NEUROGENETICS Flashcards
What are chromosomes?
present in every cell of the human body. 23 pairs. each chromosome has over 100 million base pairs of DNA.
What is DNA?
double helix made of 2 chains of phosphate and deoxyribose. 4 nucleotide bases -> adenine, thymine, cytosine, guanine.
Human Genetics
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.
Two cell division processes
mitosis -> somatic cells (daughter cells) identical to parents - forming diploid cells. meiosis -> gamete cells (haploid cells) containing half number of chromosomes
Homologous recombination?
It is the crossing over which allows for genetic diversity (natural selection and evolution) sharing a mix of paternal and maternal DNA
Genes
23,000 genes on the human chromosome -> genes are long sequences of base pairs that encodes proteins. genes are turned on by transcription factors.
Protein synthesis
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
Mendels Law scenario
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.
Gene variations affecting brain and behaviour
single gene disorders (dominant/recessive), gene variations/mutations, chromosomal abnormalities and X-linked conditions
chromosomal abnormalities:
monosomy -> single copy of a chromosome. embryonic lethal.
trisomy -> 3 copies of a chromosome, very high rate of embryonic lethality.
Down Syndrome:
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
X and Y-linked roles
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.
X-inactivation in females
ensures that dosage of active genes is maintained in all individual since they have two. Only one X chromosome is active in all individuals.
XX risks in genetic disease
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
Rett’s syndrome
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.
Fragile X (X-linked)
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.
Huntington’s Chorea
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.
What is Phenylketonuria
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.
Epigenetics
inherited change in phenotype and not due to changes in genotype. genes can be environmentally activated.
Maternal care in epigenetics
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).
Absence of pup-licking causes:
lower levels of glucocorticoid receptor, increased stress hormones (cortisol), increased anxiety/depression. promoter methylated
Transgenerational Epigenetics
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).
Gene association studies
looking for sorting of single nucleotide polymorphisms (SNP)
Genome Wide association studies (GWAS)
looking for what SNPs links with disease state
Alzheimer’s disease
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.
Polygenic factors - twin studies
concordance rates in twins. MZ twins = Huntington’s = 100%, schizophrenia = 50%, bipolar disorder = 69%
DZ twins = Huntington = 50%, schizophrenia = 15%, bipolar = 13%
Genetics of schizophrenia
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).
Genes -> Behaviour
environment can change gene expression (epigenetics). genes can alter how we interact and react to a particular environment.
When measuring genes->behaviour. it is difficult to:
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.
Looking at animal studies:
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.
Mice studies in genetics
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.
Genetically engineered mouse models
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
Rett Syndrome in Mice
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.
Genetic studies using rodents
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.
