Identification of a New QTL Region on Mouse Chromosome 1 Responsible for Male Hypofertility: Phenotype Characterization and Candidate Genes

Abstract

Male fertility disorders often have their origin in disturbed spermatogenesis, which can be induced by genetic factors. In this study, we used interspecific recombinant congenic mouse strains (IRCS) to identify genes responsible for male infertility. Using ultrasonography, in vivo and in vitro fertilization (IVF) and electron microscopy, the phenotyping of several IRCS carrying mouse chromosome 1 segments of Mus spretus origin revealed a decrease in the ability of sperm to fertilize. This teratozoospermia included the abnormal anchoring of the acrosome to the nucleus and a persistence of residual bodies at the level of epididymal sperm midpiece. We identified a quantitative trait locus (QTL) responsible for these phenotypes and we have proposed a short list of candidate genes specifically expressed in spermatids. The future functional validation of candidate genes should allow the identification of new genes and mechanisms involved in male infertility.

Deletion of the Spata3 Gene Induces Sperm Alterations and In Vitro Hypofertility in Mice

“…In order to understand which gene within the Mafq1 QTL interval was responsible for the hypofertility phenotype observed in the Rc3 IRCS mice [ 7 ], we explored the list of candidate genes present in the interval. Spata3 matched all potential criterion of selection: the specific expression profile, regarding both the timing and location in differentiating sperm cells, the evolutionary conservation, the high number and predicted impact of missense changes between B6 and spretus SPATA3 proteins.…”

“…When mated with WT females, homozygous KO males could sire normally and produce normal litters. The absence of Spata3 did not reproduce the in vivo hypofertility observed in Rc3 males [ 7 ]. However, in IVF assays, sperm lacking Spata3 expression were less efficient to fertilize WT oocytes.…”

“…We identified in an Interspecific Recombinant Congenic Strain (IRCS) a region of mouse chromosome 1 whose presence in a Mus spretus version within a Mus musculus domesticus (C57Bl/6) background is associated with signs reminiscent of globozoospermia. This quantitative trait locus (QTL), named Mafq1 for male fertility QTL chromosome 1, is associated with an interval of approximately 4 Mb between markers D1Mit438 and D1Mit305 [ 7 ].…”

“…Spata3 is expressed specifically in the testis both in mice and humans. Precisely, its expression can be detected during spermatogenesis from the round spermatid stage to mature sperm [ 7 ]. Spata3 is conserved in many mammalian species, with mouse and human proteins sharing 55% of their identity.…”

“…These variations could be responsible for important modifications of the structure and/or the function of the spretus SPATA3 protein compared to the C57Bl/6 version. This spretus version of the protein could therefore be inapt to interact/bind/function with any receptor/cofactor/partner in the C57Bl/6 version in the IRCS model to accomplish its normal activity, resulting in the hypofertility phenotype observed in the Rc3 IRCS male mice [ 7 ].…”