7. Genetics and Epigenetics

12 01neurLecture 6 ; Sept 26, 2013Genetics & epigenetics

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Book recommendations

DNA: The Secret of Life James D. Watson


Molecular biology Virtually everything that happens

inside of cells involves various proteins.

Studying genetics and epigenetics will show us how cells control the proteins they make.

To do this we will work backwards, starting with proteins and tracing back to see how they come from deoxyribonucleic acid (DNA).


What are proteins? Proteins do a lot of dierent things, so

are several types to consider: Structural: Help to hold cells and tissue

together, e.g. collagen. Enzymes: Catalyze chemical reactions

and aid in metabolism, e.g. monoamine oxidase (MAO).

Cell signaling: Peptide neurotransmitters, receptors for hormones, neurotransmitters, and cytokines.

Proteins are giant, complex molecules, but they are built from a very simple set of supplies. Proteins are chains of amino acids.

There are 20 different amino acids to choose from, and the specific combination changes the function and structure of the protein.

Structure of Monoamine Oxidase (MAO). This e n z y m e b r e a k s d o w n m o n o a m i n e neurotransmitters (serotonin, etc.), clearing them from the synaptic cleft.

Proteins are chains of amino acids. The specific combination of amino acids determines the proteins structure and function.

Illustration from Kolb & Wishaw, An Introduction to Brain and Behavior. Sinauer, 2014


What are proteins? If proteins do pretty much

everything in your body, how does your body make them?

Since proteins are chains of amino acids, building a protein is as simple as stringing together the right amino acids in the right order.

DNA is the recipe that tells your cells how to build proteins which amino acids to use, and which order to put them in.

Like the alphabet can be used to make words of all different lengths and meanings, amino acids can build proteins of many different shapes and function. The secret in both cases is putting the right ingredients together in the correct order.


The role of DNA Like proteins, DNA is a chain of simple

molecules. There are four nucleotide bases that can make up DNA: Adenine (A) Thymine (T) Guanine (G) Cytosine (C)

Unlike proteins, DNA can be copied. This allows for cell division and reproduction.

Genes are segments of DNA that code for particular proteins.

So genes are like recipes for proteins. Proteins do all of the work in the cell, but genes tells the cell how to build those proteins.

DNA is made from a sequence of nucleotides. Because it is made from two complementary strands, each strand can be used as a template for copying itself.

Illustration from J.P.J. Pinel, Biopsychology. Allyn & Bacon, 2011


Putting it together the role of mRNA DNA cannot be directly made into

proteins.

The process of transcription is the first step in gene expression. During transcription, a gene is copied into a strand of messenger RNA (mRNA).

The sequence of each mRNA strand

matches the DNA sequence of that gene.

The second step of gene expression is when mRNA strands are translated into proteins by ribosomes.

Illustration from Kolb & Wishaw, An Introduction to Brain and Behavior. Sinauer, 2014

DNA

mRNA

Protein

1.

2.


Gene expression in 4 steps

Illustration from J.P.J. Pinel, Biopsychology. Allyn & Bacon, 2011


Basic genetics Since the structure and function of

proteins depends on them having the right amino acids in the correct order, anything that aects this will change how the protein works.

Minor dierences in the DNA sequence

of a gene can aect the function of the protein it codes for. These differences are heritable, since

DNA is duplicated during cell division.

These dierences in protein function can lead to all sorts of physical dierences in the organism. Some can be minor (changes in hair or

eye color), others can be major (birth defects, genetic disorders etc.,)

The fruit fly on the left has a mutation in a gene that codes for a protein that is critical for eye formation.


Basic genetics Not all genetic variation leads to huge problems.

Minor genetic variations allow for the great diversity we see among humans.

Genes are not just for simple things like eye color, they also aect the workings of things inside the body. Since proteins do almost everything, changes to

the recipes for those proteins (the genes) can affect nearly anything.

Variations in genes that are expressed in the brain can lead to dierences in behavior, intelligence, and all sorts of other things. Eg. Genes that code for receptors, reuptake

transporters, or enzymes can all affect synaptic function.

Humans have approximately 20,000 genes. Other species can have dierent numbers. Interestingly, the number of genes a species has

is nothing to do with its sophistication or intelligence.

The water flea Daphnia pulex has over 31,000 genes compared to the 20,000 humans have.


Gene expression controls:1. Location

Where genes are expressed.

2. Timing When genes are expressed.

3. Quantity How much mRNA/protein is

produced.


Gene expression: location

Dierent parts of the brain express dierent genes. Therefore they have dierent types of proteins, and this is part of the reason why dierent parts of the brain have dierent functions.

A gene expressed only in the mouse hypothalamus. A gene expressed only in the mouse amygdala and hippocampus.


Gene expression: timing A lot of the time, certain proteins are not needed.

To maintain homeostasis, gene expression is

controlled so that genes are only expressed when their protein products are needed.

Gene expression is controlled by various kinds of stimuli. Neural or hormonal signaling. Physiological conditions. Sensory stimuli. Developmental programs. Other genes


Gene expression: quantity Dierent stimuli can aect gene

expression, causing genes to be up-regulated or down-regulated.

Up-regulation results in more mRNA

and protein. Down-regulation is the opposite.

More of a certain protein (i.e. up-regulation of its gene expression) leads to an increase in whatever that protein does. Similarly, less of a protein decreases its

function.

Gene

exp

ress

ion!

Gene expression (cFos) in the rat hippocampus

Up-regulation


Introduction to epigenetics Experience can alter how genes are expressed. This happens

throughout the lifespan. Some examples: Stress Traumatic events Drugs Culture Disease

Epigenetics upon/over genetics (G.) - is the study of changes in gene expression that are not caused by changes in DNA sequence.

Because of epigenetics, it is possible for identical twins to have dierent patterns of gene expression.

Genetic mutations alter the meaning of genes. Epigenetic changes alter the activity of genes.


Introduction to epigenetics

Epigenetic changes are caused by the environment. Because of this they vary across the lifespan, depending on the type of life the individual leads.


A ramen noodle recipe analogy

1) Put noodles into boiling water.2) Add flavor packet. Genetic change

(change in meaning)

Epigenetic change (change in activity)

1) Put noodles into boiling water.2) Add two flavor packets.

1) Put noodles into boiling water.2) Add flavor packet.

1) Put noodles into boiling water.2) Add flavor packet.

Note: you can skip this step


Epigenetic mechanisms Epigenetic changes do not re-write

the genetic code, rather they act like notes or markers on genes, telling the body whether or not they should be expressed.

DNA in the cells nucleus is organized around clusters of proteins called histones. This combination of DNA and supporting proteins is called chromatin.

Epigenetic changes are often caused by physical changes in the structure of chromatin.

Histones act like spools for DNA, helping it stay compact and organized in the nucleus.


Chromatin remodeling When epigenetic marks are added to histone proteins, the

chromatin changes shape.

Chromatin that is condensed is tightly packed inside the nucleus. This makes it dicult for the enzymes that control gene transcription to access the DNA.

Therefore, gene transcription goes down.

On the other hand, chromatin that is relaxed is loosely packed, and therefore gene transcription goes up.


Histone acetylation

Histone acetylation is an epigenetic mark that relaxes/loosens the chromatin and increases gene transcription.

Histone

DNAA!

A!

A!

A!

A!

A!

A!

A!

A!

Acetyl group

Condensed chromatin

Relaxed chromatin


Histone methylationHistone

DNA

Methyl group

M% M%M%

M%

M%

M%

M%M%

Relaxed chromatin

Condensed chromatin

Histone methylation is an epigenetic mark that tightens/condenses the chromatin and decreases gene transcription.


Epigenetics of addiction Exposure to drugs like cocaine

leads to changes in gene expression in the brains reward system. These changes are often long-lasting they persist long after cocaine has left the system.

1 hour post-injection, nearly 100 genes are activated in the brain.

Some of these genes are desensitized by multiple exposures, but most are sensitized. This means that the genes are easier activate on the next exposure to cocaine.


Epigenetics of addiction Chronic cocaine administration increases histone

acetylation and decreases histone methylation on genes related to addiction. Activation of enzymes that add acetyl groups

(writers). Deactivation of enzymes that remove acetyl groups

(erasers) and methyl groups.

The end result of this is that repeated exposure to

cocaine leads to changes in histone acetylation that aect how addiction genes are expressed in the brain.

These changes seem to make animals more

sensitive to the pleasurable eects of cocaine. Importantly, these changes stay long after cocaine

has left the system.


Epigenetics of depression Chronic social defeat stress is a

commonly used animal model of depression. A mild-mannered mouse is house with an aggressive bully mouse for 10 days. During this time, the mild-mannered mouse

is bullied incessantly and develops depressive-like behavior (just like any human would).

This model causes increased histone methylation in a large number of genes in the brains reward center. This decreases the transcription of feel-

good genes. Treating animals with anti-depressants

reverses many of these changes.


A mothers legacy Human data tell us that early life

experience has a huge impact on mental health later in life. Individuals who had stressful childhoods

(abuse, neglect, bullying, etc.) tend to have more mental health problems later in life.

A rodent model of that is the licking/grooming model. Good rat mothers spend a lot of time licking and grooming their pups. Bad rat mothers ignore their pups. Offspring of good mothers turn into good

mothers themselves. This is not a genetic effect, because it works equally well in pups born to bad moms that were fostered to good moms.

Pups from bad mothers are more anxious and stress-prone when they grow up.


A mothers legacy Normally, cortisol binds to

glucocorticoid receptors in the hippocampus to activate negative feedback and shut down the stress response.

Pups with bad moms have increased DNA methylation of the glucocorticoid receptor gene in the hippocampus. This causes reduced glucocorticoid

receptor expression in the hippocampus, and impairs the negative feedback loop.

Because they have fewer glucocorticoid receptors, these animals have a harder time shutting down their stress response (see the Stress lecture for a reminder)

--

-

Hippocampus!

Hypothalamus!

Ant. Pituitary!Cortisol!

CRH (reduced)!

ACTH (reduced)!

Reminder of the negative feedback loop that shuts down the stress response (see stress lecture)


The take-home message Your genes are not your destiny. Because

epigenetic changes regulate the activity of genes, you are not necessarily doomed by the genes you were born with.

The science of epigenetics is showing us that the environment we live in (and make for ourselves) can aect how our genes operate. This appears to be especially important during childhood. For this reason, it is incumbent on us to seek out the

most positive environments for ourselves, and to help create the most positive environments for others.

Epigenetics can help explain addiction and other mental disorders. It shows how these conditions create long-term changes in the working of the brain. Epigenetics may, in the future, help us treat these

conditions.

We cannot change our genes, but we can change our environment, and therefore our epigenetics. This is a lovely message of hope

7. Genetics and Epigenetics

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