How the Mus musculus is furthering our understanding of human inherited diseases
In 1907 Cuenot mated two yellow mice giving an unexpected, unmendelian 2:1 offspring ratio.
5 years later Castle and Little repeated the experiment, determining that 1 in every fourth offspring had died during embryonic development.
Nearly a century ago, mice where already paving the way to crucial discoveries, such as that of lethal genes, imagine what they have taught us to this day.
The film set of a laboratory is never truly complete without several cages of our rodent acquaintances, the Mus musculus. However, it may come as a shock to know that these creatures are lifting the lid on a number of human inherited diseases such as Marfan’s Syndrome, which affects 1 in 4,000 people and Huntington’s disease affecting 1 in 15,000. The concept of man and mouse being essentially constructed by nearly identical genetic instructions seems ludicrous; nevertheless scientifically unravelling our genetic code has brought up numerous startling findings.
The human genome consists of approximately 20,000-25,000 genes, hereditary units of coded information determining specific characteristics displayed by living organisms and unnervingly more than 3,700 are known to have 100,000 germline mutations associated with human inherited diseases. Research is crucial to understand these diseases, though the use of human subjects springs up an endless list of complications, from timescale needed to gather results and observations to unethical risk to life. As a result, scientists use a whole host of creatures to further our understanding of human genetics from the roundworm Caenorhabditis elegans, to the humble fly, Drosophila melongaster. The questions ‘What exactly do I have in common with these creatures?’ and ‘Surely the research could never be directly applicable to humans?’ may come to mind and are more than fair to ask. The correct term for these creatures is model organisms; organisms such as the Mus musculus with their mammalian origin and 99% genes in common with human beings. In addition, the Haldane report has fully sequences the mouse genome, another advantage to having a much smaller genome than ours. On a practical level, mice are easy to care for, quick to breed and provide results within a feasible timescale. The key is that mice can be afflicted with the same diseases as humans; therefore duplicating a gene such as exon 3 on the cftr allele swiftly creates a mouse model for cystic fibrosis. Experimentation further allows us to understand the nature of the disease, as 40% of the mice died within 7 days due to intestinal obstruction.
The importance of maternal diet during pregnancy is relatively well acknowledged, however a study using mice coat colours, may have mothers-to-be everywhere thinking twice about what they consume. Mutation of the agouti gene by unmethylation led to mice with yellow coat colour, it was discovered that these mice where more likely to be obese as well as prone to diabetes and cancer. Mice with brown coats have methylated agouti genes and these where found to be of healthy weight and at a lower risk of disease. Pregnant yellow mice with a methyl-rich diet birthed brown coat colour mice, indicating that nutrition does genetically affect a foetus during pregnancy also highlighting that human disease such as obesity can be inherited as a result of maternal diet during pregnancy. In another study researchers drew a similar conclusion that nutrition influences gene expression during embryonic development, which was passed down through generations because of epigenetic inheritance; intracisternal A-particle (repeated transposable elements e.g. there are one thousand copied in the mouse genome) (IAP) reterotransposon was inserted in front of the agouti gene to produce patchy mouse coat colour down the female germ line but not the male germ line.
Most recently gene targeting in embryonic stem cells produces mice with alterations to specific endogenous genes, knock-out mice are providing great insight into human inherited disorders as individual genes can be targeted and more advanced techniques are being developed. With over 300 new inherited disease genes being found every year, and one hundred year’s on since their first (if accidental) use, the role of mus musculus in broadening our knowledge of human inherited disorders is unarguably spectacular. So next time a mouse scuttles into the kitchen, perhaps it would be more fitting for it to find a piece of cheese on a plate rather than a mouse trap.
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