## Genetically identical mice can differ from each other

One of the favourite mammalian models for studying the influence of the external environment on the genome are mice, specifically their Agouti gene, which determines coat coloration. In this model, coat coloration correlates with epigenetic marks established early in development, and therefore allows investigation of the influence of nutritional and environmental factors on the foetal epigenome. The Agouti gene is transcribed only in a certain phase of mouse development and even then only in certain tissues, which is why such mice have dark fur. However, Duke University scientists led by Professor R. Jirtl obtained mice in which the Agouti gene was transcribed continuously, resulting in yellow mice which had a tendency towards obesity and a predisposition to cancer and diabetes (Figure 6.8). Using such mice, they then monitored the effect of adding food supplements to the mothers' diet.

If Agouti mice were fed normal food, obese yellow males mated with obese yellow females and produced obese yellow offspring. However, if obese yellow females were fed food fortified with nutritional supplements containing vitamin B12, folic acid and choline two weeks before mating and during pregnancy, after mating with obese yellow males, they gave birth to slender brown pups. These offspring were not predisposed to cancer or diabetes and were agile and alert until old age. A big surprise was the discovery that the lean mice had the same genes (no new mutations appeared) as their obese parents. It turned out that the added nutritional supplements were sources of methyl groups that were used to methylate DNA around the Agouti gene. By making a small change in the diet, it was possible to turn off the Agouti gene without changing the sequence of nucleotides in the DNA.

Another interesting finding was that not only diet, but also maternal care can cause epigenetic changes that affect the development of the organism for life. Moreover, these changes do not only concern physical characteristics, such as coat colour and height, but also psychological characteristics. As follows from another series of experiments, rats that received sufficient maternal care in their youth grew up to be calm and courageous individuals. Rats that were not cared for by their mothers after birth became very shy later in life. Epigenetic changes in the brain were confirmed in these rats. Thanks to the chemical substance trichostatin A, which inhibits enzymes that remove acetyl groups from histones, scientists even managed to increase stress resistance in shy rats. On the contrary, L-methionine, which serves as a source of methyl groups, succeeded in inducing timidity in courageous rats. The results of these experiments show that epigenetic markers can be changed even in old age.