19 May 2008
ByAppeared in BioNews 458
Many of the genes required for human life are not needed by mice, according to an intriguing study published in the Proceedings of the National Academy of Sciences, USA (PNAS). Mice are used extensively in the study of human disease, as they share 85 per cent of their genome with us. In a study of existing data on mouse and human genomes, Ben-Yang Liao and Jianzhi Zhang of the University Michigan first identified genes known to be essential to humans that had a direct mouse counterpart. To their surprise, many of these genes could be removed or 'knocked out' from mice, without them dying or being unable to reproduce.
'Everyone assumes that deletion of the same gene in the mouse and in humans produces the same effect. That's the basis of using the mouse to study human disease',' said Zhang. 'Our results show that may not always be the case'.'
The absence of essential genes leads to death or infertility, and it was assumed that mice and humans would need the same, or very similar, essential genes. Liao and Zhang identified 120 essential human genes with a direct mouse counterpart. However, when they looked at a database of 'knockout' mouse experiments they found that 22 per cent of the mouse versions of human essential genes were dispensable for mouse survival. 'I expected there would be some, but I never expected the percentage to be so high', said Zhang.
When the researchers looked more closely at the functions of the genes needed by humans but not mice, they found a fascinating link to the cell's 'waste disposal' system. Many of the essential human genes were instructions for making proteins found in the vacuole, which receives the waste products from a cell's metabolic processes. Without a functioning vacuole, waste products accumulate and can cause fatal neurological damage. Although mice also produce metabolic waste, the researchers calculated that they do so at a rate 18 times slower than humans. Mice can therefore survive to reproductive age without the genes for vacuole proteins essential to humans.
'Waste management is much more important in humans than in the mouse for maintaining proper cellular functions until the time of reproduction,' Zhang said. 'And when a biological process becomes more important to a species, the genes involved in that process tend to become essential.'
The study calls into question the relevance of mouse 'models' of some diseases, particularly neurological conditions linked to the vacuole. Although mice can still provide useful information, according to Zhang, primate studies may be necessary for some diseases. Zhang and Liao's work raises fundamental questions about the practice of drawing parallels between genomes of different species, as they demonstrate that very similar genes may have very different relevance to the function of the cell.