Cell survival depends on chromosome integrity

UCLA researchers report that thousands of genes behave differently in the same organs of males and females - something never detected to this degree.

Published in the August issue of Genome Research, the study sheds light on why the same disease often strikes males and females differently, and why the genders may respond differently to the same drug.

"We previously had no good understanding of why the sexes vary in their relationship to different diseases," explained Xia Yang, Ph.D., first author and postdoctoral fellow in cardiology at the David Geffen School of Medicine at UCLA. "Our study discovered a genetic disparity that may explain why males and females diverge in terms of disease risk, rate and severity."

"This research holds important implications for understanding disorders such as diabetes, heart disease and obesity, and identifies targets for the development of gender-specific therapies," said Jake Lusis, Ph.D., co-investigator and UCLA professor of human genetics.

The UCLA team examined brain, liver, fat and muscle tissue from mice with the goal of finding genetic clues related to mental illnesses, diabetes, obesity and atherosclerosis. Humans and mice share 99 percent of their genes.

The scientists focused on gene expression -- the process by which a gene's DNA sequence is converted into cellular proteins. With the help of Rosetta Informatics, the team scrutinized more than 23,000 genes to measure their expression level in male and female tissue.

What they found surprised them. While each gene functioned the same in both sexes, the scientists found a direct correlation between gender and the amount of gene expressed.

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

UCLA is the first to uncover a gender difference in gene expression in fat and muscle tissue. Earlier studies have identified roughly 1,000 sex-biased genes in the liver, and other research has found a combined total of 60 gender-influenced genes in the brain - about one-tenth of what the UCLA team discovered in these organs.

Even in the same organ, the researchers identified scores of genes that varied in expression levels between the sexes. Gender consistently influenced the expression levels of thousands of genes in the liver, fat and muscle tissue. This effect was slightly more limited in the brain, where hundreds, not thousands, of genes showed different expression patterns.

"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 Yang. "This suggests that gender influences how disease develops."

The gender differences in gene expression also varied by tissue. Affected genes were typically those most involved in the organ's function, suggesting that gender influences important genes with specialized roles, not the rank-and-file.

In the liver, for example, the expression of genes involved in drug metabolism differed by sex. The findings imply that male and female livers function the same, but work at different rates.

"Our findings in the liver may explain why men and women respond differently to the same drug," noted Lusis. "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 produce an effect."

"At the genetic level, the only difference between the genders is the sex chromosomes," said Drake. "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."

The UCLA findings support the importance of gender-specific clinical trials. Most medication dosages for women have been based on clinical trials primarily conducted on men.

"This research represents a significant step forward in deepening our understanding of gender-based differences in medicine," said Dr. Janet Pregler, director of the Iris Cantor-UCLA Women's Health Center. The center's executive advisory board, a group of businesswomen interested in advancing women's health, helped fund the study.

"Many of the genes we identified relate to processes that influence common diseases," said Yang. "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."

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