BioWorld International Correspondent

LONDON - An unexpected number of genes vary in their level of expression between different individuals, a study has shown.

While many genes produce proteins at similar rates and amounts in all individuals, others vary significantly - and undoubtedly will provide new clues to the genetic causes of disease.

In the future, similar studies using the same type of technology will be able to tell researchers more about the causes of cancer, the workings of the immune system and the body's response to hormones and drugs.

William Cookson, professor of respiratory genetics at Imperial College London, told BioWorld International: "We have looked at the expression of all human genes, and we now know, for about one-third of genes, how much their expression varies between individuals. Our study shows that there is much more variation in the level of expression of genes than we previously imagined."

To the surprise of Cookson and his colleagues, levels of expression varied greatly in genes that are involved in DNA repair and replication. "It is likely that these genes are relevant to susceptibility to cancer," Cookson said. "The study also identified new mechanisms for how the immune system works, which is also unexpected."

A report on the work appears in the Sept. 16, 2007, issue of Nature Genetics in a paper titled, "A genome-wide association study of global gene expression."

Cookson and his group used DNA microarrays to measure the level of gene expression in white blood cells, for more than 25,000 human genes.

"This method allowed us to measure the expression level of every single one of these genes, and for each of these levels, we did a genome-wide association study," Cookson said. "As a result, we are able to say which genes differ the most between people in their level of expression."

The study involved samples from 400 children in families in which at least one person has asthma.

The results also identified the polymorphisms in the genome that modify gene expression to give rise to the different levels of protein production, and showed that the variations can be inherited from generation to generation.

Researchers studying polygenic diseases can now access the database created by Cookson's group to find out if genes they are interested in are among those that vary between individuals. Cookson and his colleagues already have used the database in that way to identify a new gene for asthma, called ORMDL3. (See BioWorld International, July 18, 2007.)

Their paper in Nature Genetics cited an additional example of genes that are associated with Crohn's disease, diabetes and resistance to thalassemia.

Ultimately, Cookson added, scientists will be able to apply the technology used for this study on other cells, and on cells that are being subjected to different stimuli. For example, other types of immune system cells could be investigated, including their response to inflammatory stimuli. Examination of the differences in gene expression in cells from the intestinal epithelium might shed light on gastrointestinal disorders. Researchers could study differential gene expression in cells exposed to various drugs, hormones or other signaling molecules.

In a paper published in the same issue of Nature Genetics, researchers from the Wellcome Trust Sanger Institute in Cambridgeshire describe how they surveyed gene expression by measuring messenger RNA levels of approximately 48,000 transcripts in cell lines from 270 individuals drawn from four populations.

All the individuals previously had been genotyped for the International HapMap project, which aimed to identify and catalogue genetic similarities and differences in human beings from four populations with African, Asian and European ancestry.

In that publication, titled "Population genomics of human gene expression," the researchers looked for genetic variants that were associated with differences in gene expression levels.

Barbara Stranger, first author of the paper and a postdoctoral fellow at the Sanger Institute, told BioWorld International, "We found that there is abundant heritable genetic variation contributing to gene expression variation both among individuals of a population and among populations."

Ultimately, Stranger added, genes in pathways known to influence the risk or progress of a disease might be candidates for drug development.

"It is known that there are differences among individuals and populations with respect to drug metabolism, and there are known drug-metabolizing genes," she said. "Identifying the regions influencing regulation of these genes and studying their genomic characteristics will likely contribute to understanding how to optimize drug treatment."