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Monday, January 30, 2012

Parental conflict, genes and obesity

We inherit two copies of each gene in our DNA, one from Mum and one from Dad. There are no exceptions. However, there are about 100 genes, known as imprinted genes, in which one of the parental copies is completely silenced. Effectively, we have only one functioning copy of these genes, either a paternal copy or a maternal copy. Somehow or other, cells know that they carry either the maternal or paternal copy and they behave differently depending on the parental version they carry.
In a normal person, there are about equal amounts of the maternal-only and the paternal-only copies. Mice can be bred to have the usual two sets of DNA but instead of having 50:50 maternally or paternally imprinted genes, we can make all the imprinted genes paternal or maternal. All of these mice contain each and every gene a normal mouse needs, except that for the 100 imprinted genes, they are either all maternal or all paternal. These embryos do not survive which tells us that we need some maternally imprinted genes and some paternally imprinted genes. However, geneticists can modify the normal 50:50 ratio to enrich an embryo in one or the other. The embryos of mice enriched in paternal genes, develop big bodies and small brains. In contrast, mouse embryos enriched in maternal genes, develop small bodies and large brains. This is the first sign of what is termed parental conflict. Daddy wants the foetus to grow big and strong and thus the paternally imprinted genes promote an enhanced flow of nutrients across the placenta and also promote growth of foetal tissue. Mum is responsible for nourishing the growing foetus, so her version of imprinted genes counteracts Dad’s influence, to conserve some of her nutrient reserves for the weaning period and for future pregnancies.
To understand the differences in brain structures caused by enriching a mouse embryo with maternally imprinted genes, we need to see where in the brain are the maternal genes and paternal genes preferentially located. The paternally imprinted genes are predominantly found in that region of the brain known as the hypothalamus, which just happens to be the area of the brain that drives appetite and sex. These are fairly animal instincts. The maternally imprinted genes are mostly found in the cortex. Humans have by far the largest cortex in the animal kingdom and the is the site of the brain which drives intelligence, memory, consciousness, thought, good social behaviour and other higher attributes of human kind. Tarzan may be big but Jane is brighter!

In rare instances, mutations are found in these imprinted genes. Because there is only one copy of each, any mutation is bound to lead to problems. If there are mutations in paternally imprinted genes, a common outcome is the development of the Prader-Willi syndrome. This is associated with a voracious appetite and a lethal level of obesity. If there are mutations in maternally imprinted genes, the child develops the Angelman syndrome. This is associated with a very happy demeanour and a lot of laughter, sometimes inappropriate.

The impact of variation in the balance of maternally and paternally imprinted genes on nutrition continues after birth. There is a protein bearing the code Gs-Alpha, which is very centrally involved in energy metabolism. The gene that encodes for Gs-alpha known as GNAS, is an imprinted gene and in humans, mutations of that gene lead to a condition called Albright hereditary osteodystrophy (AHO), which is associated with short stature and very severe obesity. Again, we see imprinted genes playing a role in growth and energy metabolism. In mice, it is possible to delete either the maternal copy or the paternal copy of GNAS meaning that the mouse has only paternally derived or maternally derived GNAS. These two genetically altered mice are strikingly different. Those lacking the paternal variety will be thin, small, have much less fat, have a higher metabolic rate and are more active.  Those lacking the maternal variety have the complete opposite profile.

What does all this mean for human nutrition and obesity? Firstly, as I have mentioned in previous blogs, obesity has a very strong genetic component. When we come to study this, we must be mindful that the genetic dimension can operate in many ways. We may find that an uneven distribution of the maternal or paternal varieties of an imprinted gene may play a subtle but powerful role. We may find that there are differences in this distribution in different tissues. Finally, we learn that parental conflict is a perfectly normal biological phenomenon.  It only goes wrong when the parental influences are imbalanced.

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