DNA array courtesy of Todd Carter, The Salk Institute, La Jolla, California, USA.

The idea that genotypic differences among inbred strains of mice might explain the variability of their phenotypes may sound like a tautology. The fact is, however, that some of the brain phenotypes found in early studies of genetically modified animals were difficult to interpret because of differences in the genetic background of non-isogenic littermates. Therefore, it has become important to identify the genes that account for the phenotypic variability among strains and the use of DNA arrays has become a powerful tool to address this issue. Now, as Sandberg et al. report in the 26 September issue of PNAS, the differences in gene expression may be subtler than we think.

The authors used DNA arrays with more than 10,000 genes and searched for differences between two inbred mouse strains — 129SvEv and C57BL/6 — in the whole brain and across several brain regions. They found that only about 0.33% of the genes screened showed differential brain expression between the two strains. Moreover, a search for genes differentially expressed in at least one brain region across the two strains increased the fraction to a mere 1%. It is noteworthy that the relatively low number of genes showing differential expression was not exclusive of the comparison between strains. Sandberg et al. used the same strategy to identify region-specific genes within the same strain and observed that only 0.54% of the genes screened showed clear differences.

Some of the genes identified in this screening correspond to previously known differences between strains or among regions, an observation that underscores the reliability of the approach. Some others could indeed help to explain a few of the differences in brain phenotypes documented between the two strains, such as their differential susceptibility to neurotoxic insult. A third group of genes consists of novel sequences whose function remains to be discovered, opening new avenues of research. Other genes could help to refine the results from quantitative trait loci analysis, in which large chromosomal regions are linked to specific phenotypes. Finally, the existence of region-specific genes should lead to the identification of the sequences that regulate their restricted expression, which could then be used to drive the region-specific expression of any transgene.

The differences in gene expression might be subtle but they provide some valuable signposts for future work.