Males and Females Found Different in Unexpected Ways

LOS ANGELES, July 7 - Throughout the genome, males and females express the same genes differently.

Researchers here reported that in mice the specific sex determines how genes will operate in a host of organ systems - a finding that may help explain well-established differences in how men and women respond to medical treatment.

"Males and females share the same genetic code, but our findings imply that gender regulates how quickly the body can convert DNA to proteins," said Xia Yang, Ph.D., a post-doctoral fellow at UCLA. "This suggests that gender influences how disease develops."

Aspirin, for instance, is more effective at preventing heart attack in men than in women, said Jake Lusis, Ph.D., a professor of human genetics at UCLA, but the underlying cause of the difference is not well understood.

However, in a large-scale study in mice, Drs. Yang and Lusis and colleagues found that the genes governing drug metabolism in the liver are expressed differently by the sexes.

If the pattern is the same in humans, "our findings in the liver may explain why men and women respond differently to the same drug," Dr. Lusis said in a statement. "One gender may metabolize the drug faster, leaving too little of the medication in the system to produce an effect."

In the liver, adipose tissue, and muscle of mice, "thousands of genes showed sexual dimorphism," the researchers reported today in the online issue of the journal Genome Research. In the brains of the animals, however, there were fewer differences - only a comparative handful of genes differed by sex.

"We saw striking and measurable differences in more than half of the genes' expression patterns between males and females," said co-investigator Thomas Drake, M.D., a UCLA professor of pathology. "We didn't expect that. No one has previously demonstrated this genetic gender gap at such high levels."

The researchers crossed two common, but not closely related, strains of laboratory mice and then examined gene expression using microarray technology. They found high numbers of genes showing at least one-fold difference in activity (significant at P<0.01) between males and females:

• In the liver, 72% of 12,845 active genes had a least a one-fold difference in activity.
• In adipose tissue, 68% of 16,664 genes showed a one-fold activity difference.
• In muscle, 54% of 7,367 genes were differentially active.
• In the brain, 13.6% of 4,508 active genes showed sexual dimorphism.

Moreover, the researchers found there was little overlap between tissues: only 1.5% of 1,768 genes shared by all four tissue types were consistently overactive in the same direction - biased toward either male or female in all tissues. "Sexually dimorphic genes are highly tissue-specific," they noted.

The differences in activity were mostly modest, the researchers noted, but some genes had more than a three-fold difference in activity between males and females.

"Many of the genes we identified relate to processes that influence common diseases," Dr. Yang said. "This is crucial, because once we understand the gender gap in these disease mechanisms, we can create new strategies for designing and testing new sex-specific drugs."