Genetic mapping of a male factor subfertility locus on mouse chromosome 4

Male reproductive anomalies are widely distributed among mammals, and male factors are estimated to contribute to approximately 50% of cases of human infertility. The B10.M/Sgn (B10.M) mouse strain exhibits two adverse reproductive phenotypes: severe teratospermia and male subfertility. Although teratospermia is known to be heritable, the relationship between teratospermia and male subfertility has not been well characterized. The fertility of B10.M male mice is considerably lower (~ 30%) than that of standard laboratory mouse strains (~ 70%). To genetically analyze male subfertility, F2 males were produced by intercrossing the F1 progeny of female B10.M and male C3H/HeN mice. The fertility of each F2 male mouse was assessed based on the outcomes of matings with five females. Statistical analysis of correlations between the two reproductive phenotypes (teratospermia and subfertility) in F2 males (n = 177) revealed that teratospermia is not the cause of male subfertility. Quantitative trait loci (QTL) analysis of the male subfertility phenotype (n = 128) using GigaMUGA markers mapped one significant QTL peak to chromosome 4 at 62.9 centimorgans (cM) with a logarithm of odds score of 11.81 (P < 0.05). We named the QTL locus Mfsf1 (male factor subfertility 1). Further genetic analysis using recombinant males restricted the physical area to 1.53 megabasepairs (Mbp), encompassing 22 protein-coding genes. In addition, we found one significant QTL and one indicative QTL on chromosome 5 and 12, respectively, that interacted with the Mfsf1 locus. Our results demonstrate that genetic dissection of male subfertility in the B10.M strain is a useful model for characterizing the complex genetic mechanisms underlying reproduction and infertility.