Chapter 6: The Sins of the Fathers

Darwin’s model of the evolution of species via natural selection has been the singly most powerful conceptual framework in biological science.  Its power became even greater once married to Mendel’s work on inheritance and our molecular understanding of DNA as the raw material of inheritance.

Random variation in genes creates phenotypic variation in individuals. Some individuals will survive better than others in a particular environment, and these individuals are likely to have more offspring.  These offspring may inherit the same advantageous genetic variation as their parent, so they too will have increased breeding success. Eventually, over a huge number of generations, separate species will evolve ---- mutating rates are generally very low and so it takes a long time for advantageous mutations to develop and to spread through a population.

But there is very little evidence that this happens except occasionally in response to chemicals or irradiation which damage DNA(mutagens), causing a change in the actual base-pair sequence. --- even these mutagens only affect the genome at a relatively small percentage of base-pairs and in random pattern, so these still can’t drive inheritance of acquired characteristics in any meaningful way.

The overwhelming body of data argues against Lamarckian inheritance, so there’s very little reason for individual scientists to work on this experimentally.  --- Paul Kammerer scientific fraud that he had demonstrated the inheritance of acquired characteristics in a species called the midwife toad.  

It’s certainly hard to imagine how an environmental influence on the cells of an individual could act at a specific gene to change the base-pair sequence. But it’s all too obvious that epigenetic modification -- be these DNA methylation or alterations to the histone proteins --- do indeed occur at specific genes in response to the environmental influences on a cell. ---

example --- the estrogen and the receptor stay together and move into the nucleus of the cell. They bind to specific motifs in DNA – A,C,G,T bases in a particular sequence – which are found at the promoters of certain genes. → This helps to switch on the genes. When it binds to these motifs, the estrogen receptor also attracts various epigenetic enzymes. → These alter the histone modifications, removing marks that repress gene expression and putting on marks that tend to switch genes on. → In this way, the environment, acting via hormones, can change the epigenetic pattern at specific genes.

Epigenetic modifications can be transmitted from a parent cell to a daughter cell. As this why there are no teeth in your eyeballs. --- if a similar mechanism transmitted an environmentally-induced epigenetic modification from an individual to their offspring, we would have a mechanism for a sort of Lamarckian inheritance.

Heresy and the Dutch Hunger Winter

Some of the strongest evidence for transgenerational inheritance in humans comes from the survivors of the Dutch Hunger Winter. – because the Netherlands has such excellent medical infrastructure and high standards of patient data collection and retention, it has been possible for epidemiologists to follow the survivors of the period of famine for many years.

Malnutrition during the first there months of the pregnancy, their babies were born with normal weight, but in adulthood were at higher risk of obesity and other disorders. --- when women from this set of babies became mother themselves, their first-born child tended to be heavier than in control groups.  --- this seems like a good example of transgenerational (Lamarckian)inheritance.

Intrauterine environment & cytoplasmic abnormality --- mother factor --- if we see transgenerational inheritance from father to child, it isn’t likely to be caused by intra uterine or cytoplasmic effects. Likely epigenetic mechanism would be an attractive candidate for explaining transgenerational inheritance of an acquired characteristic.

Greedy fellows in Sweden

Overkalix in northern Sweden 19 and early 20^소 centuries there were periods of terrible food shortages(caused by failed harvests, military actions and transport inadequacies) interspersed with periods of great plenty.

Analyze food intake during a stage in child hood known as the slow growth period(SGP).--- if food was scarce during a father’s SGP, his son was at decreased risk of dying through cardiovascular disease(stroke, high blood pressure or coronary artery disease)  VS. a man had access to  surfeit of food during the SGP, his grandsons were at increased risk of dying as a consequence of diabetic illnesses. --- the sons and grandsons had an altered phenotype (a change in the risk of death through cardiovascular disease or diabetes) in response to an environmental challenge they themselves had never experienced.

The heretical mouse

If the coat color could be inherited, it would show that it’s not only DNNA that gets transmitted from parent to offspring, but also epigenetic modifications to the genome. This would provide a potential mechanism for the transgenerational inheritance of acquired characteristics.

Epigenetically mediated effect (the DNA methylation -dependent coat pattern) in an animal was transmitted to its offspring. – but the effects seen were not directly cause by inheritance of the epigenetic modification at the A^표 retrotransposon, but through some other mechanism.

Epigenetic inheritance has taken place. An epigenetic meditation (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 al 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.

Gender-specific phenomenon in agouti strain. ---

It’s far more likely that here is the transmission of an epigenetic modification at the Axin^Fu gene(kinked tail 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. --- but the agouti and kinked tail phenotypes in mice both really on the presence of specific retrotransposons in the genome. Are these special cases or is there a more general effect in play?

The epigenetic of obesity

2/3 adults is overweight and obese, ---die on average, 6-7 years earlier than non-obese people.

At least rodents, a father’s diet can directly influence the epigenetic modifications, gene expression and health of this offspring. --- the most likely explanation is that diet induces epigenetic effects that can be transmitted form father to child.  

If you look at all the data in its entirety – from humans to rodents, from famine to feast – a quite worrying pattern emerges. Maybe the old saw of ‘we are what we eat’ doesn’t go far enough.  Maybe we’re also what our parents ate and what their parents ate before them.

We are epigenetic determinism?

Vinclozolin fungicide --- vinclozolin binds to the androgen receptor, it prevents testosterone from transmitting its usual signals to the cells. And so blocks the normal effects of the hormone. --- the same effect is found for the next three generations. --- in rat experiments only one generation was exposed to vinclozolin, yet the effect lasted for at least four generations, so this is another example of Lamarckian inheritance. --- this is another example of an epigenetic inheritance mechanism. (unusual DNA methylation patterns)