Quiet mice wear the genes for the study of human disease

IN the People’s Republic of China, 2003 is the year of the sheep. However, for the community of geneticists around the world investigating thousands of human genetic disorders, 2003 is most definitively the year of Mus musculus — the common mouse.
At the end of 2002, the Mouse Genome Sequencing Consortium, an international collaboration of scientists, published a high-quality draft sequence and analysis of a common laboratory mouse strain known as C57BL/6J.

The consortium consisted of three major sequencing centres: the Wellcome Trust Sanger Institute in Britain; the Whitehead Centre for Genome Research in Cambridge, Massachusetts, US; and the Washington University Genome Sequencing Centre, US. The fruits of their labours appeared in the December 5th 2002 issue of the journal Nature.
For those involved in clinical ophthalmology, the achievement of this significant milestone will have enormous implications for the study of many common eye disorders.
Most critically however, the raw data will stimulate the development of novel and inventive therapies for the treatment of many currently untreatable eye conditions.
Remarkably, a taste for cheese is not the only trait mice and humans share. In fact, from a genetic perspective, mice and humans have a lot in common.
Although a mouse has about 2.5 billion base pairs of DNA – half a billion less than a human – a mouse does have about 30,000 or so genes, similar to the number of genes found in humans.

Over 99% of the genes in mice have direct counterparts in humans. That makes mice a critical research tool and biomedical model for the study of human disease.
The humble mouse has a long and distinguished history in the service of medical research dating back to the early 1900s when Harvard biologist, Clarence Cook, began developing in-bred mouse strains.
Dr Cook quickly saw the potential of these small rodents for studying the mechanics of human diseases such as cancer. It was the mouse strain C57BL, bred in Dr Cooks’ laboratory nearly a century ago, that has now had its complete genetic sequence described late in 2002.

The first transgenic mouse was introduced in 1982. It was "engineered" to carry a rat growth hormone gene demonstrating the principle of genetic manipulation in rodents.
This was shortly followed in the late 1980s by revolutionary technology whereby genes could be "knocked out" in lab mice and the effects of missing genes closely analysed.
Finally, in 1998, following on from the cloning of Dolly the sheep, a research team in Hawaii produced the first cloned mice.

Although the publication of the human genome met with far greater media attention, it is the publication of the mouse genome, with far less press column inches, that is of greater significance to genetic researchers around the globe.
The mouse is an ideal animal model for medical studies due its rapid reproduction cycle, its similarity to human physiology, its ease of genetic manipulation and its cost.
Now armed with the complete sequence of DNA that makes up the mouse, researchers have a unique opportunity to pose and answer a vast number of experimental questions previously undreamt of.

So what does this mean for ophthalmology? Firstly, the acquisition of the mouse DNA sequence will permit a far more detailed study of ocular disorders by finding the genes responsible for certain conditions far more rapidly.
Before the sequence was available, it could take many years to find a mutation that caused a particular disease. Now with a full complement of mouse DNA, database searching can provide an instant list of candidate genes and their full sequence.

This will swiftly allow the physical characteristics of a disorder to be immediately linked to the underlying genetic cause. Knowledge of the underlying genetic cause is, of course, a critical step to devising a practical solution.
Secondly, knowledge of the mouse sequence relevant to ocular biology – through a broad array of modern genetic techniques – will permit researchers to probe the precise biochemistry of vision physiology in the context of both health and disease.

Thirdly, the mouse sequence will allow researchers to make a direct comparison between the mechanics of mouse and human vision, thus enabling researchers to focus on the evolutionary pathways of both mammals.
And finally, the mouse genome will contribute to the design and execution of novel therapeutic approaches to regulating the expression profile of genes known to cause ocular disorders. Testing such therapies in mice is a significant milestone in accelerating new therapies to the market place.

The mouse is only the second mammalian genome to be fully sequenced; the sequencing of the third, the lab rat, is expected later this year, following a recent announcement from the director of the genome centre at Baylor College of Medicine in Houston, Texas, US.

The availability of the human, mouse and rat genomes will provide a treasure trove of genetic data that will stimulate an increased understanding of the molecular biology of disease and health.
Although these developments represent milestones, there is much work to be done before such a wealth of data can be translated into real therapies for the treatment of human medical disorders, including a wide range of ocular diseases.

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