LONDON – A full range of about 5,000 mutant mice, each with a single known gene inactivated, will be openly available to researchers within the next few years for further study of abnormal features that will shed light on numerous human diseases.

The mice are being generated by the International Mouse Phenotyping Consortium, an organization set up to explore the similarities at the genetic level between mice and humans, which have more than 95 percent of their genes in common.

A founding member of the International Mouse Phenotyping Consortium, the Sanger Institute Mouse Genetics Project, has just released detailed data on the first 250 of those mouse mutants – the first batch of data in the long haul to systematically catalogue the phenotypes that result when each and every gene in the mammalian genome is knocked out or knocked down.

The researchers are using mutants generated from an existing library of murine embryonic stem cells, each of which has one copy of a known gene inactivated. They are generating each mutant in turn, before running a battery of tests on each mutant line and cataloguing the results.

Data from the project are freely available on the Mouse Resource Portal on the website of the Wellcome Trust Sanger Institute. Researchers who want to explore the phenotypic features of particular mutants also will be able to obtain frozen embryos, so that they can carry out further studies in their own laboratories.

Karen Steel, professor of sensory function at the Wolfson Centre for Age-Related Diseases at King's College London, told BioWorld Today: "This large new resource of mouse mutants, each of which is a potential new mouse model of a human disease, is available to any scientist or clinician around the world, who wants to carry out further experiments. If we want to develop new treatments for diseases in humans, we need to understand the molecular mechanisms underlying those diseases. People will be able to make these associations between genes and disease features by studying these mutants."

Her own sphere of interest is hearing loss. "It is, for example, possible to identify all the mutants with a phenotype involving hearing impairment, and by following up on these we were able to find interesting new pathways that include completely unexpected genes involved in deafness," she said.

The contributors to the project have reported their initial results in the July 18, 2013, issue of Cell, in a paper, titled "Genome-wide Generation and Systematic Phenotyping of Knockout Mice Reveals New Roles for Many Genes."

Jacqui White, leader of the Mouse Genetics Phenotyping Team at the Wellcome Trust Sanger Institute in Hinxton, Cambridgeshire, and first author of the Cell paper, said: "Already 447 research teams in 25 different countries across the world are using our mouse lines and taking this research to new levels. Our hope is that other research teams will take our research forward to better understand disease and develop new and effective therapies against these diseases."

Steel said one of the main scientific findings from the study was that mutants lacking activity of genes that had never been studied in detail before were just as likely to show interesting phenotypes as mutants lacking well-known genes that had been studied in-depth. "This suggests that the less well-known genes are well worth looking at and will provide a rich resource with new information about which genes are involved in which disease processes," she said.

A strength of the study was that all the mutants were put through the same broad and consistent screening "pipeline," she said. "We didn't make any assumptions about what the function of each gene was. When we found a new phenotype in a mouse mutant, this sometimes suggested that we should go back and look again at the human disease, where we knew one was associated with that gene."

For example, it already was known that defects in the gene SMS can cause a rare condition in humans, called Snyder-Robinson syndrome, which is associated with certain mental and physical abnormalities. When the researchers studied the mutant mouse that lacked a functional copy of the SMS gene, they saw some phenotypic features that resembled those seen in the human disease. However, they also found that the male mutant mice were infertile.

"It may be that no one has asked if human males with Snyder-Robinson syndrome are infertile, or, if this has been noticed, it may not have been thought to be associated with the syndrome," Steel said. "But researchers can now look at this finding for SMS, together with another six genes that we discovered for the first time to be involved in fertility, and follow-up studies will lead us to new molecular pathways that are involved in infertility."

The team currently has made more than 900 mouse mutants. Phenotypic data are available for more than 500 mutants on the Wellcome Trust Sanger Institute website, with partial datasets available for another 200 mutants, and the project continues.