The Epigenetics Revolution полностью

Indeed, at the time of Emma Whitelaw’s work, scientists already knew that diet could influence coat colour in agouti mice. When pregnant agouti mice are fed a diet rich in the chemicals that can supply methyl groups to the cells (methyl donors), the ratios of the differently coloured pups changes[44]. This is presumably because the cells are able to use more methyl groups, and deposit more methylation on their DNA, hence shutting down the abnormal expression of agouti. This meant that the Whitelaw group had to be really careful to control for the effect of intra-uterine nutrition in their experiments.

In one of those experiments that simply aren’t possible in humans, they transferred fertilised eggs obtained from yellow mothers and implanted them into dark females, and vice versa. In every case, the distribution of coat patterns in the offspring was the same as was to be expected from the egg donor, i.e. the biological mother, rather than the surrogate. This showed unequivocally that it wasn’t the intra-uterine environment that controlled the coat patterning. By using complex breeding schemes, they also demonstrated that the inheritance of the coat pattern was not due to the cytoplasm in the egg. Taken together, the most straightforward interpretation of these data is that epigenetic inheritance has taken place. In other words, an epigenetic modification (probably DNA methylation) was transferred along with the genetic code.

This transfer of the phenotype from one generation to the next wasn’t perfect – not all the offspring looked exactly the same as their mother. This implies that the DNA methylation that controls the expression of the agouti phenotype wasn’t entirely stable down the generations. This is quite analogous to the effects we see in suspected cases of human transgenerational inheritance, such as the Dutch Hunger Winter. If we look at a large enough number of people in our study group we can detect differences in birth weight between various groups, but we can’t make absolute predictions about a single individual.

There is also an unusual gender-specific phenomenon in the agouti strain. Although coat pattern showed a clear transgenerational effect when it was passed on from mother to pup, no such effect was seen when a male mouse passed on the Avy retrotransposon to his offspring. It didn’t matter if a male mouse was yellow, lightly mottled or dark. When he fathered a litter, there were likely to be all the different patterns of colour in his offspring.

But there are other examples of epigenetic inheritance transmitted from both males and females. The kinked tail phenotype in mice, which is caused by variable methylation of a retrotransposon in the AxinFu (Axin fused) gene, can be transmitted by either the mother or the father[45]. This makes it unlikely that transgenerational inheritance of this characteristic is due to intra-uterine or cytoplasmic influences, because fathers don’t really contribute much to these. It’s far more likely that there is the transmission of an epigenetic modification at the AxinFu gene from either parent to offspring.

These model systems have been really useful in demonstrating that transgenerational inheritance of a non-genetic phenotype does actually occur, and that this takes place via epigenetic modifications. This is truly revolutionary. It confirms that for some very specific situations Lamarckian inheritance is taking place, and we have a handle on the molecular mechanism behind it. But the agouti and kinked tail phenotypes in mice both rely on the presence of specific retrotransposons in the genome. Are these special cases, or is there a more general effect in play? Once again, we return to something that has a bit more immediate relevance for us all. Food.

The epigenetics of obesity

As we all know, an obesity epidemic is developing. It’s spreading worldwide, although it’s advancing at a particularly fast rate in the more industrialised societies. The frankly terrifying graph in Figure 6.3 displays the UK figures for 2007[46], showing that about two out of every three adults is overweight (body mass index of 25 or over) or obese (body mass index of 30 or over). The situation is even worse in the USA. Obesity is associated with a wide range of health problems including cardiovascular disease and type 2 diabetes. Obese individuals over the age of 40 will die, on average, 6 to 7 years earlier than non-obese people[47].

^{Figure 6.3 The percentage of the UK population that was overweight or obese in 2007.}