International collaboration to coordinate discovery of human gene functions

Laboratory mouse in which a gene affecting hair growth has been knocked out, left, next to a normal lab mouse. Image Maggie Bartlett/NHGRI

The collaboration, on the scale of its predecessor the Human Genome Project, will involve producing 15,000 mouse lines, each with one gene knocked out or inactivated.

Although sequencing the human genome was an important achievement, its immediate contribution to human health was vastly oversold.

But there was solace in one of the more sobering facts to emerge from the work: that humans are 99 per cent mouse – or at least that there are that many genes in common between the human and the mouse genome. This underlined the power that knockout mice could have for elucidating the function of genes in normal physiology and development, and for creating precise animal models of human disease.

The Canadian and European parts of the project were announced last October, but the whole programme came together earlier this month with the launch of the US arm, the Knockout Mouse Project. In total the work will cost €56.6 million over the next five years, with the EU putting in €13 million and the US €39.2 million.

Duplication

The three arms will coordinate their efforts to avoid the duplication of effort that has dogged the field to date. Around 4,000 of the 20,000 mouse genes have been knocked out and published to date. But only around 740 knockouts are freely available to scientists. This means scientists spend time and money generating knock outs that already exist elsewhere, and the NIH estimates that a single mouse gene is knocked out on average 2.5 times.

“International scientific collaboration is in the interests of us all,” said European Science and Research Commissioner Janez Potočnik, welcoming the launch of the joint programme. “Pooling knowledge will increase our chance to make discoveries that can benefit human health. There is so much we still don’t know about the effect of genes on the development of our major diseases.”

The project will use two different techniques, gene trapping and gene targeting, to produce the knockouts. Embryonic stem cells harvested from mouse embryos are manipulated to remove or inactivate a gene and injected back into other mouse embryos, which are then implanted in adult females. Because embryonic stem cells are able to differentiate into any type of adult cell, the gene deletion should occur in any tissue of the resulting offspring. The mice are then crossbred conventionally to produce mice in which both copies of the gene are deleted.

Freely accessible

The embryonic stem cells with genes knocked out can be stored for up to ten years. They will be made freely available to researchers, enabling knockout mice to be generated in any laboratory in a standardised and cost-effective manner.

The aim of the international collaboration is not only to carry out the work in a systematic manner to avoid duplication, but also to concentrate the work in a few centres to maximise efficiency. In Europe much of the work will be carried out at the Wellcome Trust Sanger Institute in Cambridge and the Institute of Developmental Genetics at the National Centre for Environment and Health in Munich.

The Sanger Institute is also the recipient of a large chunk of NIH funding, as part of a collaboration with the Children’s Hospital Oakland Research Institute in Oakland, California and the School of Veterinary Medicine at the University of California, Davis. The three will be responsible jointly for producing 5,000 knockouts.

To date the Sanger has produced around 3,000 knockouts. “Through this funding [from NIH], we will be able to accelerate the contribution we can make to help researchers worldwide make advances against disease,” said Allan Bradley, the institute’s director.

The balance of the NIH grants of $18.4 million went to Regeneron Pharmaceuticals Inc., of Tarrytown, New York. The company will be responsible for generating 3,500 knockouts, using its Velocigene platform technology.

Coordination

The NIH awarded a further $2.5 million to the Jackson Laboratory in Bar Harbor, Maine, to set up a data coordination centre. This will track the scheduling and progress of knockout production, serve as a central resource for all publicly available knockouts and will integrate other databases containing mouse genome information.

In the run-up to the launch of the international project the NIH and the UK’s Wellcome Trust have bought rights to knockouts created by private companies, and made moves to ensure that mouse knock out lines in public institutions can be accessed freely.     

A steering committee composed of the scientists leading these three research projects and representatives from the funding agencies will coordinate the effort to ensure complementarity and to avoid overlaps. Other funding agencies and scientific projects involved in similar mouse mutagenesis programmes in other countries are being invited to join in.