Lecture 16 - Genetics, epigenetics, brain and behaviour

Question 1

nature and nurture

Answer 1

What we inherit +
What we experience = How we behave
(DNA/Genes Environment
+ chance factors)

Our unique behavioural profile arises from:
* Our individual DNA (genetic) sequence
* What environmental factors we are exposed to throughout life
* Complex interaction between the two

Question 2

image of DNA

Question 3

DNA

Answer 3

Our unique behavioural profile arises from:
* Our individual DNA (genetic) sequence
* What environmental factors we are exposed to throughout life
* Complex interaction between the two

Question 4

human genome

Answer 4

• Human genome (all DNA) comprises ~3.3 billion basepairs
• Most basepairs are conserved across all humans
• Some slight variations between individuals at particular genomic sites (‘polymorphisms’)

Polymorphisms/variants can affect DNA function (individual differences)

Question 5

Polymorphisms can occur:

Answer 5

a) at a single base pair (‘single nucleotide polymorphism’ or ‘SNP’, ~1 per 300 basepairs) - this is where people differ - in terms of physiology and behaviour
b) for larger chunks of DNA (deletions or duplications) ‘Copy Number Variants’ or ‘CNVs’ (rarer than SNPs)

Question 6

What is a gene and how does it influence the brain?

Answer 6

• ‘A stretch of DNA that encodes a functional molecule (protein, RNA)’
• Human genome = ~20,000 genes (key components of genes (‘exons’ - functional part of the gene) comprise 1-2% of genome)
  introns = non-functional
• Remainder: before 2000: ‘junk DNA’, after 2000: regulatory
• Genes are read (‘transcribed’→‘gene expression’) into single-stranded ribonucleic acid (RNA) molecules
• RNA molecules may be retained in the nucleus or transported outside

One class of RNA molecules, ‘messenger RNA (mRNA)’ are ‘translated’ to make a specific ‘polypeptide’ → protein (e.g. structural, catalytic, regulatory, receptor, transporter)

diagram of protein synthesis

Question 7

One gene may give rise to several slightly different transcripts (‘splice variants’), and slightly
different proteins

Answer 7

This degree of complexity may explain sophisticated human brain function

pre-mRNA - includes everything

mRNA - no introns just exons

a single gene can produce a large variety of different proteins

diagram in notes

Question 8

dna code

Answer 8

• All cells of the body contain the same DNA (genes) and DNA code is inflexible
• However, cells from different organs, and cells within organs, can be very different
• Cell function can change over time (genes constantly switched on and off)

Therefore, the DNA code must be being ‘read’ differently in different places and at different times

Question 9

gene expression

Answer 9

in humans, ~82-84% of genes are expressed in the brain to some extent at some point - in development or adulthood

STS gene present in every cell but only
expressed in particular brain regions

Question 10

How is gene expression regulated?

Answer 10

• Gene expression depends upon the extent to which RNA polymerase can bind to the start
  of the gene, and can continue along the DNA sequence - if can’t bind gene is not read
• In order to be packaged in the nucleus, DNA is wrapped around ‘histone proteins

Question 11

histone proteins

Answer 11

• Chemical modifications of the histone proteins (acetylation and methylation) affect accessibility of the
  DNA and therefore gene expression
• Chemical modifications added to the DNA itself e.g. (hydroxy)methylation can also influence binding of
  the RNA polymerase

Question 12

epigenetic

Answer 12

• In contrast to DNA sequence, these ‘epigenetic modifications’ eg methylation are dynamic and
  reversible, and are modulated by the cell’s environment; hence, they can explain
  spatiotemporally-specific gene expression
• Environmental factors can affect epigenetic marks on an individual’s DNA and
  hence influence (brain) gene expression and function
• Therapeutic or illicit drugs e.g. valproate - a histone dioselatease inhibitor
• Toxins (e.g. nicotine, alcohol) or trauma (e.g. brain damage)
• Signalling molecules
• Stress
• Diet

Question 13

dolinoy et al 2006

Answer 13

Can be demonstrated experimentally by taking a group of pregnant mice and giving them
genistein (soya) or not in their diet
* Offspring exposed to genistein-rich diet during development are phenotypically very distinct
from those not exposed (but are genetically identical)
different epigentic factors

those on geinstein rich diet -
Elevated methyl donor levels
in maternal diet
More gene methylation at coat
colour gene
Reduced gene expression
Non-obese

Low methyl donor levels
in maternal diet
Low gene methylation at coat
colour gene
High gene expression
Obese

Question 14

aberrant expression of agouti signaling protein (ASIP) as a cause monogenic severe childhood obesity

Answer 14

gene for coat colour in mice related to childhood obesity

Question 15

Dutch Hongerwinter (1944) and Great Chinese Famine (1958-61)

Answer 15

pregnant women gave birth to smaller babies
These babies were at increased risk of later obesity and schizophrenia
* Does dietary deficiency/stress influence SCZ risk via epigenetic mechanisms? - diet, stress, effecting baby
* Some evidence for altered methylation of IGF2/IL-10 genes in adult ‘Hongerwinter babies’
* Is this association causal? Which other genes are involved? What is the biological mechanism?
Nature (2010) 468: 23-30th Dec issue
*

Question 16

Environmental factors may not only affect your own behaviour via epigenetic
mechanisms, but also that of your offspring!

Answer 16

Nat Neurosci (2014) 17(1):89-96

parental olfactory experience influences behaviour and neural structure in subsequent generations

Question 17

mice

Answer 17

Male mice trained to associate smell of cherry blossom with mild
footshock (or not)
Mice then paired with behaviourally-naïve female mice to reproduce; fathers have no contact with pups
Adult offspring of conditioned male mice startled more than offspring of untrained mice upon
smell exposure; these mice were not conceived when father was exposed, and had never
encountered odour previously - passed on behavioural experience

Possible mechanism:
Olf151 gene (influencing detection of odour by receptor) showed reduced methylation in
sperm of conditioned mice (↑ gene expression)
This epigenetic change was then inherited by offspring, and could affect structure of
olfactory circuits in the brain (and interaction with ‘startle circuitry’)

Question 18

Parental behaviour may also influence offspring behaviour via epigenetic
mechanisms….

Answer 18

Nat Neurosci (2004) 7(8):847-854

epigentic programming by maternal behaviour

Question 19

rat

Answer 19

dentified two types of rat mother differing in levels of
pup licking and grooming (LG) and arched-back nursing
(ABN)

Adult offspring of low LG/ABN mothers had a greater
stress response than offspring of high LG/ABN
mothers

Mechanism: Differing levels of DNA methylation and histone acetylation of a gene
regulating the stress response (glucocorticoid receptor, GR) in hippocampus

Behavioural and molecular effects could be reversed by cross-fostering or by central infusion of HDAC inhibitor →
causal relationship?

Question 20

Epigenetic variation can influence phenotypic variability over time

Answer 20

dentical (MZ, i.e. genetically identical) twins are more alike early in life than later on

• Study examined epigenetic marks across the genome at two timepoints (3yrs, 50yrs) to see
  whether changes over time could explain this increased phenotypic divergence

Fraga et al. (2005) PNAS 102:10604-10609

graphs in notes

Question 21

Evidence for an interaction between genes and the environment?

Answer 21

‘Dunedin Longitudinal Study’
Sample (1037 individuals born 1972-1973): extensive genotypic and phenotypic information
Serotonin (5-HT) transporter suggested to be involved in vulnerability to depression
Two versions (alleles) of the gene producing the 5-HTT:
Two different 5-HTT alleles associated with different
functional outcomes i.e. different amounts of 5-HT in
synapse
Known relationship between stressful life events and likelihood of depression: GxE interaction?

diagrams in notes

Question 22

Caspi et al. (2003) Science 301: 386-389

Answer 22

diagram in notes

Question 23

Candidate gene GxE studies now outdated and replaced by genome-wide analyses e.g = Possible mechanisms of G x E

Answer 23

LOOK AT DIAGRAM IN NOTES PLEASE

Genetic risk polymorphism(s)/variant(s)
| |
e.g. SETD1A, MECP2, EHMT1 |
e.g. DNA methylation or histone- |
binding sites
| |
Altered epigenetic regulation of the genome. |
(e.g. DNA methylation, histone modification).
|
|
Altered function/levels/spatio-temporal expression pattern of
key gene(s) (neural or otherwise)
|
|
Differing brain function e.g. increased psychological disorder risk

Environmental risk factors
e.g. infection, stress, toxins, poor

Question 24

Summary

Answer 24

• The human genome is organised on 23 pairs of chromosomes; a small proportion of this is genes
• Variation at specific genomic sites can influence phenotypic variability
• Genes are transcribed into RNA and then translated into proteins; a single gene can produce multiple RNAs and proteins
• Gene transcription (‘expression’) patterns can be spatiotemporally and developmentally specific
• Gene expression and downstream physiology may be regulated by environmental factors via epigenetic effects

Genetic complement and the environment can interact in complex ways to affect phenotype

Question 25

Practice essay question:

Answer 25

‘Discuss how (epi)genetic differences between people can contribute to individual differences in behaviour’

Question 26

On Wikipedia:

Answer 26

* ‘Introduction to genetics’ * ‘DNA’ (Introduction, ‘Base modifications and DNA packaging’, ‘Transcription and Translation’) * ‘Single nucleotide polymorphism’ * ‘Copy Number Variation’ ‘Epigenetics’ (Introduction)