutch cohort comprising 99 infertile men and detected the same homozygous variant c.676dup in a man with hypospermatogenesis predominantly displaying meiotic arrest. We also identified two Portuguese men with NOA carrying likely biallelic loss-of-function (LoF) and missense variants in M1AP among men screened by the Genetics of Male Infertility Initiative (GEMINI). Moreover, we discovered a homozygous missense variant p.(Pro389Leu) in M1AP in a consanguineous Turkish family comprising five infertile men. M1AP is predominantly expressed in human and mouse spermatogonia up to secondary spermatocytes and previous studies have shown that knockout male mice are infertile due to meiotic arrest. Collectively, these findings demonstrate that both LoF and missense M1AP variants that impair its protein cause autosomal-recessive meiotic arrest, non-obstructive azoospermia and male infertility. In view of the evidence from several independent groups and populations, M1AP should be included in the growing list of validated NOA genes.

genetics↗