Everyone in biomedical research is familiar with "knockout" mice, animals that have had a particular gene silenced during their development. This can be a powerful way of figuring out what that gene's product actually does, although there are always other factors at work. The biggest one is how other proteins and pathways can sometimes compensate for the loss, a process often doesn't have a chance to kick in when you come right into an adult animal and block a pathway through other means. In some other cases, a gene knockout turns out to be embryonic-lethal, but can be tolerated in an adult animal, once some key development pathway has run its course.
There have been a lot of knockout mice over the years. Targeted genetic studies have described functions for thousands of mouse genes. But when you think about it, there have surely been many of these whose phenotypes have not really been noticed or studied in the right amount of detail. Effects can be subtle, and there's an awful lot to look for. That's the motivation behind the Sanger Institute Mouse Genetics Project, who have a new paper out here. They're part of the even larger International Mouse Phenotyping Consortium, which is co-ordinating efforts like this across several sites.
Update: here's an overview of the work being done. For generating knockout animals, you have the International Knockout Mouse Consortium at an international level - the IKMC, mentioned above, is the phenotyping arm of the effort. In the US, the NIH-funded Knockout Mouse Project (KOMP) is a major effort, and in Europe you have the European Conditional Mouse Mutagenesis Program (EUCOMM), which has evolved into EUCOMMTOOLS. Then in Canada you have NorCOMM, and TIGM at Texas A&M.
I like the way that last link's abstract starts: "Nearly 10 years after the completion of the human genome project, and the report of a complete sequence of the mouse genome, it is salutary to reflect that we remain remarkably ignorant of the function of most genes in the mammalian genome." That's absolutely right, and these mouse efforts are an attempt to address that directly. The latest paper describes the viability of 489 mutants, and a more complete analysis of 250 of them - still only a tiny fraction of what's out there, but enough to give you a look behind the curtain.
29% of the mutants were lethal and 13% were subviable, producing only a fraction of the expected number of embryos. That's pretty much in line with earlier estimates, so that figure will probably hold up. As for fertility, a bit over 5% of the homozygous crosses were infertile - and in almost all cases, the trouble was in the males. (All the heterozygotes could produce offspring).
The full phenotypic analysis on the first 250 mutants is quite interesting (and can be found at the Sanger Mouse Portal site.. Most of these are genes with some known function, but 34 of them have not had anything assigned to them until now. These animals were assessed through blood chemistry, gene expression profiling, dietary and infectious disease challenges, behavioral tests, necropsy and histopathology, etc. Among the most common changes were body weight and fat/lean ratios (mostly on the underweight side), but there were many others. (That body weight observation is, in most cases, almost certainly not a primary effect. Reproductive and musculoskeletal defects were the most common categories that were likely to be front-line problems).
What stands out is that the unassigned genes seemed to produce noticeable phenotypic changes at the same rate as the known ones, and that even the studied genes turned up effects that hadn't been realized. As the paper says, these results "reveal our collective inability to predict phenotypes based on sequence or expression pattern alone." About 35% of the mutants (of all kinds) showed no detectable phenotypic changes, so these are either nonessential genes or had phenotypes that escaped the screens. The team looked at heterozygotes in cases where the homozygotes were lethal or nearly so (90 lines so far), and haploinsufficiency (problems due to only one working copy of a gene) was a common effect, seen in over 40% of those mutants.
Genes with some closely related paralog were found to be less likely to be essential, but those producing a protein known to be part of a protein complex were more likely to be so. Both of those results make sense. But a big question is how well these results will translate to understanding of human disease, and that's still an open issue. Clearly, many things will be directly applicable, but some care will be needed:
The data set reported here includes 59 orthologs of known human disease genes. We compared our data with human disease features described in OMIM. Approximately half (27) of these mutants exhibited phenotypes that were broadly consistent with the human phenotype. However, many additional phenotypes were detected in the mouse mutants suggesting additional features that might also occur in patients that have hitherto not been reported. Interestingly, a large proportion of genes underlying recessive disorders in humans are homozygous lethal in mice (17 of 37 genes), possibly because the human mutations are not as disruptive as the mouse alleles.
As this work goes on, we're going to learn a lot about mammalian genetics that has been hidden. The search for similar effects in humans will be going on simultaneously, informed by the mouse results. Doing all this is going to keep a lot of people busy for a long time - but understanding what comes out is going to be an even longer-term occupation. Something to look forward to!