NEUROGENETICS

Question 1

What are chromosomes?

Answer 1

present in every cell of the human body. 23 pairs. each chromosome has over 100 million base pairs of DNA.

Question 2

What is DNA?

Answer 2

double helix made of 2 chains of phosphate and deoxyribose. 4 nucleotide bases -> adenine, thymine, cytosine, guanine.

Question 3

Human Genetics

Answer 3

we share 99% of our DNA sequence, 1% variance. natural variations in our DNA is called single nucleotide polymorphisms. 3 million SNP identified through human genome project sequencing.

Question 4

Two cell division processes

Answer 4

mitosis -> somatic cells (daughter cells) identical to parents - forming diploid cells. meiosis -> gamete cells (haploid cells) containing half number of chromosomes

Question 5

Homologous recombination?

Answer 5

It is the crossing over which allows for genetic diversity (natural selection and evolution) sharing a mix of paternal and maternal DNA

Question 6

Genes

Answer 6

23,000 genes on the human chromosome -> genes are long sequences of base pairs that encodes proteins. genes are turned on by transcription factors.

Question 7

Protein synthesis

Answer 7

Transcription -> gene’s DNA sequence is copied into messenger RNA (mRNA)
Translation -> a ribosome attaches to the mRNA moves along, reading each triplet code (3 bases) and using transfer RNA (tRNA) to form amino acid chain to form a protein

Question 8

Mendels Law scenario

Answer 8

pea plant scenario -> dichotomous traits (short or tall peas) -> alleles. controlled by a single gene. tall gene is dominant. short gene is recessive. if genes are identical (TT or ss) -> homozygous. if genes are not identical (Tt) -> heterozygous.

Question 9

Gene variations affecting brain and behaviour

Answer 9

single gene disorders (dominant/recessive), gene variations/mutations, chromosomal abnormalities and X-linked conditions

Question 10

chromosomal abnormalities:

Answer 10

monosomy -> single copy of a chromosome. embryonic lethal.
trisomy -> 3 copies of a chromosome, very high rate of embryonic lethality.

Question 11

Down Syndrome:

Answer 11

Trisomy in chromosome 21 (error in first meiosis division). symptoms -> narrowed down to 20-40 genes on chromosome 21. they have smaller brain size frontal lobes + cerebellum. mild-moderate intellectual activity. high risk of early onset Alzheimer’s disease

Question 12

X and Y-linked roles

Answer 12

Y = very few genes, mainly governing male sexual function.
X = many genes playing vital roles. X-inactivation in females switches off (cancels out) one copy of the X chromosome during embryogenesis. may vary according to sex of person.

Question 13

X-inactivation in females

Answer 13

ensures that dosage of active genes is maintained in all individual since they have two. Only one X chromosome is active in all individuals.

Question 14

XX risks in genetic disease

Answer 14

all cells inactive the same X chromosome, but between which one is random. if she happens to be a carrier of an X-linked recessive disease, can have implications

Question 15

Rett’s syndrome

Answer 15

X-linked. progressive neurodevelopmental disorder almost exclusively on females. disabilities. 1 in 10,000 mutations in gene Mecp2. due to extra X-chromosome allows to mediate the penetrance and effects. whereas in males they immediately die cos they do not have a good copy of MePC2 gene.

Question 16

Fragile X (X-linked)

Answer 16

most common inherited form of learning disability. 1 in 4000 males, 1 in 6000 females. carrier of pre-mutation -> 1 in 259 females, 1 in 800 males. mutation in one end of the fMRI gene consisting of an amplification of CGG repeat (200+ copies) FMR1 gene encodes the FMR protein which is thought to select mRNAs between cytosol and nucleus. milder penetrance in females.

Question 17

Huntington’s Chorea

Answer 17

degeneration of the brain striatum. bad progression of movement, cognition. autosomal dominant inheritance -> single copy will be dominant and lead to disease regardless. on chromosome 4 -> excessive repat of CAG bases (has 40 copies of it rather than 11-34). Disease onset is 35-55. unstable triplet base therefore can increase in subsequent generations.

Question 18

What is Phenylketonuria

Answer 18

recessive inheritance - mutations in the PAH gene (phenylamine hydroxylase). enzyme breaks down dietary phenylamine. carrier -> 1 in 50. disease -> 1 in 10,000. build up of phenylamine is toxic to developing brain and can impair cognitive function. = learning disabilities, behavioural difficulties, epilepsy. PKU screening at birth in UK. symptoms can be prevented with diet.

Question 19

Epigenetics

Answer 19

inherited change in phenotype and not due to changes in genotype. genes can be environmentally activated.

Question 20

Maternal care in epigenetics

Answer 20

pup-licking switches on serotonin-action through 5-HT7 receptor (intracellular cascade) to activate transcription factor NDPIA which switches on genes Nr3Cl, which expresses glucocorticoid receptor (GR).

Question 21

Absence of pup-licking causes:

Answer 21

lower levels of glucocorticoid receptor, increased stress hormones (cortisol), increased anxiety/depression. promoter methylated

Question 22

Transgenerational Epigenetics

Answer 22

environmental influence on parents can affect offspring e.g., disrupted histones in sperm cells, altered RNA profile in offspring, histones can be modified by chemicals (smoking/drinking).

Question 23

Gene association studies

Answer 23

looking for sorting of single nucleotide polymorphisms (SNP)

Question 24

Genome Wide association studies (GWAS)

Answer 24

looking for what SNPs links with disease state

Question 25

Alzheimer’s disease

Answer 25

mutation in amyloid precursor protein on chromosome 21. risk genes identified in gene association or GWAS studies. Found one SNP difference between APOE3 (common allele) and APOE4 (changes in amino acid protein). accumulation of APOE4 shows highest risk.

Question 26

Polygenic factors - twin studies

Answer 26

concordance rates in twins. MZ twins = Huntington’s = 100%, schizophrenia = 50%, bipolar disorder = 69%
DZ twins = Huntington = 50%, schizophrenia = 15%, bipolar = 13%

Question 27

Genetics of schizophrenia

Answer 27

high correlation between risk of developing schizo -> genetics. GWAS study of over 150k people (36k w schizo). genes -> synaptic transmission, glutamate + dopamine (dopamine DR receptor).

Question 28

Genes -> Behaviour

Answer 28

environment can change gene expression (epigenetics). genes can alter how we interact and react to a particular environment.

Question 29

When measuring genes->behaviour. it is difficult to:

Answer 29

define genetic/non genetic factors, understand interactions, allow for individual differences, no particular combination of genes and experiences is ever replicated exactly. limited experiments on human ethical issues.

Question 30

Looking at animal studies:

Answer 30

similar genes and biological function. conservation of behaviour with humans. create inbreed stains of animals that are genetically identical. can control environments, manipulate genes, mutate, remove, genetically engineer.

Question 31

Mice studies in genetics

Answer 31

22,000 genes, chromosome pairs, 99% of genes are same in humans (homologues). similar organised brain, mice genes can be mapped onto the human chromosome.

Question 32

Genetically engineered mouse models

Answer 32

knockout mice -> what happens in the absence of specific genes?
knock-in mice -> introduce a specific mutation ‘humanised mice’.
transgenic mice -> constructing and targeting tag cells. specific gene manipulations

Question 33

Rett Syndrome in Mice

Answer 33

mutation in gene MeCP2, turns off unwanted genes during synapse formation. disease is a result of inactive MeCP2. mouse with knockout MeCP2 display similar symptoms to rett syndrome. knockin mice -> genes switched off during development reverts to wildtype (normal) form with drug treatment…can symptoms be reversed.

Question 34

Genetic studies using rodents

Answer 34

inbred stains and BXD recombinant lines, mutagenesis and knockouts. genetic tools for neuroscience. comparison of these stains can tell use about how genetics influence behaviour. BXD recombinant breeding -> which mice show high preference for alcohol? what C57 genes do they have. DBA genes in mice. through meiosis recombination.