Mitochondria are inherited maternally in most metazoans, but in bivalves with Doubly Uniparental Inheritance (DUI) a mitochondrial lineage is transmitted through eggs (F-type), and another through sperm (M-type). In DUI species, a sex-ratio distortion of the progeny was observed: some females produce a female-biased offspring (female-biased family), others a male-biased progeny (male-biased family), and others a 50:50 sex-ratio. A peculiar segregation pattern of M-type mitochondria in DUI organisms appears to be correlated with the sex bias of these families. According to a proposed model for the inheritance of M-type mitochondria in DUI, the transmission of sperm mitochondria is controlled by three nuclear genes, named W, X, and Z. An additional S gene with different dosage effect would be involved in sex determination. In this study, we analyzed structure and localization of three transcripts (psa, birc, and anubl1) with specific sex and family biases in the Manila clam Ruditapes philippinarum. In situ hybridization confirmed the localization of these transcripts in gametogenic cells. In other animals, homologs of these genes are involved in reproduction and ubiquitination. We hypothesized that these genes may have a role in sex determination and could also be responsible for the maintenance/degradation of spermatozoon mitochondria during embryo development of the DUI species R. philippinarum, so that we propose them as candidate factors of the W/X/Z/S system. J. Exp. Zool. (Mol. Dev. Evol.) 320B: 442–454, 2013. © 2013 Wiley Periodicals, Inc.