First, cross two strains of laboratory mice, and take heart, brain and liver tissue samples from 31 progeny. Then use microarrays to determine how the unique genetic background of each mouse influences messenger RNA levels from a checklist of hundreds of genes in each tissue.

Result: clear evidence that we have a long way to go before we really understand the molecular mechanisms that make us individuals.

At the 2007 Lorne Genome conference, molecular geneticist Professor Peter Little, formerly from the University of NSW and now at the National University of Singapore, will present the surprising results of his correlation-based analysis of gene expression in C57Black/DBA recombinant mice.

Little's team went looking for coordinated changes in expression patterns among 755 genes that are responsive to genetic variation. Coordinated change would imply shared control mechanisms: for example, by the same transcription complexes, through shared regulatory elements in the genes' promoters.

"We imagined that all the mice derived from the C57-DBA cross were genetically different, so we should see variation in their mRNA levels," Little says. "Given that genes are controlled by molecular machines that may contain tens to hundreds of components, we would expect that any genetic variation in this control machinery would affect not just one gene, but all genes under the control of that complex. So we looked for correlated variation across the 31 individual mice, and we found it."

Little and his colleagues identified coordinated gene sets by constructing graphs showing every possible pair-wise combination of all 755 genes. Extracting significant correlations was statistically challenging, but Little describes the resulting colour-coded graphs as "strikingly beautiful".

They confirmed the correlations were not an artifact of chance recombination in any individual mouse by showing they were co-regulated in all 31 mice. But they were amazed to find that while the sets were co-regulated, the direction of co-regulation differed, not just between the individual mice, but between the three tissue types in each mouse.

"We simply asked the question: how do groups of genes behave? We weren't asking if the genes are expressed at the same level in each mouse, but whether they all head in the same direction coherently, irrespective of the amount of mRNA expression."

What the team found was that they behave paradoxically. "The same group of genes might be up-regulated in the brain of one mouse, for example, but down-regulated in the kidney or liver. Even though each mouse has the same genetic background, the influence of these genetic variations on coordinated groups of genes is essentially unpredictable." Little says the end result shows that this class of genetic variation is unpredictable across the tissues of the same mouse. The second conclusion is that the same group of genes might be up-regulated in the brain of one mouse, and down-regulated in the brain of another.

"So this class of genetic variation is also unpredictable between individuals - although statistically, we may be able to make guesses about the direction of change."