The nucleoside diphosphate kinase gene nme3 acts as quantitative trait locus promoting non-mendelian inheritance

The t-haplotype,a variant form of the t-complex region on mouse chromosome 17,acts as selfish genetic element and is transmitted at high frequencies (>95%) from heterozygous (t/+) males to their offspring. this phenotype is termed transmission ratio distortion (trd) and is caused by the interaction of the t-complex responder (tcr) with several quantitative trait loci (qtl),the t-complex distorters (tcd1 to tcd4),all located within the t-haplotype region. current data suggest that the distorters collectively impair motility of all sperm derived from t/+ males; t-sperm is rescued by the responder,whereas +-sperm remains partially dysfunctional. recently we have identified two distorters as regulators of rho small g proteins. here we show that the nucleoside diphosphate kinase gene nme3 acts as a qtl on trd. reduction of the nme3 dosage by gene targeting of the wild-type allele enhanced the transmission rate of the t-haplotype and phenocopied distorter function. genetic and biochemical analysis showed that the t-allele of nme3 harbors a mutation (p89s) that compromises enzymatic activity of the protein and genetically acts as a hypomorph. transgenic overexpression of the nme3 t-allele reduced t-haplotype transmission,proving it to be a distorter. we propose that the nme3 protein interacts with rho signaling cascades to impair sperm motility through hyperactivation of smok,the wild-type form of the responder. this deleterious effect of the distorters is counter-balanced by the responder,smok tcr,a dominant-negative protein kinase exclusively expressed in t-sperm,thus permitting selfish behaviour and preferential transmission of the t-haplotype. in addition,the previously reported association of nme family members with rho signaling in somatic cell motility and metastasis,in conjunction with our data involving rho signaling in sperm motility,suggests a functional conservation between mechanisms for motility control in somatic cells and spermatozoa. © 2012 bauer et al.