The Epigenetics Revolution

^{Figure 8.2 Two children may each have the same deletion on chromosome 15, shown schematically by the absence of the horizontally striped box. The phenotype of the two children will be different, depending on how they inherited the abnormal chromosome. If the abnormal chromosome was inherited from their father, the child will develop Prader-Willi syndrome. If the abnormal chromosome was inherited from their mother, the child will develop Angelman syndrome, which is a very different disorder from Prader-Willi.}

This is a clear case of epigenetic inheritance of a disorder. Children with PWS and AS had exactly the same problem genetically – they were missing a specific region of chromosome 15. The only difference was how they inherited the abnormal chromosome. This is another example of a parent-of-origin effect.

There’s another way in which patients can inherit PWS or AS. Some patients with these disorders have two totally normal copies of chromosome 15. There are no deletions, and no other mutations of any type, and yet the children develop the conditions. To understand how this can be, it’s helpful to think back to the mice who inherited both copies of chromosome 11 from one parent. Some of the same researchers who unravelled the story of the PWS deletion showed that in certain examples of this condition, the children have two normal copies of chromosome 15. The trouble is, they’ve inherited both from their mother, and none from their father. This is known as uniparental disomy – one parent contributing two chromosomes[74]. In 1991, a team from the Institute of Child Health in London showed that some cases of AS were caused by the opposite form of uniparental disomy to PWS. The children had two normal copies of chromosome 15, but had inherited both from their father[75].

This reinforced the notion that PWS and AS are each examples of epigenetic diseases. The children with uniparental disomy of chromosome 15 had inherited exactly the right amount of DNA, they just hadn’t inherited it from each parent. Their cells contained all the correct genes, in all the correct amounts, and yet still they suffered from these severe disorders.

It’s important that we inherit this fairly small region of chromosome 15 in the right way because this region is normally imprinted. There are genes in this region that are only expressed from either the maternal or the paternal chromosome. One of these genes is called UBE3A. This gene is important for normal functioning in the brain, but it’s only expressed from the maternally inherited gene in this tissue. But what if a child doesn’t inherit a copy of UBE3A from its mother? This could happen if both copies of UBE3A came from the father, because of uniparental disomy of chromosome 15. Alternatively, the child might inherit a copy of chromosome 15 from its mother which lacked the UBE3A gene, because part of the chromosome had been lost. In these cases, the child can’t express UBE3A protein in its brain, and this leads to the development of the symptoms of Angelman syndrome.

Conversely, there are genes that are normally only expressed from the paternal version of this stretch of chromosome 15. This includes a gene called SNORD116, but others may also be important. The same scenario applies as for UBE3A, but replace the word maternal with paternal. If a child doesn’t inherit this region of chromosome 15 from its father, it develops Prader-Willi syndrome.

There are other examples of imprinting disorders in humans. The most famous is called Beckwith-Wiedemann syndrome, again named after the people who first described it in the medical literature[76][77]. This disorder is characterised by over-growth of tissues, so that the babies are born with over-developed muscles including the tongue, and a range of other symptoms[78]. This condition has a slightly different mechanism to the ones described above. When imprinting goes wrong in Beckwith-Wiedemann syndrome, both the maternal and paternal copies of a gene on chromosome 11 get switched on, when normally only the paternally-derived version should be expressed. The key gene seems to be IGF2, which codes for the growth factor protein that we met earlier, on mouse chromosome 7. By expressing two copies of this gene, rather than just one, twice as much IGF2 protein as normal is produced and the foetus grows too much.