Posts Tagged ‘imprinting’
epigenetics and imprinting 6: when things go wrong
So imprinting involves parent-of-origin effects of which we find evidence in certain segments of certain chromosomes, in which genes are switched on or off, depending on inheritance. It often seems that these parent-of-origin effects counter-balance each other, as both parents have their own mutually exclusive way of trying to ensure the continuation of their genetic line.
It’ll be tough (for me) to take this down to a molecular level, but I’ll rely heavily on Nessa Carey’s book. It describes work on chromosome 7 in mice. I should first mention that there’s a convention in naming genes using italics, and the proteins they code for without italics. So there’s a gene in chromosome 7 called insulin-like growth factor 2 (Igf2) which promotes embryonic growth, and is usually expressed from the paternal copy. When researchers introduced a mutation which prevented the gene from effectively coding for the Igf2 protein, the offspring of this mutation were unaffected when the mutated gene was inherited from the mother, but the litter of offspring were much smaller when the gene was mutated in the father, showing that it was the paternal copy of the Igf2 gene that was required for foetal growth.
Fascinatingly for this ‘battle of the sexes’, there’s a gene in mouse chromosome 17 – Igf2r – which acts against the Igf2 protein, stopping it from promoting growth. This gene is also imprinted, from the maternal side. And so it goes.
According to Wikipedia, we now know of at least 80 imprinted genes in humans, mostly related to embryonic and placental growth and development. This is almost twice the amount Carey reported on less than a decade ago, so discoveries in this area are moving fast. As Carey writes, it’s uncertain whether there’s less imprinting in humans than in other mammals (we know of about 150 imprinted genes in mice) or whether they’re just harder to detect. Imprinting evolved about 150 million years ago (how do they know that? – as the much-treasured Bill Bryson would say), and is particularly prevalent amongst placental mammals.
This post was supposed to be about the mechanisms involved in imprinting, but my vast readership will have to wait awhile. I’m going to follow Carey, because I’m learning a lot from her, into the next area she writes about – ‘when imprinting goes bad’. She describes two very different conditions from birth, Angelman syndrome (AS) and Prader-Willi syndrome (PWS). Researchers separately studying these conditions found that the parents of the sufferers were usually healthy, yet everything pointed to something genetic going on, presumably during the production of eggs or sperm.
The separate work on the origins of these two permanently debilitating but very different conditions eventually converged, when it was found that in both AS and PWS, the patients were missing a small, identical stretch of chromosome 15. What caused the two entirely different results of this defect was whether it was inherited from the mother (resulting in AS) or the father (resulting in PWS). So the disorder is epigenetically inherited, a further example of a parent-of-origin effect.
Yet some children inherit these disorders without any deletions to chromosome 15. They have two normal copies of chromosome 15 but not from each parent. Instead they have two copies from the mother and none from the father – called uniparental disomy. In another variation on the theme it was later discovered that AS was in some cases caused by the opposite form of uniparental disomy, in which two normal copies of the chromosome were inherited from the father. So, because the particular region of the chromosome is normally imprinted, it’s essential, for healthy offspring, that the region is inherited in the ‘correct’ way, from each parent.
I’ll be looking at more examples of problematic inheritance and imprinted genes next time.
References
https://en.wikipedia.org/wiki/Genomic_imprinting
Nessa Carey, The epigenetics revolution, 2011
epigenetics and imprinting 5: mouse experiments and chromosome 11
So we were looking at how we – mammals amongst others – are engaged in a kind of battle for the best way to ensure our genetic survival into the future, beyond our insignificant little selves. This battle begins in the very early phase of life, as zygotes multiply to form a blastocyst.
Remember from my last post on this topic, the male mammal is interested in the offspring above all else. He’s even happy to sacrifice the mother for the sake of the child – after all there’s plenty more fish in the sea (or mammals in the – you know what I mean). The female, on the other hand, is more interested in self-preservation than in this pregnancy. She wants more than one chance to pass on her genes.
So, by the blastocyst stage, cells have differentiated into those that will form the placenta and those that will form the embryo itself. Experiments on mice have helped to elucidate this male-female genetic struggle. Mouse zygotes were created which contained only paternal DNA and only maternal DNA. These different zygotes were implanted into the uterus of mice. As expected, the zygotes didn’t develop into living mice – it takes DNA from both sexes for that. The zygotes did develop though, but with serious abnormalities, which differed depending on whether they were ‘male’ or ‘female’. In those in which the chromosomes came from the mother, the placental tissues were particularly underdeveloped. For those with the male chromosomes, the embryo was in a bad way, but the placental tissues not so much.
In short, these and other experiments suggested that the male chromosomes favoured placental development while the female chromosomes favoured the embryo. Thus, the male chromosomes are ‘aiming’ to build up the placenta to drain as many nutrients as possible from the mother and feed them into the foetus. The female chromosomes have the opposite aim, resulting in a ‘fine balance’ in the best scenarios.
Further work in this area has identified particular chromosomes responsible for these developments, and some of the epigenetic factors involved. For example, mouse chromosome 11 is important for offspring development. When the offspring inherits a copy of chromosome 11 from each parent, the offspring will be of normal size. If both copies come from the mother it will abnormally small, while if both come from the father it will be abnormally large. These experiments were carried out on inbred mice with identical DNA. Nessa Carey summarises:
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.
So this means that chromosome 11 is an imprinted chromosome – or at least certain sections of it. This is the same for other chromosomes, some of which aren’t imprinted at all. But how is it done? That’s the complex biochemical stuff, which I’ll try to elucidate in the next post on this topic.
Footnote: the photo above shows a bi-maternal mouse with healthy offspring, and further work in deleting imprinted genetic regions has allowed researchers to create healthy bi-paternal mice too. There’s a fascinating account of it here.
References:
Nessa Carey, The epigenetics revolution, 2011
https://www.the-scientist.com/news-opinion/first-mouse-embryos-made-from-two-fathers-64921