July 9, 2006
 
Genetic Behaviors Go Beyond X and Y Chromosomes
 
By Lee Bowman
Scripps Howard News Service
 
Genetic differences between men and women hardly end at the X and Y chromosomes.
 
A new study by researchers at UCLA has determined that thousands of human genes behave differently in the corresponding organs of males and females -- even in fat and muscle tissue.
 
The findings help explain why the same disease often affects men and women differently, and why the effects of some drugs may vary drastically between the sexes.
 
"This research holds important implications for understanding disorders such as diabetes, heart disease and obesity, and identifies targets for gender-specific therapies," said Jake Lusis, a professor of human genetics at UCLA and a co-author of the report, published in the August issue of the journal Genome Research.
 
The researchers examined brain, liver, fat and muscle tissue from mice with the goal of finding genetic clues related to mental illness, diabetes, obesity and heart disease in humans. Humans and mice share 99 percent of their genes.
 
The scientists looked at gene expression -- the process by which a gene's DNA sequence is converted into proteins that carry out various functions inside cells. Working with the scientific data management firm Rosetta Inpharmatrics, the team scrutinized more than 23,000 genes to measure their expression levels in male and female tissue.
 
While each gene basically functioned the same in both sexes, the scientists found a direct correlation between gender and the volume and pace by which proteins were expressed.
 
"We saw striking and measurable differences in more than half of the genes' expression patterns between males and females," said Dr. Thomas Drake, a professor of pathology at UCLA and a co-investigator. "We didn't expect that. No one has previously demonstrated this genetic gender gap at such high levels."
 
"At the genetic level, the only difference between men and women is the sex chromosomes," Drake said. "Out of the more than 30,000 genes that make up the human genome, the X and Y chromosomes account for less than 2 percent of the body's genes.
 
"But when we looked at the gene expression in these four tissues, more than half of the genes differed significantly between the sexes. The differences were not related to reproductive systems; they were visible across the board and related to primary functions of a wide variety of organs."
 
Earlier studies had identified about 1,000 sex-influenced genes in the liver and about 60 gender-biased genes in the brain, but that was only about 1/10 of the number that the UCLA team found in those organs.
 
Gender consistently influenced the expression of thousands of genes in liver, fat and muscle tissues, but the effect was actually more limited in the brain, where hundreds, rather than thousands, of genes showed different expression patterns between the sexes.
 
"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, first author of the study and a postdoctoral fellow in cardiology at the David Geffen School of Medicine at UCLA.
 
Affected genes were typically those most involved in the organ's function, suggesting that gender mainly influences important genes with specialized roles.
 
"Many of the genes we identified relate to processes that influence common diseases," 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."
 
In the liver, for instance, gene expression involved in drug metabolism differed by sex. This implies that while male and female livers function the same, they may work at different rates.
 
"Our findings in the liver may explain why men and women respond differently to the same drug," Lusis said. "Studies show that aspirin is more effective at preventing heart attack in men than women. One gender may metabolize the drug faster, leaving too little of the medication in the system to have an effect."
 
The authors also point out that their findings underscore the need for gender-specific clinical trials of drugs. Most medication dosages for women are based on trials done mostly on men.
 
On the Net: http://www.genome.org
 
www.ucla.edu
 
Contact Lee Bowman at BowmanL@SHNS.com. Distributed by Scripps Howard News Service, http://www.shns.com