neur1201

Genetics & Epigenetics

 What are we learning today?
• The basics of genetics
– What is a gene? What is a protein? How are proteins made?
• The basics of epigenetics
• Examples of how epigenetic processes can influence behavior
– Addiction
– Depression

NEUR 1201 – Summer 2014 – Harry MacKay

 Molecular Biology: Introduction
• By the early 20th century, living tissue was taken to
consist largely of three different materials:
carbohydrates, fats, and proteins.

• Proteins are by far the most complex molecules in

our body. They are large, often very delicate, and Egg whites are made mostly of a
seem to be critical for all of the biochemical protein called albumen.

reactions that take place in our bodies.

– The size and complexity of proteins makes them
very fragile. By analogy a larger and more
complex house of cards is more easily toppled than
a smaller one.

• For this reason, the name protein comes from a

Receptors are proteins as well.
Greek word meaning ‘of first importance’.

NEUR 1201 – Summer 2014 – Harry MacKay

 Of first importance…
• Proteins do a lot of different things, so there 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,
Structure of Monoamine Oxidase (MAO). This
receptors for hormones, neurotransmitters, and enzyme breaks down monoamine
cytokines. neurotransmitters (serotonin, etc.), clearing them
from the synaptic cleft.

• 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 Proteins are chains of amino acids. The specific
and structure of the protein. combination of amino acids determines the
protein’s structure and function.

NEUR 1201 – Summer 2014 – Harry MacKay 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?
– Proteins do not last forever, so your body must
not only make new ones as needed, it must also
work to replenish old and degraded ones.

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

• How does this happen?

NEUR 1201 – Summer 2014 – Harry MacKay

 The role of DNA
• Deoxyribonucleic acid (DNA) is packaged into chromosomes in the
cell’s nucleus. Humans have 23 pairs of chromosomes, and receive
one per pair from each parent.

NEUR 1201 – Summer 2014 – Harry MacKay Illustration from Kolb & Wishaw, An Introduction to Brain and Behavior. Sinauer, 2014
 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 DNA is made from a sequence of nucleotides.
build those proteins. 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

NEUR 1201 – Summer 2014 – Harry MacKay
 The genetic code
• When DNA is sequenced, the end product is
simply a string of letters, with each letter
representing one of the four nucleotides.

• You might be wondering how genes can be a

recipe for protein.
– After all, proteins have 20 amino acids to choose
from, but DNA only has 4 nucleotide bases to
encode that information.

• Genes are organized into codons. Each codon is 3

nucleotides long, and ‘codes’ for a specific amino An example sequence from the human CRH gene.

acid.
– For example, AAG codes for the amino acid
lysine, and GAC for aspartic acid.
– There are 43 possible codons (a total of 64), but a
lot of them are redundant.

NEUR 1201 – Summer 2014 – Harry MacKay

 Putting it together – the role of mRNA
• DNA cannot be directly made into proteins.

• The process of transcription is the first step in DNA

gene expression. During transcription, a gene is
copied into a strand of messenger RNA (mRNA). 1.

• The sequence of each mRNA strand matches the mRNA

DNA sequence of that gene.
– The sole exception to this is that in RNA, thymine 2.
is replaced by uracil. Since it’s a 1:1 swap, the
meaning of the sequence is not affected.
Protein
• The second step of gene expression is when
mRNA strands are translated into proteins by
ribosomes.

NEUR 1201 – Summer 2014 – Harry MacKay Illustration from Kolb & Wishaw, An Introduction to Brain and Behavior. Sinauer, 2014
 Gene expression in 4 steps

NEUR 1201 – Summer 2014 – Harry MacKay Illustration from J.P.J. Pinel, Biopsychology. Allyn & Bacon, 2011
 Gene expression in 4 steps

NEUR 1201 – Summer 2014 – Harry MacKay Illustration from J.P.J. Pinel, Biopsychology. Allyn & Bacon, 2011
Optogenetics

• Transgenic technique that

combines genetics and light to
control targeted cells in living
tissue
– Based on the discovery that
light can activate proteins
• Proteins can occur naturally
or can be inserted into cells
• Fiber-optic light delivered to
selective brain regions such
that all neurons exposed to the
light respond immediately
Epigenetics

• Changes in gene expression

related to experience
– Wide range of experiential
factors
• Chronic stress, traumatic
events, drugs, culture, disease
• Example: born in a hot country,
move to a cold climate
• Fraga and colleagues (2005)
– Twins have nearly identical
patterns of gene expression
early in life, but remarkably
different by age 50
The Story of Greg

• What made Greg so

susceptible to cocaine?
• How did his identical twin
escape a similar fate?
• How is it that some of us are
able to maintain recreational
drug use, whereas others go
on to become addicts?
• Epigenetics: the environment
can switch on or off some
genes
• Nature via nurture
Genetic mutations alter meaning

Epigenetic changes alter activity

Epigenetics: The Basics

• DNA wrapped around clusters of

proteins: histones
– Further bundled into chromosomes
• Combination of protein and DNA
in chromosomes: chromatin
– Helps regulate behaviour of genes;
keeps them in inactive state
– If gene is needed, section of DNA
unfurls, making gene accessible
• Epigenetic changes are often
caused by physical changes in
the structure of chromatin.
 Histone acetylation
• Histone acetylation is an epigenetic mark that relaxes/loosens the Histone
chromatin and increases gene transcription.
Condensed
chromatin

DNA
A A
A A
A
Relaxed
A
chromatin
A
A
A
Acetyl group

NEUR 1201 – Summer 2014 – Harry MacKay

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

DNA

Methyl group

M M
M M

Condensed
chromatin
M
M
M M

NEUR 1201 – Summer 2014 – Harry MacKay

 The Role of the Environment
• Can influence gene activity by regulating the behaviour of
epigenetic writers and erasers
– Addition/removal of acetyl and methyl groups can help the brain
respond and adapt to environment

However, these processes can go awry!

NEUR 1201 – Summer 2014 – Harry MacKay
Primed for Addiction

• Can cocaine alter the activity

of genes in the brain’s reward
center by changing their
epigenetic tagging?
– 1h post-injection, 100 new genes
switched on
– Chronic exposure: some genes
turned on by acute exposure fall
silent if given every day
(“desensitized”); majority show
greater activity, highly sensitized
• Allows them to “remember”
rewarding effects of the drug?
Relapse?
Primed for Addiction

• Chronic cocaine
administration:
– Reconfigures acetyl and
methyl tags
• Loosens chromatin structure,
more prone to activation
– Dampens activity of erasers
that remove acetyl groups, and
writers that add inhibitory
methyl groups
– Can artificially do this – get
animals that are more sensitive
to effects of cocaine, despite
never having had the drug!
Marked for Depression

• Animal model: chronic

social defeat
– Pair mild-mannered
mouse with aggressive
mouse; 10 days of  This model causes increased histone
‘bullying’ leads to methylation in a large number of genes
depressive-like in the brain’s reward center.
 This decreases the transcription of “feel-
behaviour in mild- good” genes.
mannered mice  Treating animals with anti-depressants
reverses many of these changes.
 Some mice more vulnerable (1/3rd were
resistant)
 Do not show epigenetic changes!
A Mother’s Legacy

• Different levels of
maternal care
– High licking/grooming
• Offspring less anxious,
produce less stress hormone
 females become high
lick/grooming mothers!
– Low licking/grooming
• Effects of maternal
behaviour mediated
through epigenetic
mechanisms
A Mother’s Legacy

• Low lick/grooming pups

– More DNA methylation
in a gene encoding the
glucocorticoid receptor
(mediates stress response)
– Less of receptor is made
in the hippocampus
– Means less able to turn
off stress response 
more anxious
 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 affect 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.

• This highlights the importance of providing support to mothers, particularly

while they are pregnant.
– The environment they encounter during this critical time has a large impact on
the future health of their children.

NEUR 1201 – Summer 2014 – Harry MacKay