Deletions of the DAZ gene family in distal Yq11 are always associated with deletions of the azoospermia factor c (AZFc) region, which we now estimate extends to 4.94 Mb. Because more Y gene families are located in this chromosomal region, and are expressed like the DAZ gene family only in the male germ line, the testicular pathology associated with complete AZFc deletions cannot predict the functional contribution of the DAZ gene family to human spermatogenesis. We therefore established a DAZ gene copy specific deletion analysis based on the DAZ-BAC sequences in GenBank. It includes the deletion analysis of eight DAZ-DNA PCR markers [six DAZ-single nucleotide varients (SNVs) and two DAZ-sequence tag sites (STS)] selected from the 5' to the 3'end of each DAZ gene and a deletion analysis of the gene copy specific EcoRV and TaqI restriction fragments identified in the internal repetitive DAZ gene regions (DYS1 locus). With these diagnostic tools, 63 DNA samples from men with idiopathic oligozoospermia and 107 DNA samples from men with proven fertility were analysed for the presence of the complete DAZ gene locus, encompassing the four DAZ gene copies. In five oligozoospermic patients, we found a DAZ-SNV/STS and DYS1/EcoRV and TaqI fragment deletion pattern indicative for deletion of the DAZ1 and DAZ2 gene copies; one of these deletions could be identified as a 'de-novo' deletion because it was absent in the DAZ locus of the patient's father. The same DAZ deletions were not found in any of the 107 fertile control samples. We therefore conclude that the deletion of the DAZ1/DAZ2 gene doublet in five out of our 63 oligozoospermic patients (8%) is responsible for the patients' reduced sperm numbers. It is most likely caused by intrachromosomal recombination events between two long repetitive sequence blocks (AZFc-Rep1) flanking the DAZ gene structures.

Key Points Mutational trajectories are defined by complex patterns of molecular heterogeneity in MDS, including lower-risk cases. Therapeutic intervention dynamically reshapes mutational patterns often resulting in branched or independent evolution of MDS clones.

Early life stress (ELS) is associated with increased vulnerability for diseases in later life, including psychiatric disorders. Animal models and human studies suggest that this effect is mediated by epigenetic mechanisms. In humans, epigenetic studies to investigate the influence of ELS on psychiatric phenotypes are limited by the inaccessibility of living brain tissue. Due to the tissue-specific nature of epigenetic signatures, it is impossible to determine whether ELS induced epigenetic changes in accessible peripheral cells, for example, blood lymphocytes, reflect epigenetic changes in the brain. To overcome these limitations, we applied a cross-species approach involving: (i) the analysis of CD34+ cells from human cord blood; (ii) the examination of blood-derived CD3+ T cells of newborn and adolescent nonhuman primates (Macaca mulatta); and (iii) the investigation of the prefrontal cortex of adult rats. Several regions in MORC1 (MORC family CW-type zinc finger 1; previously known as: microrchidia (mouse) homolog) were differentially methylated in response to ELS in CD34+ cells and CD3+ T cells derived from the blood of human and monkey neonates, as well as in CD3+ T cells derived from the blood of adolescent monkeys and in the prefrontal cortex of adult rats. MORC1 is thus the first identified epigenetic marker of ELS to be present in blood cell progenitors at birth and in the brain in adulthood. Interestingly, a gene-set-based analysis of data from a genome-wide association study of major depressive disorder (MDD) revealed an association of MORC1 with MDD.