Neurogenetics

Question 1

Facts about chromosomes:
1- where are they present?
2- what is each pair of chromosomes?
3- how many do humans have?
4- how many per diploid and in human body?

Answer 1

1) Chromosomes are present in every cell of the human body (every living organism has a unique genetic make up)

2) Each chromosome is a long winding chain of double stranded DNA- double helix structure

3) Humans have 23 pairs of chromosomes (46 in total)

4) ~ 6 billion bp DNA per diploid cell. ~50 trillion cells in human body… sun and back 300 times.

Question 2

DNA structure function:
1- when and who discovered the double helix structure?
2- what is the double helix structure made from?
3- what does dna stand for?
4- what does each chromosome have?
5- what hold the structure together + explain?
6- _____, _____, _____ are what encode the info that is carried on genes?

Answer 2

1- discovered in 1953 by Watson, Crick, Williams & Franklin
2- 2 chains of phosphate and deoxyribose (type of sugar)
3- Deoxyribonucleic acid
4- over 100 million base pairs of DNA
5- Deoxy chains hold the structure together and have nucleotide base pairs in between the wrongs of the ladder and they hold this ladder together. The vertical strands are strong, their strong chemical bonds keep them in place. These pairs binding together form weaker bonds.
6- Base pairs + 4 bases + sequences of bases along double helix

Question 3

DNA structure function:
What are the 4 nucleotide bases?

Answer 3

adenine (A)
thymine (T)
cytosine (C)
guanine (G)

Question 4

Human genetics
How much of our DNA sequence do we share with each other?

Answer 4

~99.9% (the .1% where we do differ are called SNP)

Question 5

SNP:
1- stands for?
2- what are they?
3- how many are identified through human genome project sequencing?
4- what is the unique combination that we inherit from our parents responsible for?

Answer 5

1- Single Nucleotide Polymorphisms

2- def= Natural variations in our DNA

3- ~ 3,300,000 SNPs identified through human genome project sequencing

4- The unique combination of SNPs that we inherit from our parents are responsible for the genetic component that makes us different to one another.

Question 6

Cell division: Mitosis

Answer 6

Somatic cells (daughter cells identical to parent)

Every time a cell divides, the daughter cells carry identical DNA to the parents

Every cell is identical

(eg. no difference between dna in toe vs dna in brain or skin. The actual genetic sequence in all of those cells/ organs should be identical).

Question 7

Cell division: Meiosis

Answer 7

Gametes (daughter cells contain half the number of chromosomes)

Cell duplicates so there are 4 chromosomes that will split off into daughter cells but before they do that there is a process of recombination where you have crossing over between the pairs of chromosomes so they mix up DNA on the chromosomes. So when they divide to form 2 chromosomes per cell and then divide again to make gametes, none are identical to the original chromosomes. Each of these would carry a different combination of either their mothers or their fathers dna.

Gamete cells end up being haploid because each only have one of the pairs of chromosomes (23 pairs).

Question 8

Genetic inheritance: Meiosis
- what?
- allows?
- what does crossing over do?
- % composed by offspring?

Answer 8

• Homologous recombination or “crossing over”
• allows genetic diversity
• (natural selection and evolution)
• crossing over events between them which mixes up the DNA across the chromosomes
• Offspring all share 50% of each parents genes, but a different 50%

Question 9

Genes:
- how many genes on human chromosome?
- what are genes?

Answer 9

• approx. 23,000
• Genes are long sequences of base pairs in the DNA that encode proteins

Question 10

Genes to protein
Sequence of events

Answer 10

On a gene, at the top end there is a binding sequence (sequence of dna that is specific to attract a protein called a transcription factor). This transcription factor binds to that sequence of dna and activates a process of transcription which reads the dna down the gene and this makes messenger rna.

Genes are turned on by transcription factors.
Transcription factors are activated during development or by intracellular signalling cascades from other parts of the cell

Question 11

Gene expression
What happens?

Answer 11

The DNA partially unravels, allowing a transcription factor to bind to the gene

Transcription: In the nucleus, the gene’s DNA sequence is copied into messenger RNA (mRNA).

Translation: A ribosome attaches to the mRNA and moves along the mRNA, reading each triplet codon (3 bases) and using transfer RNAs (tRNA) to put together the amino acid chain to make a protein. Proteins are the machinery of our cells.

All genes are switched on by transcription factors at relevant times in development in order to drive expression of the gene to make the proteins that it needs in order for the function of those cells.

sum:
DNA transcribed to mRNA → mRNA goes into cytoplasm where its translated to make proteins

Question 12

Mendel’s law (Mendelian Inheritance)
- what did he work out
- pea example

Answer 12

Gregor Mendel (1865): inheritance through “transmissible units”

Peas
- Inherited properties in pea plants: tall v short
- Height in peas: dichotomous trait
(tall or short, no in between)
- Trait that is controlled by a single gene –
either tall or short

When cross-fertilised all of the first generation (F1) offspring are tall. But

The short character reappears in the second generation (F2) in just a quarter of the offspring.
(When you breed tall pea plants together, which had previously been read from a short plant, a quarter of them by probability was always a shorter plant.)

Question 13

Mendel’s law (how it works in genes)
- what is a gene?
- how many copies in parent?
- how many copies in offspring?
- for height, what is tall/short?
- term for genes identical or not identical?

Answer 13

• Gene is in one of two forms (known as alleles) – either tall or short
• 2 copies of the gene in each parent pea
• 1 copy is carried to each of the offspring
• Height: Tall (T) is dominant
• Short (s) is recessive
• If the genes are identical (TT or ss): homozygous
• If the genes are not identical (Ts): heterozygous

Question 14

Mendel’s law (how it works in genes)
What happens?

Answer 14

When you breed TT and ss together, all of the offspring will have one of each. The tall gene is dominant so its expressed over the recessive gene.

Dominant and recessive inheritance… not just peas

End up with some that are homozygote for tall some that are homozygote for short and some that are heterozygote- carry short and tall gene and when looking at the T is dominant.

To sum- you can have dominant genes that when they’re expressed next to recessive gene, its the dominant gene that you see expressed. And then you can describe these offspring by their genes so when the genes are identical they’re known as homozygote (two identical copies of the gene). When they’re not identical, they’re known as Heterozygote because they have 2 different copies of the gene.

Question 15

Genotype, Phenotype, Alleles

Answer 15

Genotype = genetic information (eg. the actual genetic sequence). (whether offspring are homo or hetero)

Phenotype = how it displays

(Interaction of genotype with environment)- (eg. phenotype being tall or short)

Alleles – variants of a gene
e.g tall vs short alleles of height gene in peas

Question 16

Intro to genetics summary:
1- What does DNA carry?
2- What is the DNA helix composed of?
3- What are DNA strands packaged into?
4- Where are chromosomes held?
5- What do sequences of base pairs correspond to?
6- What is genetic information inherited from + law?
7- What is genetic diversity due to?

Answer 16

1- Genetic information
2- 2 strands that are held together by nucleotide base pairs (A-T, C-G)
3- chromosomes (humans: 23 pairs)
4- in the nucleus of each cell
5- Sequences of base pairs correspond to amino acids (20), and the amino acids join in order to proteins
6- Genetic information is inherited from 1 paternal and 1 maternal chromosome (Mendel’s law)
7- Genetic diversity is due to recombination between pairs of chromosomes during meiosis.

Question 17

Genetic variations affecting brain and behaviour
4 things

Answer 17

Single gene disorders
- dominant
- recessive

Gene variations/mutations
- affect function (coding sequence)
e.g. PKU / Huntington’s
- affect expression (non-coding, regulatory sequences)

Chromosomal abnormalities

X – linked conditions

Question 18

Huntington’s Chorea
1- symptom?
2- type of inheritance?
3- what happens if you have a mutation of this gene?

Answer 18

1- Degeneration of the brain (striatum) leading to progressive deterioration of movement, temperament and cognition.

2- Autosomal dominant inheritance: single copy will be dominant and lead to the disease (if 1 parent has Huntington’s, 50% of the offspring will develop Huntington’s).

3- If you have a mutation of this gene, you are pretty much certain to get huntingtons

Question 19

Huntington’s Chorea
4- what type of gene disorder on what chromosome?
5- what gene?
6- due to?
7- onset + number of repeats?
8- when onset?
9- unstable what?

Answer 19

4- Single gene disorder on Chromosome 4 (Gusella et al., 1983)
5- Its in the Huntington gene
6- Due to excessive repeat of CAG bases (normal chromosome has 11 to 34 copies of this base repeat. Huntington’s gene has excess of 40 copies of this base repeat) If you end up with over 40 copies, that is what causes the mutation to become dominant and causes dysfunction of that gene leading to this disorder.
7- Disease onset (age 35-55)- late onset disease, number of repeats (average 44)
8- Early onset (if 60+ repeats)
9- Unstable triplet and can therefore increase in subsequent generations

Question 20

Phenylketonuria
1- what type of inheritance?
2- mutation in what gene?
3- what does the enzyme break down?
4- carrier and disease
5- what happens if both parents are carriers?

Answer 20

1- recessive inheritance
2- PAH gene (phenylalanine hydroxlase)
3- dietary phenylalanine
4-
Carrier: 1 in 50
Disease: 1 in 10,000
5-
- their child will be born with PKU if they receive one copy of the faulty gene from each parent

When both parents are carriers, the possibilities in each pregnancy are:
- 1 in 4 chance of having an affected child (25%)
- 2 in 4 chance of having a child that is a carrier (50%)

Question 21

Phenylketonuria
1- what can a build up of phenylalanine lead to?
2- how can phenylalanine only happen?
3- how can symptoms be prevented
4- what genotype or phenotype

Answer 21

1- Build up of phenylalanine toxic to developing brain. As a result they can have:
- learning disabilities
- behavioural difficulties
- epilepsy

2- Build up of phenylalanine can only happen if they have phenylalanine in their diets.

3- PKU screening at birth in UK, as symptoms can be prevented by diet

(same genotype, different phenotype- by recognising early and change diet (interplay of genes and environment- changing diet changes outcomes of this genotype)

Question 22

Chromosomal abnormalities:
Monosomy and Trisomy

Answer 22

Monosomy: single copy of a chromosome.
Embryonic lethal

Trisomy: three copies of a chromosome
Very high rate of embryonic lethality

Question 23

Chromosomal abnormalities: down syndrome
- trisomy in?
- symptoms narrowed down to?
- smaller?
- what intellectual ability?
- high risk?

Answer 23

Trisomy in chromosome 21 (extra copy of ch 21)
(error in first meiotic division)

Symptoms narrowed down to 20-40 genes on chromosome 21. Overexpression of these genes?

• Smaller brain size frontal lobes and cerebellum.
• Mild to moderate intellectual ability
• High risk of early onset Alzheimer’s Disease- gene for the amyloid precursor protein is on chromosome 21 and we know that mutations in that amyloid precursor protein can cause Alzheimer’s disease.

Gene dosage effect in actual chromosome number

Question 24

X-linked conditions
1- what does the wrong number of chromosomes impact?
2- what do males and females have?
3- Y vs X chromosome
4- need to ensure?
5- what does X inactivation in females do?
6- what do x-linked disorders vary in?

Answer 24

1- The wrong number of chromosomes impacts normal development reflecting importance of gene dosage e.g. Downs syndrome
2- But males have XY and females have XX therefore major variation in gene dosage between sexes

3- Y chromosome - very few genes, mostly governing male sexual function.
- X chromosome - many genes that play vital roles in both sexes

4- Need to ensure that cells function normally with either one or two X chromosomes.
5- X inactivation in females (happens early in development) switches off one copy of X chromosome during embryogenesis. So you inherit one active X chromosome and one inactive X chromosome.
6- X-linked disorders vary in their penetrance according to sex. So if you’ve got a mutation in X chromosome, its potentially going to look different in a male compared to how it looks in a female.

Question 25

X-inactivation in females (XX)
How does it work?

Answer 25

If you take cells when they’re at about blastocyst stage (before they have differentiated) x-inactivation occurs. In every cell in this blastocyst stage, one x-chromosome is going to be switched off and one is going to be left active. This is going to be different in all the cells. 50% of the cells will have the maternal X switched off and 50% of the cells will have the paternal X switched off. The offspring from each of these cells will stick with the pattern that the cell it was divided from was switched off.

Question 26

X-inactivation in females (XX) vid breakdown

Answer 26

• Cell divide, embryo gets bigger
• Each cell has both X chromosome active
• But in early in the genesis, each cell will inactivate one of its X’s and one cell will remain with the paternal X as active while the other one the maternal one.
• The process will happen at random
• You will have almost half of the cells with the maternal X active and half with paternal X
• Embryo will continue to grow, cells divide, all the decedents will keep the same X active
• See this in colourful cats

Question 27

X-inactivation in females (XX)
- what does x-inactivation ensure?
- XY and XX cells difference in activation
- what is an adult female?
- X and inheriting
- X chromosome arrangement in females
- X in males

Answer 27

1- X – inactivation ensures that the dosage of active genes is maintained in all individuals
2- XY cells - no inactivation XX cells - inactivate one X
3- An adult female is a mosaic of clones derived from different embryonic cells. Within a clone, all the cells inactivate the same X, but between clones the choice is random. If she happens to be a carrier of an X-linked recessive disease, this can have major implications
4- In some, the X chromosome is going to be the chromosome you inherited from your mother and in others the X chromosome will be the chromosome you inherited from your father
5- Females have mixture of expression of X chromosomes that is random depending on which one was inactivated and which of the cells that then went on to make that part of the brain.
6- Males don’t have X inactivation so they only have one copy. Their brain will be expressing genes from the maternal X chromosomes.

Question 28

Rett syndrome (X linked)
1- what disorder, affecting who, leading to?
2- what condition?
3- mutation in what gene? causing?
4- What chromosome linked to?
5- what does inactivation mean?
6- what do affected males not have?

Answer 28

1- Progressive neurodevelopmental disorder almost exclusively affecting females, leading to profound disabilities.

2- Rare condition: 1in 10,000

3- Mutation in the gene MeCP2. This “transcriptional repressor” turns off the expression of unwanted genes during synapse formation.

4- X-linked – gene the X chromosome
(spontaneous mutation rather than inherited)

5- X – inactivation means that not all cells will express mutated MeCP2 gene (because half of the ones that are active are half mothers and half fathers. It’s likely only one of these carries that mutation. SO only some areas of the brain will be affected), therefore variable penetrance, sometimes see milder symptoms.

6- Affected males do not have a “good copy” of MeCP2. Much more severe phenotype, embryonic lethal or die soon after birth)

Question 29

Rett syndrome (X linked)
- what do individuals lose?
- girls with Rett development

Answer 29

They lose purposeful use of their hands and are seriously disabled for life, with reduced muscle tone and seizures. A temporary “autistic-like” phase often occurs at the onset of the disorder, and older children are known for their social engagement through intense eye gaze.

Girls with Rett syndrome start off developing normally but then begin to show deficits that are similar to autism like deficits. These become more profound as they get older.

Question 30

Fragile X
1- most common…
2- prevalence in gender?
3- what linked?
4- mutation in?
5- gene and protein
6- milder penetrance in?

Answer 30

1- Most common inherited form of learning disability

2- Relatively common: 1 in 4000 males; 1 in 6000 females (carrier of ‘premutation’: 1 in 259 females; 1 in 800 males). Dominantly seen in males because if you have a mutation in males, every copy will be the bad copy (mutated version) and every cell in the brain will have this copy and not function as well.

3- X-linked : symptoms predominantly in males

4- Mutation in one end of the FMR1 gene (the 5’ untranslated region), consisting of an amplification of a CGG repeat (200+ copies; normally between 6 and 40 repeats).

5- The FMR1 gene encodes the FMR protein, which is thought to shuttle select mRNAs between the cytosol and nucleus.

6- Milder penetrance in females due to X – inactivation, so not always recognised

Question 31

What are epigenetics?

Answer 31

Regulating whether the genes are switched on or not

Question 32

How does epigenetics work?
- DNA sequences structure?
- What are different parts of the DNA?
- methylation on gene?
- DNA sequence and phenotype?
- what can epigenetic changes be inherited from?

Answer 32

The DNA sequences tend to be wrapped around proteins called histone

Different parts of the DNA are more or less opened to be transcribed. This depends on methylation or histone proteins. So that a gene if its wrapped around histone in a certain way isn’t actually going to be able to unwrap and be transcribed so that gene is permanently switched off.

Genes themselves can be methylated. A methylation on a gene means a transcription can’t bind and so that gene can’t be switched on.

Within a gene you can have exactly the same DNA sequence but depending on those inactivation processes you’re going to have a different phenotype.

Epigenetic changes can be inherited changes from generation to generation. So they can be inherited changes in that aren’t due to changes in the actual DNA sequence. They’re just due to these changes, permanent changes in the way that that DNA sequence can be expressed.

Question 33

DNA methylation, histones and histone modification

Answer 33

DNA methylation:
Methyl group (an epigenetic factor found in some dietary sources) can tag DNA and activate or repress genes.

Histone:
Histones are proteins around which DNA can wind for compaction and gene regulation.

Histone modification:
The binding of epigenetic factors to histone “tails: alters the extent to which DNA is wrapped around histones and the availability of genes in DNA to be activated.

Question 34

Epigenetics
phenotype and genotype

Answer 34

Inherited change in phenotype
Not due to changes in genotype (DNA sequence)

Question 35

Epigenetics and the environment
- what are they?
- end up with?
- phenotypic differences?
- epigenetic modifications?
- BUT…
- early development influence on?

Answer 35

• What genes are switched on and off.
• Can end up with differently behaving or a different situation in the offspring.
• Phenotypic differences- what genes are switched on or off can change which cells we have in the body- neuron a neuron (because muscle genes are switched off), muscle cell a muscle cell (because all the neuron genes are switched off) etc).
• Epigenetic modifications can be stable through life course (e.g. cellular differentiation)
• BUT… Some affected by environment
• Early developmental influence on stress resilience / depression (in later life)

Question 36

Epigenetics and the environment:
- what does maternal care switch on?
- what receptor?
- activates?
- which switches on?
- and expresses?

Answer 36

Maternal care (pup licking) switches on serotonin, action through 5-HT7 receptor (intracellular cascade) to activate transcription factor NGFIA, which switches on gene (Nr3C1) which expressed Glucocorticoid receptor (GR). (This GR protein is important in the hippocampus for regulating stress).

(the release of serotonin because of the maternal licking is causing this gene to be switched on and activated)

Question 37

Absence of licking (poor maternal care)…

Answer 37

• promoter methylated
• low levels of GR

Question 38

Methylation retained through?
Without GR…

Answer 38

Methylation retained through lifetime. Without GR loss of feedback in HPA axis, increased stress hormones, increased anxiety/depression

Question 39

High vs low maternal licking?

Answer 39

High maternal licking:

High licking are activating GR to be expressed in the hippocampus and as a result of that if later in life these rat pups are stressed, the stress release pathway activates the release from the hypothalamus of CRF to the pituitary to activate the adrenal glands which release glucocorticoids. This glucocorticoid feeds back up to the hippocampus where it activates GR. And the activation of these receptors switches off this downstream stress pathway.

So the hippocampus is modulating the reaction to stressful life evens for those parts and doing it by a feedback mechanism where its responding to the stressor. There will be other signals saying whether its a stressful event.

GR are important early and late through life.

Low maternal licking:

If we have a rat where mother rat has poor maternal behaviour and this gene isn’t activated at this stage of development, then because this transcription factor isn’t sitting on this dna, instead this dna becomes methylated. (methylation= epigenetic modifications that switches off genes). The transcription factor then can’t bind to the gene because its methylated so it can’t make the sane amount of GR. This methylation is permanent.

Later in life, when you have this pathway being activated it won’t work anymore because you haven’t got the GR responding to the glucocorticoids.

These pups go through life with high glucocorticoids because you haven’t got this switch off, consequently mean suffer from high anxiety.

Question 40

Transgenerational Epigenetics

Answer 40

Environmental influence on parents can affect offspring

Disrupted histones in sperm cells:

Showed altered RNA profile in offspring (and grand-offspring)

(Histones can be modified by chemicals (e.g. smoking / drinking))

They showed: Histone modifications passed to the offspring and then passed to the next generation

Therefore these epigenetic changes can have quite dramatic impacts across generations as well as just within one generation.

Question 41

Human genetics:
1- how much of our DNA sequence do we share with each other
2- What are SNPs
3- how many SNPs identified through human genome project sequencing?
4- what is each SNP a change in
5- what are they?

Answer 41

1- We share over 99.9% of our DNA sequence with each other

2- Natural variations in our DNA are known as Single Nucleotide Polymorphisms (SNPs)

3- ~ 3,300,000 SNPs identified through human genome project sequencing

4- Each SNP is a change in base pair sequence so its causing a one nucleotide difference between 2 people.

5- These are naturally occurring

Question 42

Gene association studies:
1- What do they look for?
2- What do Genome wide association studies (GWAS) look for?
3- _______ vs ________

Answer 42

1- Gene association studies look for sorting of SNPs in candidate genes

2- GWAS – look for what SNPs sort with disease state

3- Functional SNPs vs genetic tags

Question 43

Alzheimers disease:
1) what type of disease?
2) 2 things that if you see them under a microscope you can do a postmortem diagnosis that finite of alzheimers disease
3) structures from healthy brain to mild/ severe alzheimers disease

Answer 43

1) Age related disease (more likely to get it the older you are)
2) Tau microfibullary tangles and amyloid plaques
3) (degeneration of the brain through brain imaging)
- Enlarged ventricles- as brains shrinking- space being taken up with liquid in ventricles
- Cortical shrinkage
- Shrinking of hippocampus

Question 44

Genetics and Alzheimer’s disease:
1- mutations in what cause early onset Alzheimers disease?
2- higher number of what gene?
3- nucleotide difference?
4- onset linked to PSEN and APOE4

Answer 44

1- amyloid precursor protein (APP) or in PSEN (on chromosome 21- Downs trisomy)
2- Higher number of APOE4 gene in people with alzheimers disease than the more common variant (APOE3 gene)
3- One SNP difference between APOE3 and APOE4 gene and it changes an amino acid in protein
4- PSEN → tell you about early onset
APOE4 → more late onset

Question 45

Polygenetic factors: Twin Studies
- concordance definition
- Huntingtons, Schizophrenia and bipolar disorder in monozygotic and dizygotic twins

Answer 45

concordance= the degree to which a trait is seen in 2 individuals

Huntington’s:
Purely genetic
MZ- 100% (if one of you have Huntington’s the other one will probably get it too)
DZ- 50% (you’ve got the same chance as just a brother or sister, you may inherit the healthy copy from a parent so you see 50% chance of that being carried through.)

Schizophrenia and Bipolar:
Schizophrenia:
MZ- 50%
DZ- 15%

Bipolar:
MZ- 69%
DZ- 13%
Have some hereditary, so there is a genetic component to these diseases which changes between MZ and DZ twins. We know this is a polygenetic trait.

Question 46

Genetics of schizophrenia

Answer 46

High correlation between risk of developing schizophrenia and genetic relationship (Gottesman, 1991).
Large genetic component, but not purely genetic.

Share of genetic material:
MZ twin: 100%
DZ twin or sibling: 50%

Question 47

Genetics of schizophrenia
Study and results

Answer 47

GWAS study of over 150k people (36,000 with schizophrenia)- it took this number to pull out 108 genes because each individual gene is quite small

Tried to find some of those genes creating polygenetic risk for sz

They found 108 genes that show small risk- lots of genes contributing polygenetic risk to sz

Lots of the genes to do with synaptic transmission, glutamate and dopamine (Dopamine D2 receptor)

Question 48

Genes to behaviour
- Interaction
- What is it difficult to do?

Answer 48

Environment can change gene expression (Epigenetics)
Genes can alter how we interact and react to a particular environment

Difficult:
- to define genetic and non-genetic factors
- to understand the interactions among these many factors
- to follow the steps between gene expression and behaviour
- to allow for individual differences
as no particular combination of genes and experiences is ever replicated exactly.
- limited experimental control and ethnical issues in human studies

Question 49

Animal models

Answer 49

• Similarity of genes and biological function with humans.
• Conservation of behaviour with humans.
• Create inbreed strains of animals that are genetically identical.
• Control environmental conditions.
• Manipulate genes: mutate or remove particular gene, or insert copy of a human gene.

Question 50

Animal models:
- what models
- what do humans have?
- high number of genes due to?

Answer 50

• Nematodes
• Drosophila
• Zebrafish
• Mouse

Humans have 3-4x as many genes but about the same number of gene families.
High number of genes due to two rounds of genome doubling during the evolution of vertebrates.

Question 51

Animal models:
Mice-
1) what is it?
2) Life cycle
3) what % of mouse genes have homologues in man
4) what is similar across mammalian species?
5) wealth of….
6) targeted mutagenesis
7) example

Answer 51

Known genome
Relatively short life cycle

The mouse genome:
22,000 genes
20 chromosome pairs.

Why Mouse?
- 99% of mouse genes have homologues in man
- Similarly organised brain, and behavioural traits common across mammalian species.
- Wealth of background information on biological processes and well defined behavioural tests, including models of disease states.
- Targeted mutagenesis: mutate a particular gene and look for subtle changes in behaviour.
- For example, mutations in the leptin gene cause morbid obesity and in myosin VII cause deafness both in humans and in mice.

Question 52

Genetic studies using rodents

Answer 52

• Inbred strains and BXD recombinant lines
• Mutagenesis and Knockouts
• Genetic tools for neuroscience

Question 53

Inbred strains:
- what do imbred strains have?
- what do comparison of these strains tell us?

Answer 53

• Inbred strains will have different genetics, neurobiology and behaviour.
• Comparison of these strain can tell us about how genetics influence behaviour.

Question 54

1- Which mice show high preference for alcohol?
2- Genetics: QTLs for activity mapped to chromosomes…

Answer 54

1- C57
2- 2, 5, 12, 13 and X

Question 55

Genetically engineered mouse models
- Knockout mice
- Knock-in mice
- Transgenic mouse

Answer 55

Knockout mice:
- What happens in absence of specific gene

Knock-in mice:
- Introduce a specific mutation
- ‘humanised’ mice

Transgenic mice:
- Reporter constructs to tag cells
- Constructs to target cell specific or time specific gene manipulations

Question 56

From human condition to animal model and back: Rett syndrome

Answer 56

Progressive neurodevelopmental disorder almost exclusively affecting females, leading to profound mental impairment.

Mutation in the gene MeCP2. This “transcriptional repressor” turns off the expression of unwanted genes during synapse formation.

Disease a result of inactive MeCP2

Mouse with knockout of MeCP2 display similar symptoms to Rett Syndrome

Inducible KNOCKIN… gene switched off during development… reverts to wildtype (normal) form with drug treatment… can symptoms be reversed?

They lose purposeful use of their hands and are seriously disabled for life, with reduced muscle tone and seizures. A temporary “autistic-like” phase often occurs at the onset of the disorder, and older children are known for their social engagement through intense eye gaze.