Variations in methylation linked to age in the human sperm epigenome

A higher risk of reproductive and child health issues is linked to advanced paternal age. Increasing evidence points to age-related alterations in the sperm epigenome as one underlying cause.

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In a new study, researchers Laura Bernhardt, Marcus Dittrich, Andreas Prell, Ramya Potabattula, Charis Drummer, Rüdiger Behr, Thomas Hahn, Martin Schorsch, Tobias Müller, and Thomas Haaf from Julius Maximilians University, Partner Site Göttingen, and Fertility Center Wiesbaden recently used reduced representation bisulfite sequencing (RRBS) on 73 sperm samples from male patients at a fertility clinic in Germany.

The researchers stated, “We identified >1,000 candidate genes with genome-wide significant age-related methylation changes in sperm. We identified 1,162 (74%) regions which were significantly (FDR-adjusted) hypomethylated and 403 regions (26%) being hypermethylated with age.”

There were no connections between paternal BMI, semen quality, or ART efficacy. The bulk of age-related differentially methylated regions (ageDMRs) (1,152 of 1,565; 74%), including 1,002 genes with symbols, were found inside genic regions.

Compared to hypermethylated DMRs, half of which are found in gene-distal areas, ageDMRs with hypomethylation were found closer to transcription start sites.

A total of 2,355 genes have been found to have substantial sperm ageDMRs in this and conceptually similar genome-wide research, with the majority of them (90%) appearing in just one study.

The 241 genes that have been duplicated at least once displayed notable functional enrichments in 10 cellular components linked to synapses and neurons and also in 41 biological processes related to the development and the nervous system.

This lends credence to the idea that behavior and neurodevelopment are influenced by the methylome of the father’s sperm. The discovery that sperm ageDMRs were not randomly distributed across the human genome was fascinating to the researchers; chromosome 19 revealed a highly significant twofold enrichment with sperm ageDMRs.

The orthologous marmoset chromosome 22 did not seem to demonstrate an enhanced regulatory potential by age-related DNA methylation alterations, despite the high gene density and CpG content being preserved.

The study authors concluded, “Collectively, our data support the conclusion that age-induced methylation changes in the sperm epigenome contribute to the increased offspring disease susceptibility for neurodevelopmental disorders.”