Effects of quantitative trait loci determining testicular weight in DDD/Sgn inbred mice are strongly influenced by circulating testosterone levels

OBJECTIVE: Testicular growth and development are strongly influenced by androgen. Although both testis weight and plasma testosterone level are inherited traits, the interrelationship between them is not fully established. Males of DDD/Sgn (DDD) mice are known to have extremely heavy testes and very high plasma testosterone level among inbred mouse strains. We dissected the genetic basis of testis weight and analyzed the potential influence of plasma testosterone level in DDD mice. METHODS: Quantitative trait loci (QTL) mapping of testis weight was performed with or without considering the influence of plasma testosterone level in reciprocal F(2) intercross populations between DDD and C57BL/6J (B6) mice, thereby assessing the influence of testosterone on the effect of testis weight QTL. Candidate genes for testis weight QTL were investigated by next-generation sequencing analysis. RESULTS: Four significant QTL were identified on chromosomes 1, 8, 14, and 17. The DDD-derived allele was associated with increased testis weight. The F(2) mice were then divided into two groups according to the plasma testosterone level (F(2) mice with relatively “low” and “high” testosterone levels), and QTL scans were again performed. Although QTL on chromosome 1 was shared in both F(2) mice, QTL on chromosomes 8 and 17 were identified specifically in F(2) mice with relatively high testosterone levels. By whole-exome sequencing analysis, we identified one DDD-specific missense mutation Pro29Ser in alpha tubulin acetyltransferase 1 (Atat1). CONCLUSION: Most of the testis weight QTL expressed stronger phenotypic effect when they were placed on circumstance with high testosterone level. High testosterone influenced the QTL by enhancing the effect of DDD-derived allele and diminishing the effects of B6-derived allele. Since Pro29Ser was not identified in other inbred mouse strains, and since Pro29 in Atat1 has been strongly conserved among mammalian species, Atat1 is a plausible candidate for testis weight QTL on chromosome 17.