The RGSP ran two simultaneous tracks. They created a BAC library, without the depth for a fully accurate sequence. And they used this "BAC skim" as bait to fish for the corresponding fragments from the WGS. The combined sequence information allowed the assembly of eBACs, extended BACs, that married the superior speed and cheapness of WGS to the greater assembled accuracy of BACs. The debate between WGS and BAC methods is far from over, and other combined strategies are still being worked on. But the RGSP has shown the way. What of the biology?

The paper title’s cautious claim is that the rat genome "yields insights into mammalian evolution." Indeed it does, which there is barely space to summarize, let alone explore. The mouse genome had already shown that large chunks of sequence are similar between mouse and human. A gene’s immediate neighbors are likely to be the same in both species, although larger stretches of DNA have shifted and shuffled across the chromosomes. Adding the rat sequence to the comparison confirms the overall sequence similarity, or synteny, and showed that most of the differences between human and mouse happened in the rodent line after it had split from the human line.

Looking in detail at the shared genes among the three species revealed some surprises. The rat showed evidence of recent duplications in several gene families. These duplications are important because they allow genes to evolve in different directions, giving natural selection additional raw material to work on. When it comes to smell, for example, rat and mouse are obviously more dependent on their noses than are humans. That is reflected in the genes. Rodents have far more olfactory receptor genes than humans do. But surprisingly, rats have far more than mice. These additional genes seem to be the result of a recent burst of gene duplication in the ancestor of the rat after it had split from the mouse.

Another area where the rat seems to have evolved more rapidly than mouse and human is in detoxification. The cytochrome P450 gene family, which codes for enzymes that metabolize many toxic compounds, is considerably larger in the rat. One subfamily, for example, contains eight members in the rat, four in mice, and just one in humans. Given that rats so often substitute for humans in studies of pharmacology and toxicity, and that cytochrome P450 is such an important element of so many pharmacological pathways, this may give researchers pause for thought.

The use of rats in biomedical and physiological research is boosted by genome analysis. Of more than 1,100 genes associated with human diseases, almost 80% were predicted by a database program to have direct one-to-one corresponding rat genes. Careful human inspection of the remainder left only six human-disease genes that did not have a rat counterpart. This knowledge will speed the creation of better rat models to investigate human diseases.

The mutation rate of different disease genes showed that some kinds of disease are under different selection pressure. Mutations can be either silent, making no change to the protein for which the gene codes, or active, changing the protein. The ratio of active to silent mutations is a measure of the strength of selection to keep the genome stable. Neurological and malformation diseases were most alike between rat and human, while pulmonary, hematological, and immune-system diseases were most different. The suggestion is that immune-system genes evolved rapidly to cope with the pressure of rat-specific pathogens and therefore may be of less relevance to human immune system genes.