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BackgroundMale-factor infertility is a common condition, and etiology is unknown for a high proportion of cases. Abnormal epigenetic programming of the germline is proposed as a possible mechanism compromising spermatogenesis of some men currently diagnosed with idiopathic infertility. During germ cell maturation and gametogenesis, cells of the germ line undergo extensive epigenetic reprogramming. This process involves widespread erasure of somatic-like patterns of DNA methylation followed by establishment of sex-specific patterns by de novo DNA methylation. Incomplete reprogramming of the male germ line could, in theory, result in both altered sperm DNA methylation and compromised spermatogenesis.Methodology/principal findingWe determined concentration, motility and morphology of sperm in semen samples collected by male members of couples attending an infertility clinic. Using MethyLight and Illumina assays we measured methylation of DNA isolated from purified sperm from the same samples. Methylation at numerous sequences was elevated in DNA from poor quality sperm.ConclusionsThis is the first report of a broad epigenetic defect associated with abnormal semen parameters. Our results suggest that the underlying mechanism for these epigenetic changes may be improper erasure of DNA methylation during epigenetic reprogramming of the male germ line.

For decades, classical crossover studies and linkage disequilibrium (LD) analysis of genomic regions suggested that human meiotic crossovers may not be randomly distributed along chromosomes but are focused instead in “hot spots.” Recent sperm typing studies provided data at very high resolution and accuracy that defined the physical limits of a number of hot spots. The data were also used to test whether patterns of LD can predict hot spot locations. These sperm typing studies focused on several small regions of the genome already known or suspected of containing a hot spot based on the presence of LD breakdown or previous experimental evidence of hot spot activity. Comparable data on target regions not specifically chosen using these two criteria is lacking but is needed to make an unbiased test of whether LD data alone can accurately predict active hot spots. We used sperm typing to estimate recombination in 17 almost contiguous ~5 kb intervals spanning 103 kb of human Chromosome 21. We found two intervals that contained new hot spots. The comparison of our data with recombination rates predicted by statistical analyses of LD showed that, overall, the two datasets corresponded well, except for one predicted hot spot that showed little crossing over. This study doubles the experimental data on recombination in men at the highest resolution and accuracy and supports the emerging genome-wide picture that recombination is localized in small regions separated by cold areas. Detailed study of one of the new hot spots revealed a sperm donor with a decrease in recombination intensity at the canonical recombination site but an increase in crossover activity nearby. This unique finding suggests that the position and intensity of hot spots may evolve by means of a concerted mechanism that maintains the overall recombination intensity in the region., Synopsis Meiotic crossover events are not randomly distributed across the human genome, but are concentrated in many small regions of a few kb with high recombination rates compared to surrounding regions. How the distribution of recombination events affects the association of different alleles along the chromosome (linkage disequilibrium, or LD) was recently addressed using sperm typing in regions already known or suspected to contain unusually high recombination intensities. In the current paper, the authors used sperm typing to examine recombination in a region not known or suspected of containing recombination hot spots. They first established the crossover distribution pattern within a 103-kb region of human Chromosome 21. Then, they compared their data to predictions of crossover distributions estimated by statistical analyses of polymorphism in the region. They found a good concordance between the two, although it was not perfect. To the authors' knowledge, this work is the first to compare LD-based estimates of recombination to sperm-typing data from regions not previously known or suspected of containing recombination hot spots. In addition, one of the studied hot spots revealed an example of a decrease in recombination intensity with a concurrent increase at a nearby site. This unique observation suggests that the activity of hot spots may evolve in a concerted fashion such that the overall recombination activity of the region is maintained.