Gene

Male infertility

Cell biology

Heterozygote advantage

Biology

Sperm

Sperm motility

Endocrinology

Compound heterozygosity

Mutation

Genetics

Mitochondrial DNA

Spermatogenesis

Inheritance (genetic algorithm)

Loss of heterozygosity

Infertility

Andrology

Medicine

Allele

Non-Mendelian inheritance

Pregnancy

eLife

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.

Oligogenic heterozygous inheritance of sperm abnormalities in mouse