Why Maturing Sperm Cells Activate so Many of Their Genes

Maturing sperm cells turn on most of their genes, not to follow their genetic instructions like normal, but instead to repair DNA before passing it to the next generation, according to a paper published in Cell today by NYU Grossman School of Medicine researchers.

"It now seems obvious that sperm activate so many more genes as they develop because doing so runs them through a DNA repair process, and protects the integrity of messages about to be inherited," says senior author Itai Yanai.

"We also found that such repair in sperm is less active in genes that are activated, or transcribed, less often," adds Yanai. "This supports the theory that evolution is using transcription frequency as a lever, dialing it up to preserve the DNA code in some genes, but turning it down to enable changes elsewhere when it contributes to survival."

An example of genes not activated, not repaired, and free to accumulate changes in sperm were those related to immunity, which must continually evolve if the body is to recognize and attack ever-changing bacterial and viral invaders.

To conduct the new study, the authors analyzed gene expression patterns during sperm maturation at single-cell resolution. They first collected samples of human testes tissue. Using microfluidics, they then passed all cells in the samples down a tube just large enough for them to flow through in single file. Within the tube each cell was pushed into its own water droplet, which acted like a mini-test tube in which enzymes opened the cells and then attached cell-specific barcodes to each transcribed snippet of genetic material. The labeled transcripts were then used to create maps of which genes were turned on at each point during sperm maturation. The team then cross-referenced these findings with known DNA variations in human population databases to estimate how often repair occurred in a given gene.

Surprisingly, researchers found that genes activated even a few times during sperm cell development contained 15-20 percent fewer DNA code errors than unexpressed genes, with the difference attributed to transcription-coupled repair (TCR).

Cellular processes, including transcription, along with toxins in the environment, continually introduce errors into DNA chains, with TCR weeding out some of the altered code. The difference, the researchers say, is that sperm cells appear to apply TCR to more genes than is normal, but then to halt gene expression by mechanisms unknown before proteins are made.

Moving forward, the research team will seek to confirm whether sperm-derived genetic changes occur more often in genes not expressed during the maturation of sperm. This may reveal insights into the causes of many genetic diseases linked to changes in the sperm of aging fathers.