DNA repair activity linked to paternal age effect
Scientists have long known that a woman’s age at the time she conceives can affect her offspring’s genetic make-up. Women age 35 and older are at greater risk of delivering a child with a genetic disorder, such as Down syndrome, due to an incorrect number of chromosomes. Less well known is that a man’s age can affect his offspring as well. In what is called the paternal age effect, men 38 years and older have a greater probability than younger men of fathering a child with some kind of genetic defect because of new mutations in the father’s reproductive cells.
The reason, says Dr. Christi Walter, Department of Cellular and Structural Biology, is that as males age, the DNA in their reproductive cells has an increased mutation frequency. DNA is generally susceptible to spontaneous changes in its molecular structure. Yet, as living organisms have evolved they have developed DNA repair pathways that counteract the damage.
Dr. Walter and her colleagues have found that mutation frequency in young male mice is lower in the testes than in other tissues. The investigators have used a transgenic mouse model in which they can trace the effect of mutagens during spermatogenesis (the development of sperm).
"Before we had transgenic models," Dr. Walter said, "results would have to be inferred from the offspring of the study mice. This method is much faster and allows us to directly assess the germ cells, not just the resulting offspring." More active DNA repair in the testes than in other areas of the body could contribute substantially to the lower mutation frequency found in the testes of young mice.
In a paper published two years ago in the Proceedings of the National Academy of Sciences, Dr. Walter and her co-authors reported a decrease in mutation frequency in male germ cells at a particular stage of spermatogenesis. The decrease in mutation frequency corresponds to a peak in cell death, leading Dr. Walter and her colleagues to suggest that a stage-specific checkpoint allows only healthy cells to develop into sperm. Such findings could apply to human males as well, resulting in sustained genetic integrity and few birth defects or malformations. In old mice, the mutation frequency in germ cells increases.
Dr. Walter’s co-authors were Dr. Gabriel W. Intano, Department of Cellular and Structural Biology; Dr. John R. McCarrey, Southwest Foundation for Biomedical Research; Dr. C. Alex McMahan, UTHSC Department of Pathology; and Dr. Ronald B. Walter, Southwest Texas State University. The investigators found that a repair activity is greatest in the testes of young mice compared to other tissues; however, this activity diminishes in old mice. This suggests that DNA repair plays a role in maintaining the low mutation frequency in young animals.
"DNA repair is an interesting mechanism," Dr. Walter said. "Some mutations are necessary and good from an evolutionary perspective, but some cause disease, such as birth defects or cancer. There is a delicate balance between the two. DNA repair has evolved for a good reason, but at least some DNA repair activities become less efficient with age. In terms of human health, it could be a good thing to restore that functioning to a younger level."
Dr. Walter and her team have a second paper, scheduled for publication in the fall, that will detail the results of studies examining the role of a DNA repair pathway in aging. "So far we have looked at one DNA repair pathway and are beginning to look at others," Dr. Walter said.
Dr. Walter began her career in developmental biology. Her interest in genetics grew, she said, "at being in awe of the fact that so many of us turn out normal, when so much has to happen at just the right time. That led me to an interest in how we maintain our DNA."
In addition to her position as associate professor, Dr. Walter is the director of the Health Science Center’s transgenic mice laboratory. Part of the Department of Cellular and Structural Biology and jointly funded by UTHSC, the San Antonio Cancer Institute and the Nathan Shock Aging Center, the facility is a service for all researchers who use transgenic animals.