Of mice and men

The sequence of the mouse genome was published in 2002. When compared with the human genome it was found that the two genomes were of similar size and almost every gene in the human genome has a counterpart in the mouse. As a result, researchers have been able to develop thousands of mouse strains with mutations that mirror those seen in human genetic disease.

History of mice in science

Almost every gene in the human genome has a counterpart in the mouse.

During the 1700s, collecting and breeding ‘fancy’ mice with different coloured coats became a popular hobby in Japan. The trend then began to find its way to Europe during the 1800s where it increased in popularity, particularly in Victorian England.

Gregor Mendel started his investigations into inheritance by breeding different coloured mice.

In the mid-19th-century,the Austrian monk-turned-scientist Gregor Mendel started his investigations into inheritance by breeding different coloured mice in his living quarters. It was only when Mendel’s bishop banned the mice that Mendel had to resort to working with pea plants to inform his theory of inheritance.

Over time, the mouse has become the preferred organism for research into mammalian genetics because of its rapid generation time, small size and the ease with which it can be bred.

In 1902, French biologist Lucien Cuénot was the first to demonstrate Mendel’s theories of inheritance by highlighting the genetics of coat colour characteristics in mice. In Harvard, William Castle began his research in the same year, buying mice from a local mouse enthusiast. Together with his student Clarence Little, Castle produced a series of important papers on the genetics of coat colour in mice.

Inbreeding allows scientists to stabilise the genome and fix certain traits through different generations.

Clarence Little, whose father had bred dogs, is probably best known for his development of the inbred ‘lab’ mouse, which he produced by mating generation after generation of mouse siblings. The benefit of inbreeding is that it allows scientists to stabilise the genome and fix certain traits through different generations. The result is lots of mice with almost identical genomes. It took Clarence four years between 1909 and 1913 to create a healthy, genetically stable inbred strain. But once it was finished, Clarence was able to choose one characteristic, for example a brown coat, and produce an endless supply of animals with that trait. He could then use these mice to investigate which genes were responsible for that charact.

Clarence Little observed that many mouse tumours acted in the same way as human ones.

During his work, Clarence also carried out investigations into cancer and observed that many mouse tumours acted in the same way as human ones. At that time there was a lot of debate as to whether cancer was infectious, inherited or whether it developed in another way. Clarence Little’s work creating an inbred population of mice paved the way to answering these questions once and for all.

Now, there are over 100 different inbred strains of mice, each with a different genetic background.

Transgenic mice

Transgenic mice are mice that contain additional, artificially introduced genetic material in every cell.

In the early 1980s ‘transgenic mice’ became a valuable tool in research. Transgenic mice are mice that contain additional, artificially introduced genetic material in every cell. This additional genetic material either results in a gain or loss of function of a certain gene. For example, this may mean the mouse starts to produce a new protein. This allows scientists to investigate what specific genes do in the body.

A transgenic mouse is usually created in one of two ways. In one method the foreign DNA is introduced directly via a fine needle into mouse eggs that have been isolated just after fertilisation. The eggs are then implanted into a foster mother and allowed to develop to term. Usually around 20 per cent of the resulting offspring will then have the injected DNA inserted into their genome. Those that have the inserted DNA will then be used to establish a line of transgenic offspring.

Transgenic mice are extremely useful for scientists studying gene function.

A second method involves introducing the transgenic DNA into embryonic stem cells (ES cells) derived from a mouse embryo at the very early stages of development. These early stem cells have the potential to become any cell type when introduced into another embryo. The embryonic stem cells need a host embryo in which to develop and this is isolated usually from a mouse with different colour fur. The resulting mouse is called a ‘chimera’, it is a mixture of cells from two different coloured mice. Embryonic stems cells often contribute to the germ line, resulting in the production of some sperm carrying the extra DNA. When the sperm then fertilises a normal egg, a transgenic mouse is produced with the same foreign DNA in every cell. The transgenic DNA is then carried across to future generations.

Transgenic mice are extremely useful for scientists studying gene function or regulation and human diseases, such as Alzheimer’s disease.

Knockout mice

Knockout mice are the result of the inactivation of a specific gene.

Knockout mice are the result of the inactivation of a specific gene. The resulting change in the appearance, behaviour or biochemical characteristics of the mouse then gives an indication of the gene’s normal role in the mouse, and perhaps in humans.

Knockout mice are produced by a technique called ‘gene targeting’. This involves ‘knocking out’ a gene sequence from the mouse genome and inserting an artificial gene sequence that has been generated in the lab.

As with transgenic mice, gene targeting is carried out in mouse embryonic stem cells (ES cells) derived from a very early (usually male) mouse embryo. By manipulating the cells at this early stage of development, scientists aim to get the modified ES cells to contribute to the germ line, and give rise to sperm. This way the sperm can then carry the mutation and fertilise a normal egg to carry on the knocked-out genome on to the next generation.

More than 4,000 genes have been ‘knocked-out’ using this method to help scientists investigate exactly what each gene’s role is in the body.

Sequencing the mouse genome

Before the sequenced genome was available, looking for a gene or a mutation was like looking for a needle in a haystack.

When sequencing of the mouse genome was completed in 2002, a powerful scientific tool was made available. Before the sequenced genome was available, looking for a gene or a mutation was like looking for a needle in a haystack. Now, with a huge database of information available online, all that is needed are a few clicks for researchers to be able to look up specific genes and their location on the mouse chromosomes. From this they can then choose one or two areas that look the most promising to search for a mutation. Consequently geneticists are able to make much better use of their time in the lab.

Being able to go back and forth between the mouse and human genomes so easily has also made it much simpler and quicker to target related human genes that could be candidates for drug development. Now, discoveries that would once have taken years can now be done in a matter of months.

Researchers have developed an array of mouse models to help scientists understand a whole collection of human diseases. This has been made possible by the ability to create transgenic and knockout mouse models which give scientists the means to observe the function of individual genes. The genetic similarities between mice and men means that the knowledge derived from experiments with these mice can provide invaluable insights into human biology.