Dad's Genes May Play Greater Role Than Thought

MONDAY June 15, 2009 -- Biologists say they have discovered a clever packaging scheme that allows the genetic material in sperm to have far more influence over development of a fertilized egg than had been imagined.

The discovery has potential applications in helping infertile men, said Brad Cairns, a professor of oncological sciences at the University of Utah and a leader of the team reporting the finding in the June 14 online edition of Nature.

The vast majority of the DNA molecules that carry genetic information are tightly packaged in sperm cells, Cairns said. That tight packaging enables a win in what is literally a race for life because the first sperm to reach an egg fertilizes it, and the tightest packages are the most streamlined.

"But when it comes to development, the sperm is at a real disadvantage," Cairns said. "The vast majority of their genes are tightly packed in material that is not helpful in giving them full expression."

In every cell other than sperm, DNA molecules are wrapped around structures called histones, an arrangement that allows for easy transmission of their genetic instructions. But only 4 percent of sperm DNA is arranged around histones. The other 96 percent is in a dense, impenetrable material called protamine.

"The hypothesis has been that this 4 percent of DNA in histones is randomly distributed," Cairns said. "We challenged the hypothesis and found that the DNA that is in histones is not randomly distributed but is located at important genes for embryonic development."

The discovery was made by using DNA from sperm at the University of Utah's in vitro fertilization clinic. "We isolated the DNA attached to histones and sequenced it," Cairns said. "We found genes that are important in guiding the development of the embryo."

The discovery raises "obvious questions" about the importance of DNA packaging in sperm on human fertility, he said.

"Do infertile men have problems in packaging, and is that the basis of their problem?" Cairns asked. "We already have preliminary evidence that the majority of infertile men have problems in gene packaging. There is an incorrect ratio of histones to protamine."

Cairns said that the gene packaging issue is related to another biological aspect of DNA expression -- DNA methylation. Some subunits of the DNA molecules ordinarily have molecules called methyl groups attached to them. Lack of methylation can also contribute to infertility, he said.

The Utah group is working on a test that could define the root issues in men with fertility problems, Cairns said. "We are working toward a clinical diagnostic test for infertile men that would assess their packaging and DNA methylation status so that we could counsel them on whether they can have success in achieving fertility," he said.

The concept of possible intervention to improve fertility is much more distant, he said.

From the basic science point of view, one major lesson of the discovery is that DNA is not the only molecule that can carry genetic information from generation to generation, said William G. Kelly, an associate professor of biology at Emory University, whose review article will appear in the same issue of the journal.

What the study shows "is that the histones still sitting there have really important information that actually guides the genes that regulate early events in the development of the next generation," Kelly said.

That idea has been proposed, but "it was not clear that this information could survive the packaging in sperm," he said.

"This firmly shows that information that's there can be information that is passed across generations and that is not encoded in DNA," Kelly said.

More information

The Yale Fertility Center has more on the causes and treatment of infertility.

Posted: June 2009


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