Once again this is consistent with the idea that there are factors in the paternal chromosomes that push towards development of larger offspring. Factors in the maternal chromosomes either act in the ‘opposite direction’ or are broadly neutral.
As we explored in the last chapter, these factors are epigenetic, not genetic. In the example above, let’s assume that the parents came from the same inbred mouse strain, so were genetically identical. If you sequenced both copies of chromosome 11 in any of the three types of offspring, they would be exactly the same. They would contain the same millions of A, C, G and T base-pairs, in the same order. But the two copies of chromosome 11 do clearly behave differently at a functional level, as shown by the different sizes of the different types of mice. Therefore there must be epigenetic differences between the maternal and paternal copies of chromosome 11.
Because the two copies of the chromosome behave differently depending on their parent-of-origin, chromosome 11 is known as an imprinted chromosome. It has been imprinted with information about its origins. As our understanding of genetics has improved we’ve realised that only certain stretches of chromosome 11 are imprinted. There are large regions where it doesn’t matter at all which parent donated which chromosome, and the regions from the two parents are functionally equivalent. There are also entire chromosomes that are not imprinted.
So far, we’ve described imprinting in mainly phenomenological terms. Imprinted regions are stretches of the genome where we can detect parent-of-origin effects in offspring. But how do these regions carry this effect? In imprinted regions, certain genes are switched on or switched off, depending on how they were inherited. In the chromosome 11 example above, genes associated with placental growth are switched on and are very active in the copy of the chromosome inherited from the father. This carries risks of nutrient depletion for the mother who is carrying the foetus, and a compensatory mechanism has evolved. The copies of these same genes on the maternal chromosome tend to be switched off, and this limits the placental growth. Alternatively, there may be other genes that counterbalance the effects of the paternal genes, and these counter-balancing genes may be expressed mainly from the maternal chromosome.
Major strides have been made in understanding the molecular biology of these effects. For example, later researchers worked on a region on chromosome 7 in mice. There is a gene in this region called insulin-like growth factor 2 (Igf2). The Igf2 protein promotes embryonic growth, and is normally expressed only from the paternally-derived copy of chromosome 7. Experimenters introduced a mutation into this gene, which stopped the gene coding for a functional Igf2 protein. They studied the effects of the mutation on offspring. When the mutation was passed on from the mother, the young mice looked the same as any other mice. This is because the Igf2 gene is normally switched off on the maternal chromosome anyway, and so it didn’t matter that the maternal gene was mutated. But when the mutant Igf2 gene was passed down from father to offspring, the mice in the litter were much smaller than usual. This was because the one copy of the Igf2 gene that they ‘relied on’ for strong foetal growth had been switched off by the mutation[66].
There is a gene on mouse chromosome 17 called Igf2r. The protein encoded by this gene ‘mops up’ Igf2 protein and stops it acting as a growth promoter. The Igf2r gene is also imprinted. Because Igf2r protein has the ‘opposite’ effect to Igf2 in terms of foetal growth, it probably isn’t surprising to learn that the Igf2r gene is usually expressed from the maternal copy of chromosome 17[67].
Scientists have detected about 100 imprinted genes in mice, and about half this number in humans. It’s not clear if there are genuinely fewer imprinted genes in humans than in mice, or if it’s just more difficult to detect them experimentally. Imprinting evolved about 150 million years ago[68], and it really only occurs to a great extent in placental mammals. It isn’t found in those classes that can reproduce parthenogenetically.
Imprinting is a complicated system, and like all complex machinery, it can break down. We now know that there are disorders in humans that are caused by problems with the imprinting mechanism.
Prader-Willi syndrome (PWS) is named after two of the authors of the first description of the condition[69]. PWS affects about one in 20,000 live births. The babies have a low birth weight and their muscles are really floppy. In early infancy, it can be difficult to feed these babies and initially they fail to thrive. This is dramatically reversed by early childhood. The children are constantly hungry, so over-eat to an incredible degree and can become dangerously obese. Along with other characteristic features such as small feet and hands, delayed language development and infertility, the individuals with PWS are often mildly or moderately mentally retarded. They may also have behavioural disturbances, including inappropriate temper outbursts[70].
There’s another disorder in humans that affects about the same number of people as PWS. This is called Angelman syndrome (AS), and like PWS it is named after the person who first described the condition[71]. Children with AS suffer from severe mental retardation, small brain size and very little speech. Patients with AS will often laugh spontaneously for no obvious reason, which led to the spectacularly insensitive clinical description of these children as ‘happy puppets’[72].
In both PWS and AS, the parents of the affected children are normally perfectly healthy. Research suggested that the basic problem in each of these conditions was likely to be caused by an underlying defect in the chromosomes. Because the parents were unaffected, the defect probably arose during the production of the eggs or the sperm.
In the 1980s, researchers working on PWS used a variety of standard techniques to find the underlying cause of this condition. They looked for regions of the genome that were different between healthy children and those with the disorder. Scientists interested in AS were doing something similar. By the mid-1980s it was becoming clear that both groups were looking at the same part of the genome, a specific stretch on chromosome 15. In both PWS and AS, patients had lost a small, identical section of this chromosome.
But these two disorders are very unlike each other in their clinical presentation. Nobody would ever confuse a patient with PWS with one who was suffering from Angelman’s syndrome. How could the same genetic problem – the loss of a key region of chromosome 15 – result in such different symptoms?
In 1989 a group from The Children’s Hospital, Boston, showed that the important feature was not just the deletion, but how the deletion was inherited. It’s summarised in Figure 8.2. When the abnormal chromosome was inherited from the father, the child had PWS. When the same chromosome abnormality was inherited from the mother, the child had AS[73].
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.
71
Angelman, H. (1965), ‘Puppet children’: a report of three cases.