Chapter 5: Why Aren’t Identical Twins Actually Identical? 

Monozygote twin --- inner cell mass of the blastocyst split into two during the early cell divisions, like slicing a doughnut in half, and gave rise to two embryos. --- Genetically identical.

MZ twin are fascinating – determine the degree to which genetics is the driving force for life events.

Concordance rate --- how often both twins in a pair present with the same disease.

Concordance rates of schizophrenia

1/250 pregnancy

How epigenetics drives a wedge between twins

Spontaneously developed mutations in genes in certain cell --- theoretically possible but failed to find much data to support this theory. Vs. different environment

In the absence of any substantial evidence for a role for somatic mutation, epigenetics seems like a strong candidate for this mechanism.

Amount of methylation or histone acetylation is different especially in their fifties.

Even genetically identical individuals are epigenetically distinct by the time of birth, and these epigenetic differences become more pronounced with age and exposure to different environments.

Of mice and men(and women)

The mouse and human lineages separated a mere 75 million or so years ago. 99 % of the genes found in mice can also be detected in humans,

Mate a pair of mice who are brother and sister --- for over 20 generations of brother sister mattings, -- all the genetic variation gets bred out, throughout the genome.

In a refinement of this, scientists can take these genetically identical mice and introduce just one change into their DNA. They may use such genetic engineering to create mice which are identical except for just on region of DNA that the experimenters are most interested in.

A mouse of a different color

Agouti mouse --- normal black at the tip, yellow in the middle and black again at the base. --- a gene called agouti is essential for creating the yellow bit in the middle,  and is switched on as part of a normal cyclical mechanism in mice.  

Over active agouti gene A^vy --- yellow hair, Inactive agouti gene a -----black hair a, A^vy dominant to a.

A strain of mice that contained one copy of A^vy and one copy of a in every cell ---- expected yellow hair --- but they don’t --- some very yellow fur, some classic appearance, and some all shades in -between

These experiments suggested that certain epigenetic proteins act as a kind of dampening field. Naked DNA is rather prone to being switched on somewhat randomly, and the over all effect is like having a lot of background chatter in our cells. This is called transcriptional noise. --- the epigenetic proteins act to turn down the volume of this random chat. They do this by covering the histones with modifications that reduce the genes’ expression.

A piece of DNA which called a retrotransposon (it code for abnormal piece of RNA and not code for a protein) inserted in the mouse chromosome just before the agouti gene.

Kinked tail --- Axin-fused

Body weight --- about 20~ 30% of variation in body weights can be attributed to the post natal environment. --- 70 ~ 80% not by genetic and environment, there has to be another source for the variation. ---- decreased level of DNMT3 results in the increased variability in body weight. Not DNMT1 because DNMT1 is the protein that maintains pre established methylation patterns on DNA. DNMT3 can add methyl groups to totally unmethylated DNA regions which means it is responsible for establishing the correct DNA methylation patterns in cells.  

The Dutch hunger winter

if mother is malnourished during pregnancy, her child may be at increased risk of ill health not just during the immediate post-birth infancy but for decades. ---- this is at least in part due to molecular epigenetic effects, which result in impaired developmental programing and life long defects in gene expression and cellular function.

The Dutch hunger winter --- was a period of terrible hardship and near-starvation during the Nazi fuel and food blockade of the Netherlands in the last winter of the Second World War.  22,000 people died and the desperate population ate anything they could find from tulip bulbs to animal blood.

In early stages of pregnancy where different cell types are developing epigenetic proteins are probably vital for stabilizing gene expression patterns.  Our cells contain thousands of genes, spread over billion of base-pairs, and we have hundreds of epigenetic proteins.

The epigenetic variation that occurs in developmental programming is at heart a predominantly random process, normally referred to as stochastic. --- random fluctuations in epigenetic modifications during early development lead to non- identical patterns of gene expression. --- these become epigenetically set and exaggerated over the years, until eventually the genetically identical twins become phenotypically different, sometimes in the most dramatic of ways. --- randomly varying levels of DNA methylation of the A^vy retrotransposon.

Cells would change their gene expression to compensate for the poor nutrition and the patterns of expression would be set for the future because of epigenetic modifications to the genes. --- random epigenetic variability, the genotypes of the individuals and early environmental events, and the responses of the genes and cells to the environment combine in one great big complicated – and as yet not easily decipherable – equation.

Alcohol and bisphenol A --- lead to a change in the epigenetic modifications in the mice. --- European Union outlawed bisphenol A in drinking bottles for babies.

Remarkable things about early development, and the importance of epigenetics in this process.

Jean-Baptiste Lamarck hypothesized that acquired characteristics can be transmitted from one generation to the next, and that this drives evolution. --- Short neck giraffe-like animal become elongated its neck by constant stretching --- the Dutch Hunger Winter cohort and the yellow mice have shown us that the heretical Lamarckian model of inheritance can, be right on the money, as we are about to see.