Samenvatting
Samenvatting Research skills - biomedical sciences
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Voorbeeld 3 van de 26 pagina's
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Research skills tentamenLecture 1 – General introduction
Autism Spectrum Disorder difficult to study
- Based on behavioral symptoms
- Lack of known causal factors
- Poor access to brain tissue
Understanding biological mechanisms as a first step towards more effective intervention strategies.
Advantages of using animal (in vivo) models:
1. Causality can be tested by experimental design
2. Control over environmental and genetic background
3. Relevant tissue can be obtained
4. Developmental aspects can be studied
The stork experiments The bigger the population, the more likely to spot storks. This has nothing
to do with causation (as been thought), but with correlation.
An observational study is where nothing changes and just record what you see, but an experimental
study is where you have a control group and a testable group.
Observational studies
- Case-control studies
- Genetic association studies
- Cohort studies
- Descriptive studies
- Ecological studies
- Cross-sectional studies
Experiments
- Experimental manipulations cellular models in vitro, animal models in vivo
testing biological mechanisms of (neuro) diseases and processes
- Clinical trials (randomized)
A correlation between variables, however, does not automatically mean that the change in one
variable is the cause of the change in the values of the other variable. Causation indicates that one
event is the result of the occurrence of the other event; there is a causal relationship between the
two events.
Association studies are a starting point for an experiment. Experiments in mice to investigate the
impact of the mutation on neurobiology.
,Lecture 2 – genes and behavior
Genetic association study (forward genetics) = phenotype genotype
Genetic manipulation (reverse genetics) = genotype phenotype
Genetic association studies
- Family studies (e.g. mendelian traits)
- Case-control studies
- Population genetics
Genetic manipulation models
- Experimental manipulation (e.g. knock-out)
- Behavioral readouts
- Conditional gene expression
Family studies
Familiality is not heritability.
Twin studies can be used dissect genetic and environmental influences. Twin designers allow to
assess the genetic and environmental influence on a trait using twin pairs. Monozygous twins share
100% of their genes, while dizygotic twins share only 50%. Estimate heritability by assessing whether
MZ twins are more similar than DZ twins.
Twin studies indicate genetic contribution to psychiatric conditions. In monozygous twins, the rate of
concordance (overeenstemming) is way higher than in dizygous twins.
Heritability = 2 x (rMZ – rDZ) note: heritability always depends on the environmental (health,
nutrition etc) context in which it was measured.
The genome map discovery: (an example)
Linkage study (1990): association of genetic locus with behavioral disorder running in family.
Aggressive behavior in a Dutch family was linked to defect in MAOA gene.
1. Only present in males suggests X-chromosome
2. Investigation of common genetic markers and haplotypes (i.e. combination of markers)
unique for affected family members.
3. Mutation likely inherited via combination of markers and pointing at marker for MAOA gene.
Using ‘sanger sequencing’ technique to read the full implicated DNA sequence. By reading the
sequence from bottom to top, the sequence becomes clear.
Trying to investigate which mutation causes the psychiatric disorder.
Association of rare mutations with neurodevelopmental disorders based on Whole Exome
Sequencing (2010-now).
1. Next generation sequencing allows to read all the exomes of a genome at once
- 180 000 exons
- 30 million base pairs (1% of the human genome)
2. NGS is used to identify genetic mutations that are likely detrimental to the gene
- Rare inherited mutation
- De novo mutation only found in affected child
Note: because so many exomes are tested, it can be very difficult to know which mutation is really
causing the disorder (all individuals have some ‘faulty genes’).
, Rare mutation that have a big effect will remain rare, because they will not produce a lot of offspring.
Not so rare disorder cannot be seen in families because they have such a small effect.
Mendelian disorders are associated with rare large-effect mutations (in families). Polygenic traits are
influenced by many variants with small effects (common in populations).
Mendelian disorders vs polygenic traits:
Mendelian disorders are associated with rare large-effect mutations (mostly investigated in
families)
Polygenic traits are influenced by many variants with small effects (common variation in
population).
Rare mutations that have a big effect will still be rare, won’t become common.
Knock out gene (KO) = gene has been inserted with stop sign?
Conditional KO mouse is an animal in which the gene of interest is:
- Inactivated only in specific cell types in a certain issue: other cell types and tissues exhibit
an unmodified functional gene expression (= tissue specific KO model)
- temporarily inactivated at a given time-point in embryonic post natal or adult animals
(=tamoxifen induces KO model)
Genome-wide association study (GWAS) to identify common genetic variation linked with
schizophrenia.
1. Testing associations between schizophrenia and genetic markers across the entire genome
(in a large population)
2. GWAS requires extremely large sample sizes as the effect-sizes for these markers are often
small.
Note: Significant markers are correlated with the actual causal variant, but not necessarily causal.
Genetic association studies can also be used across species.
Peromyscus mice make long tunnels (to escape) and maniculatus mice make shorter tunnels. Digging
a longer tunnel is a dominant pattern of inheritance (erfelijkheid).
Genetic associations for burrowing behaviors
- Multiple loci explaining difference in tunnel length – 3cm each
- Locus explaining probability to make escape tunnel
Genetic manipulations in animal models
From genetic disorders to animal models
- Animal models focus on genes disrupted by rare mutations
- Study in fixed genetic and environmental background
Knockout animals can be created by homologous recombination of a targeting vector. Insert the
knockout allele (stop inserted by recombination in exon 5) into the wild type allele. By sequencing
the DNA you can check which animal is a WT and which one is a KO (more basepairs = KO).
1. Generation of targeting construct (the knock-out vector)
2. Add that to stem cells and apply electroporation
3. Select the KO mice (positive cells)
4. Injection of targeted ES cells to blastocytes
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