In either case, these evidences together support the entire chromosome segment identified here as a key region affecting BI-D1870 growth and fertility traits in cattle. The locus detected on chromosome 6 is located 124 kb downstream of PDE5A. The phosphodiesterase encoded by PDE5A is substantially expressed in the testis, and mice overexposed to inhibitors of this protein present testicular tissue alterations, including decreased testis weight, degeneration, and atrophy of the seminiferous epithelium. This genomic region also shelters genes that interact with other proteins previously linked to small testis size. For instance, the protein encoded by MAD2 belongs to the mitotic checkpoint complex, and is recruited by the mitotic kinase Bub1. A residue change in the catalytic loop of Bub1 was shown to lead to male subfertility, with marked reduction in testicular size. Several QTLs mapping to the loci detected here were related either to body size or reproductive traits that are associated with SC. In particular, the peak on chromosome 4 mapped against one previously reported QTL for SC, which encompasses SP4. This gene encodes for a zinc finger transcription factor that is predominantly expressed in the brain, but is also detectable in the testicular tissue. Go¨llner et al. showed that SP4- knockout mice develop until birth without obvious abnormalities, but two-thirds of them die within 4 weeks after birth and the remaining one-third present growth retardation. Surviving male mice exhibit reduced testis size, although complete spermatogenesis can be observed. Surviving female mice exhibit small-sized thymus, spleen and uterus, and all mice show pronounced delay in sexual maturation. As SP4-knockout mice present growth retardation mainly after birth, it is likely that variations in the bovine SP4 affect body size and testicular growth from birth to yearling age, but they are unlikely to affect fetal development or spermatogenesis. Moreover, the evidence of delayed sexual maturation and reduced testicular size in surviving SP4-knockout mice is consistent with the known positive correlation between SC and precocity in cattle. The functional candidate gene surrounding the peak on chromosome 18 was CES4A, a hydrolase member of the carboxylesterase large family, also known as CES6, CES8 or Hydrolase A. Carboxylesterases act in the transesterification of a broad spectrum of substrates, and play an important role in the metabolism of endogenous lipid and foreign compounds such as drugs and pesticides. Hydrolase A is known to be expressed in several tissues, including the testis. Esterase activity has been found to be abundant in the testis and associated with androgen production. Two intronic SNPs in the human CES4A were found to be correlated with high density lipoprotein levels in an association analysis deposited in the dbGaP database, conducted in an expanded population sample from the original 1966 Northern Finland Birth Cohort study.