Trends in Biomedical Science

Epigenetics 1

We will watch a video called “Ghost in Your Genes”http://www.youtube.com/watch?v=fMxgkSgZoJs As we watch I will direct you the questions on your sheets.Think about these questions.

The transcript of the video can be found at http://www.pbs.org/wgbh/nova/transcripts/3413_genes.html

The following notes are from the web site http://learn.genetics.utah.edu/content/epigenetics

IDENTICAL TWINS: PINPOINTING ENVIRONMENTAL IMPACT ON THE EPIGENOME

Because identical twins develop from a single zygote, they have the same genome. This removes genetics as a variable telling scientists that the differences they observe between the individuals are caused almost solely by environmental factors. Recent studies have shown that many of these environmentally induced differences are acquired via the epigenome.

VideoTwinsmoviehttp://learn.genetics.utah.edu/content/epigenetics/twins/

Nature and Nurture (Genetics and the Environment)Studying twins helps us to understand how nature and nurture work together. For more than 100 years, researchers have compared characteristics in twins to try to find more much certain traits are inherited, like eye color, and which traits are learned from the environment, such as language.

Twin studies have identified a number of behavioral traits and diseases that are likely to have a genetic component, and others that are more strongly influenced by the environment.

Data is collected and compared from identical (monozygotic) or fraternal (dizygotic) twins who have been raised together or apart. Finding similarities and differences between these twins is the start to determining the degree to which nature and environment play a role in the trait of interest.

Twin studies have identified some traits that have a strong genetic component, including reading disabilities like dyslexia. Other traits, like arthritis, are more likely influenced by the environment.

Identical twins (left) share all their genes and their home environment. Fraternal twins (right) also share their home environment, but only half of their genes. So a greater similarity between identical twins for a particular trait compared to fraternal twins provides evidence that genetic factors play a role

Chromosome 3 pairs in each set of twins. One twin's epigenetic tags are dyed red and the other twin's tags are dyed green. When red and green overlap, that region shows up as yellow. The 50-year old twins have more epigenetic tags in different places than do 3-year-old twins.

Twin Studies Help Link Environment and Complex TraitsBecause they are genetically the same but their environments become more unique as they age, identical twins are a model for studying how environment and genes interact. This has become increasingly important when studying complex behaviors and diseases.

For example, when only one identical twin in a pair gets a disease, researchers look for elements in the twins' environments that are different. Data is collected and compared for large numbers of affected twins and coupled with DNA and gene product analysis.

These types of twin studies help find the exact molecular mechanism of a disease and determine the extent of environmental influence. Having this information can lead to the prevention and treatment of complex diseases.

Eg, for twin pairs where schizophrenia occurs, in 50% of cases both identical twins in a pair develop the disease, while only 10-15% of cases in fraternal twins show this pattern. This is evidence for a strong genetic component in susceptibility to schizophrenia. However, the fact that both identical twins in a pair don't develop the disease 100% of the time indicates that there are other factors involved.

Human genome project.Found approximately 20,000-25,000 genes in human DNA.About the same number of genes as fish and mice.These few genes didn't seem enough to explain human complexity. The same key genes that make a fruitfly, a worm or a mouse also make a human. Chimpanzees share 98.9 percent of our genome.

With only a small difference in chromosomes, how can there be such a big difference in structure and function between the species?

Let’s look at a different example.In this example there seems to be no difference in the chromosomes, but a large difference in what happens in the people.

Angelman syndrome. Children have a jerky movement when they're walking. These children have no speech; they big problems with learning but are uncharacteristically happy.The condition is caused by a genetic defect. A key sequence of DNA is deleted from chromosome 15.

The Prader-Willi syndrome.These children are very floppy at birth, but once they started eating properly, they then had an big appetite and would get very, very large.The condition is caused by the same deletion in chromosome 15.

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The inheritance pattern for the two conditions showed that:If the deletion was on the chromosome 15 that the child had inherited from father, then they have Prader-Willi syndrome, But if the deletion was inherited from the mother, they had Angelman syndrome.

How does the chromosome 15 know where it came from? There must have been a tag or an imprint placed on that chromosome, during either egg or sperm formation in the previous generation, to say whether it is from the mother or father. Although the DNA sequence is the same, the different sets of genes were being silenced depending on whether it came from the mother or from the father.

Something other than genes passed between generations, and could control genes directly, switch them on or off.

How?

Video Epigenomehttp://learn.genetics.utah.edu/content/epigenetics/intro/

Epigenetic effects can:• change the expression of genes• be passed from cell to cell, and even

from generation to generation• don’t involve changes in the DNA

sequence.

NUTRITION AND THE EPIGENOMEDiet is one of the more easily studied, and understood, environmental factors in epigenetic change.

The nutrients from food enter metabolic pathways where they are changed into molecules the body can use. One such pathway is responsible for making methyl groups - important epigenetic tags that may silence genes.

Nutrients like folic acid, B vitamins and SAM-e (S-Adenosyl methionine) are key components of this methyl-making pathway. Diets high in these methyl-donating nutrients can quickly change gene expression, especially during early development when the epigenome is first being formed.

Nutrients from food are turned into methyl groups along a pathway: the methyl groups are finally put onto DNA.

Diet During Early Development Can Cause Changes Lasting Into AdulthoodA mother's diet during pregnancy and what the child is fed as an infant can cause critical changes that stay with them into adulthood. Animal studies have shown that deficiency of methyl-donating folate or choline during late fetal or early postnatal development causes certain regions of the genome to be under-methylated for life.

For adults, a methyl deficient diet still leads to a decrease in DNA methylation, but the changes seem to be reversible with resumption of a normal diet.

Agouti MiceA mother's diet is important to determine the epigenome of her offspring. Both mice and people have a gene called agouti.

When a mouse's agouti gene is completely unmethylated it has a yellow coat color, is obese and prone to diabetes and cancer. When the agouti gene is methylated (as it is in normal mice) the coat color is brown and the mouse has a low disease risk. Fat yellow mice and skinny brown are genetically identical. The fat yellow mice look different because of epigenetics.

When researchers fed pregnant yellow mice a methyl-rich diet, most of the resulting pups were brown and healthy and stayed that way for life. These results indicate that an individual's adult health is heavily influenced by early prenatal factors. In other words, health may not only be determined by what we eat, but also what our parents ate.

If the agouti gene is switched on all the time, it blocks a receptor in the satiation center of the brain.The satiation center tells mice and us when we have eaten enough food. So the yellow animals literally eat themselves into obesity, diabetes and cancer.

Toxins and SupplementsBisphenol A (BPA) is a compound used to make polycarbonate plastic. It is in many consumer products including water bottles and tin cans.

When pregnant yellow agouti mothers were fed BPA, more yellow, unhealthy babies were born than normal. Exposure to BPA during early development had caused decreased methylation of the agouti gene.

However, when BPA-exposed, pregnant yellow mice were fed methyl-rich foods, the offspring were predominantly brown. The maternal nutrient supplement had counteracted the negative effects of exposure.

FathersCan a father's diet affect the child's epigenetic outcome? Scientists studied the well-kept, historical records of annual harvests from a small Swedish community. These records showed that food availability between the ages of nine and twelve for the paternal grandfather affected the lifespan of his grandchildren.

Shortage of food for the grandfather was associated with extended lifespan of his grandchildren. Food abundance, on the other hand, was associated with a greatly shortened lifespan of the grandchildren. Early death was the result of either diabetes or heart disease. Perhaps epigenetic mechanisms are "capturing" nutritional information about the environment to pass on to the next generation.

Can We have Nutrigenomics?As we better understand the connections between diet and the epigenome, the opportunity arises for clinical applications. We may be able to map our gene variations to help us understand our personalized medical needs.We also might be able to profile a person’s unique epigenome.

Our epigenome may provide information about how to eat better. We may be able to look at methylation patterns and design personalized nutrition plans.

Nutrient Food Origin Epigenetic Role

Methionine Sesame seeds, brazil nuts, fish, peppers, spinach SAM synthesis

Folic AcidLeafy vegetables,

sunflower seeds, baker's yeast, liver

Methionine synthesis

Vitamin B12 Meat, liver, shellfish, milk Methionine synthesis

Vitamin B6Meats, whole grain products, vegetables,

nutsMethionine synthesis

SAM-e (SAM)

Popular dietary supplement pill; unstable in food

Enzymes transfer methyl groups from SAM directly to the DNA

CholineEgg yolks, liver, soy, cooked

beef, chicken, veal and turkey

Methyl donor to SAM

Nutrient Food Origin Epigenetic Role

BetaineWheat, spinach, shellfish, and sugar

beets

Break down the toxic byproducts of SAM synthesis

Resveratrol Red wine Removes acetyl groups from histones, improving health (shown in lab mice)

Genistein Soy, soy products Increased methylation, cancer prevention, unknown mechanism

Sulforaphane Broccoli Increased histone acetylation turning on anti-cancer genes

Butyrate

A compound produced in the intestine when

dietary fiber is fermented

Increased histone acetylation turning on 'protective' genes, increased lifespan

(shown in the lab in flies)

Diallyl sulphide (DADS)

Garlic Increased histone acetylation turning on anti-cancer genes