Published online 15 June 2011 | Nature 474, 262-263 (2011) | doi:10.1038/474262a

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Mouse library set to be knockout

Global effort to disable every mouse gene nears completion.

Mutant mice generated from embryonic stem-cell lines should further understanding of human disease.Mutant mice generated from embryonic stem-cell lines should further understanding of human disease.WELLCOME LIBRARY, LONDON

Investigators are on the home stretch of the largest international biological research initiative since the Human Genome Project. Launched in 2006 in North America and Europe, the effort aims to disable each of the 20,000-odd genes in the mouse genome and make the resulting cell lines available to the scientific community.

After five years and more than US$100 million, the pace is picking up. "In the next three years or so we assume we will have it completed," says Wolfgang Wurst, director of the Institute of Developmental Genetics at the Helmholtz Centre Munich in Germany and one of the leaders of the effort's European contribution.

"This resource will be of enormous benefit, not just to the mouse genetic community but to every scientist, every company looking at mammalian physiology, and of course everyone who wants to design better drugs and better health care," says Steve Brown, director of the Mammalian Genetics Unit at MRC Harwell, UK. "It is one of the most significant biological resources in the past century of science, and I don't think I'm overstating the case here."

Previously, researchers typically spent years engineering mice to lack specific genes so that they could model human diseases involving those genes. This process was slow, laborious and piecemeal. And even after all that effort, there was often no easy way to share the animals with other researchers. So the International Knockout Mouse Consortium (IKMC) set out to create a library of mouse embryonic stem-cell lines representing every possible gene knockout, and then to distribute the cells to researchers for further study.

A new technology — pioneered by Bill Skarnes and Allan Bradley at the Wellcome Trust Sanger Institute in Hinxton, UK, and described today in Nature (W. C. Skarnes et al. Nature 474, 337–342; 2011) — helped make that possible. Using a high-throughput gene-targeting pipeline that allowed them to precisely engineer hundreds of genes every month, the Sanger team, in collaboration with colleagues in Germany and the United States, has so far inactivated more than 9,000 genes in mouse embryonic stem cells. It is on track to knock out 7,500 more in the next few years. "We're really hitting our peak production now," Skarnes says.

“It is one of the most significant biological resources in the past century of science.”


Each bespoke knockout in the Sanger group's library contains an added 'conditional allele'. This allows scientists to disrupt gene function in a living mouse at any body site and at any point in the animal's development by the timely addition of enzymes that recognize the inserted allele. By this means, the effects of the missing gene do not kill the mouse before the researchers have a chance to study it.

"It is truly a feat of genius," says Geoff Hicks, a geneticist at the University of Manitoba in Winnipeg who leads the Canadian contribution to the IKMC. "This paper really pushed the technology in an extremely innovative way and met a challenge that seemed unattainable."

Various groups in the international effort are using other, non-conditional techniques to inactivate thousands more genes. Researchers in Texas, Canada and Germany have mutated close to 12,000 genes using an untargeted approach called gene trapping, and Regeneron Pharmaceuticals, a company based in Tarrytown, New York, has specifically targeted around 3,500 genes using a technology that works well in smaller genes but results in mice that are less flexible for research than conditional knockouts. "The approaches are complementary," says Aris Economides, Regeneron's senior director of genome engineering technologies. "This is going to play out well for the end user."

To date, nearly 17,000 different genes have been knocked out, leaving only around 3,000 more to go. The Sanger team, however, hopes to replace most of the genes hit by gene trapping with conditionally targeted knockouts, because targeting allows individual genes to be manipulated with greater precision.

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Already, mutant mice have been generated from almost 1,000 of the embryonic stem-cell lines obtained, and the IKMC repositories in the United States, Canada and Europe receive hundreds of new orders every month. The next challenge is to study the function of each missing gene. To this end, the US National Institutes of Health last year committed $110 million over the next five years to characterize around 2,500 of the IKMC's mutant mice through the International Mouse Phenotyping Consortium, with plans for another $110 million to define 5,000 more if the first phase is successful.

"Knocking out the mice is simple relative to the huge task of finding out what all those genes do," says Richard Finnell, a geneticist at the Texas A&M Health Science Center in Houston. 

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  • #61917

    I think people are upset because its mammals and not dirty bacteria, c.elegans and drosophila. I mean who cares about fruit flies with eyes on their ass amirite?

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