## Gene imprinting switches off an allele from one of the parents

People inherit two copies of each gene - one from their mother and one from their father. In accordance with the common Mendelian notion of genetics, both inherited copies are expressed and contribute to the phenotype. However, there are also cases of genes that are active only when inherited from the father and others that are active only when inherited from the mother. How is this possible if there is no difference in the DNA sequence?

To explain this phenomenon, we can use as an example a cross between a horse and a donkey. If a male horse is crossed with a female donkey, an individual called a mule is created. If a male donkey is crossed with a female mare (horse), a mule is also produced. Interestingly, the offspring in both cases looks more like the mother - the mule looks more like a donkey if the mother is a donkey while the mule from a mare looks more like a horse. This is a striking morphological, anatomical and etiological difference. Such a crossbreed is sterile, i.e., it cannot have offspring, which is due to the fact that a donkey has 31 pairs of chromosomes (2n=62), while a horse has 32 (2n=64). As a result, the crossbreed (the mule) will therefore have 63 pairs of chromosomes, and with this odd number of chromosomes, it is not possible to properly divide into sex cells. Similar examples illustrating that the direction of crossing matters can be found in nature, e.g. a liger is a cross between a lion and a tigress, a tigon is a cross between a tiger and a lioness (Figure 6.3).

What is gene imprinting in humans? One gene (either from the mother or from the father) is not expressed because it is silenced and is called imprinted. The second gene, which is not silenced, is thus expressed (Figure 6.4). Imprinting occurs through the action of DNA methylation along with the modification of histones by removing acetyl groups, which changes the structure of chromatin. Germ cells are characterized as having only one set of chromosomes, and form a diploid zygote after fusion with a gamete of the opposite type. During the formation of gametes, the information about which allele originally came from the mother and which from the father is removed, and they undergo modification depending on whether the given DNA is currently in the egg or in the sperm. Therefore, in the case of an imprinted allele of paternal origin, the offspring always inherits only the allele on which the genes subject to imprinting are silenced (Figure 6.4).

Interestingly, genes that undergo imprinting are clustered in groups located on the short arm of chromosome 11 and on the long arm of chromosome 15. As for the function of imprinted genes, they play an important role during embryonic development, in the regulation of cell division, but they also influence the formation of behaviour. Possible errors in these genes can cause human diseases, and the same mutation can cause two different diseases with different manifestations, depending on which parent the mutation comes from. In the case of a deletion on the 15th chromosome, if such an allele is inherited from the father, a disease called Prader-Willi syndrome occurs. The syndrome is characterized by insatiable hunger caused by damage to the hypothalamus, leading to obesity. It is also accompanied by short stature, atrophied muscles, weak crying and mental retardation. Typical facial features for this disease are almond-shaped eyes, a narrow upper lip and a high forehead. Other problems are also related to obesity, e.g. type II diabetes and cardiovascular diseases. If the fault is on the allele inherited from the mother, the child will develop Angelman syndrome, characterised by fits of unexplained laughter and jerky movements. This syndrome is also called the Angel syndrome precisely because of the impression of happiness that the patient creates by smiling and laughing. Patients suffer from microcephaly, severe mental retardation, have very limited ability to speak and epileptic seizures. People with this condition also have typical facial features (wide mouth, protruding tongue, widely spaced teeth) and a small head that is flattened at the back. It is not yet known what causes the frequent laughter, but it is known that this manifestation is related to changes in the structures of the brain, as most of the brain centres responsible for laughter are located in the left hemisphere.