Oligogenic heterozygous inheritance of sperm abnormalities in mouse

Guillaume Martinez (1, 2) , Charles Coutton (1, 2) , Corinne Loeuillet (1) , Caroline Cazin (1) , Jana Muroňová (1) , Magalie Bouguenet (1) , Emeline Lambert (1) , Magali Dhellemmes (1) , Geneviève Chevalier (1) , Jean-Pascal Hograindleur (1) , Charline Vilpreux (1) , Yasmine Neirijnck (3) , Zine-Eddine Kherraf (1) , Jessica Escoffier (1) , Serge Nef (4) , Pierre F Ray (1) , Christophe Arnoult (3, 1)

1 IAB - Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble)
2 Laboratoire de Génétique Chromosomique [CHU de Grenoble]
3 SP - Station de primatologie
4 UNIGE - Université de Genève = University of Geneva

Male infertility is an important health concern that is expected to have a major genetic etiology. Although high-throughput sequencing has linked gene defects to more than 50% of rare and severe sperm anomalies, less than 20% of common and moderate forms are explained. We hypothesized that this low success rate could at least be partly due to oligogenic defects – the accumulation of several rare heterozygous variants in distinct, but functionally connected, genes. Here, we compared fertility and sperm parameters in male mice harboring one to four heterozygous truncating mutations of genes linked to multiple morphological anomalies of the flagellum (MMAF) syndrome. Results indicated progressively deteriorating sperm morphology and motility with increasing numbers of heterozygous mutations. This first evidence of oligogenic inheritance in failed spermatogenesis strongly suggests that oligogenic heterozygosity could explain a significant proportion of asthenoteratozoospermia cases. The findings presented pave the way to further studies in mice and man.

Domaines: Biologie de la reproduction

Guillaume Martinez, Charles Coutton, Corinne Loeuillet, Caroline Cazin, Jana Muroňová, et al.. Oligogenic heterozygous inheritance of sperm abnormalities in mouse. eLife, 2022, 11, pp.e75373. ⟨10.7554/eLife.75373⟩. ⟨hal-03818177⟩