Neurogenetics Flashcards
The building blocks of genetic code are called…
Nucleotides (or bases)
How many different types of nucleotides/bases are there in DNA?
4
What are the bases in DNA called? ACGT
- Adenine
- Cytosine
- Guanine
- Thymine
What are the building blocks of proteins?
Amino acids
What comprises the genetic code for a particular amino acid?
A specific sequence of 3 bases/nucleotides
How many bases are there in the human genome? (think: solar system)
3 Billion
How many genes code for proteins
20-25 thousand
The four bases/nucleotides appear in strict pairs. What is the pairing they appear in?
Cytosine with Guanine (C-G)
Adenine with Thymine (A-T)
What is the word for the full gamete of human chromosomes
The karyotype
How many chromosomes in the human karyoptype
46, in 23 pairs
What are the two types of chromosome
sex and autosomal
How is the function of a protein determined?
By its structure
How is the structure of a protein determined?
By its sequence of amino acids
Amino acids are made accordion got the instructions enshrined as sequences of three bases in the genome. What is the name we give to that sequence of three bases?
A codon
Does changing a single base necessarily change the associated amino acid?
No. It can, but not always
What is the name of the position on the genome at which the base/nucleotide differs between individuals (ie some of us ave a T and others have a G)
A Single-Nucleotide Polymorphism (SNP)
What is the name given to the two alternative basis of a SNP? (As in, could have a T or a G or etc )
Alleles
How is a genotype determined at a given SNP?
By the two alleles on the two copies of the chromosome
there are slight exceptions for the sex chromosomes on males
What is the term given to the presence, absence or value of a trait or traits?
Phenotype
There are a range of genetic variants.
What is the insertion-deletion variant and how can you tell if that’s what you’re looking at?
The reference string of nucleotides has got a chunk missing/added relative to the comparison string
If the strings are the same length, probably not dealing with insertion-deletion
There are a range of genetic variants.
What is the block-substitution variant and how can you tell if that’s what you’re looking at?
There’s a chunk of letters out of whack (and it’s not a inversion variant or a copy number variant)
With this one, just need to make sure it’s not actually an inversion variant
There are a range of genetic variants.
What is the INVERSION variant and how can you tell if that’s what you’re looking at?
This is the tricky one…
It’s basically A) the mirror version (like, the opposite types - the C to the G etc) and then (B) put in the reverse order… Oh lordy
There are a range of genetic variants.
What is the COPY NUMBER variant and how can you tell if that’s what you’re looking at?
This is where there is a sequence that is accidentally copied a bunch of times. Like in the reference or the alternative string, the letters CCG CCG CCG appear a bunch of times with no corresponding letters in the other string
Is mutation rare or common?
Rare
How frequent is mutation, expressed as a percentage of alleles in the population?
<1%
Is polymorphism rare or common?
Common
How frequent is polymorphism, expressed as a percentage of alleles in the population?
Greater than or equal to 1%
For females, how is excess dosage or X-chromosome protein avoided?
One copy of the X-chromosome is silenced/inactivated in each cell… can be random
What do you call it when genes are encoded by the same stretch of DNA, but transcribed in opposite directions (ie TSIX vs XIST)
They are ANTISENSE partners
In female mammals, how does the redundant extra X chromosome get switched off?
When there are two X-chromosomes in one cell:
- The XIST gene produces an RNA transcript* that coats one chromosome, which is inactivated as a ‘Barr body’
- The TSIX gene on the other chromosome produces an RNA transcript* that suppresses transcription of XIST
In the context of heritability…
what is the equation that defines phenotypical variation?
P = G + E + (G x E) + 2COVGE
2COVGE = Covariance between genes and environment
What is the equation that defines heritability
h2 = G/P
Heritability = Variance from GENES divided by PHENOTYPIC variance
Define heritability
The proportion of the phenotypical variation due to genetic causes
What are the two consideration when thinking about heritability?
- It is a local measurement - specific for a give population at a given time
- Depends on the amount of genetic and environmental variation present in the population
What is the heritability of MDD?
.40
What is the heritability of Anxiety disorders?
.40-.50
What is the heritability of Alcohol dependence?
.50-60
What is the heritability of eating disorders?
.55-60
What is the heritability of bipolar disorders?
.60-.85
What is the heritability of OCD?
.60-.70
What is the heritability of SCZ?
.70-85
What is the heritability of ADHD?
.60-.90
What is the heritability of ASD?
.90
How did we measure heritability before the advent of molecular genetics?
Genetic epidemiology
which is based on related individuals share genetic material
What’s the thing we look at in twin studies…? (Starts with C, like a plane…)
Concordance rates
If there is higher concordance in monozygotic twins than in dizygotic, this implies no genetic component, T/F?
FALSE
What are the four ‘modes of inheritance’?
For the purposes of this exam - in two pairs
Dominant vs recessive
AND
Autosomal vs X-linked
How many mutations on copies of the chromosome do dominant traits require, in order to be expressed as a phenotype?
ONE
How many mutations on copies of the chromosome do recessive traits require, in order to be expressed as a phenotype?
TWO
What tool can we use to infer the modes of inheritance in any particular case
Pedigree chart
In a pedigree chart, what does a circle signify?
A female
In a pedigree chart, what does a square signify?
A male
In a pedigree chart, what does a coloured in shape signify?
An affected person
In a pedigree chart, what does a cross line mean?
A deceased person
Autosomal characteristics are equally common in both sexes, T/F?
TRUE
If you see a pedigree map and a trait has skipped generations, what does that rule out?
Dominant characteristics… these can’t skip a generation
If you see a case of father to son passage of a trait, what does this rule out?
An X-linked trait
If you see a pedigree map and not all affected fathers have passed it on to their daughters, what does that rule out?
An X-linked trait
That is, if you see an pair of father and daughter and only one has the trait, then it is autosomal… but this doesn’t tell you whether it is dominant or recessive.
X-linked characteristics are less common in males, T/F?
FALSE
If you see a pedigree map where two affected parents have had at least SOME offspring that were unaffected, what does this mean?
It has to be recessive
… two affected parents must pass it on if it is a dominant trait
With recessive characteristics, two affected parents cannot have unaffected children, T/F?
TRUE
What is a monogenic disorder?
Origin in a single gene
What are two examples of monogenic disorders?
- Fragile-X syndrome (relevant gene = FMR1)
2. Huntington’s disease (relevant gene = HTT)
Fragile-X syndrome results from a — variant in the — region of the — gene
‘copy variant’
‘5’-untranslated region’
‘FMR1’
What is the FMR1 gene critical for?
Synaptic plasticity
What happens with a repeated CGG sequence?
WTF is a repeated CGG sequence??
Methylation
What’s the consequence of methylation? (2)
- Constricts the X-chromosome and causes ‘fragile’ appearance
- a methylated promotor region prevents transcription of the gene
What does GWAS refer to?
Genome-wide association studies (GWAS)
What is the gene for Huntington’s?
HTT
What is the gene associated with Fragile X syndrome?
FMR1
What is more common - monogenic or polygenetic?
Polygenetic
What’s the name for studies that examine the statistical; association between a phenotype and many SNP markers throughout the genome?
Genome-wide association studies
How many SNP markers are there throughout the genome?
500,000 - 2,000,000
What is the thing that allows us to observe indirect associations in GWAS?
Linkage disequilibrium (LD)
When a phenotype has a functional association with a genotyped (measured) SNP, this is called a…?
DIRECT association
When a phenotype has a functional association with a non-genotyped SNP that is in linkage disequilibrium (LD) with a genotyped SNP, this is called a…?
INDIRECT association
What is the median size of a human gene?
~25,000 bases
In a GWAS, one in every ___ bases is genotyped?
1500-6000
In a GWAS, what type of model do we use for quantitative traits?
Quantitive traits are (I think) those that are spread across a continuous measure, like IQ
Allelic dosage model…
‘Is there a statistical association between the phenotypic measurement and the number of copies of the minor allele?’
What are the three categories of traits that he talks about in relation to GWAS
- quantitive traits
- categorical traits
- binary traits
In GWAS, what type of model do we use for categorical and binary traits?
(These traits are things like ‘has SCZ or doesn’t’)
Allelic association model
‘Is one of the two alternative alleles statistically over-represented in a phenotypic group?’
In a GWAS study, what type of plot is used to to graphically summarise the results of the individual tests of association?
Manhatten plot
The vertical axis of a manhattan plot is…
transformed p values (lower p values higher on the axis)
What is the term given to the issue that means you have to set really strict alpha values when you have lots of comparisons?
‘multiple comparions’
Whats the typical alpha threshold for GWAS?
alpha = 5 x 10 to the power of negative 8
p = .00000005
What is the name of the correction for ~1 million independent (uncorrelated) tests?
Bonferroni
What’s the name of the processes by which we guess at the non0-sampled genotypes using information from a reference panel of individuals genotyped at a high density.
‘Imputation’
What two things reflect the frequency with which two markers are inherited together?
- Genetic distance
- Recombination
… this helps define the region likely to contain the functional variant
What thing indicates the extent to which a sequence is maintained across species?
‘Conservation’
… high conservation suggests an important function preserved during evolution
Which genes were found to be associated with bipolar?
ANK3 and CACNA1C
What were ANK3 and CACNA1C found to be associated with? (hint: mental disorder)
Bipolar
What substance down regulates the genes associated with bipolar (ANK3 and CACNA1C)?
Lithium
What does lithium do in relation to genes…?
Down regulates the two genes associated with bipolar (ANK3 and CACNA1C)
What is the genetic thing most significantly associated with SCZ?
The Major Histocompatibility Complex (MHC)
What do Major Histocompatibility Complex (MHC) genes do?
Code cell-surface proteins that allow immune system to recognise foreign substances
Does immunity play a role in SCZ?
Nobody knows… but this is what some of the GWAS evidence appears to point towards as a possibility
Variants in the CHRNAS-A3-B4 gene cluster are known to b strongly associated with …
heavy smoking
The CHRNAS-A3-B4 gene cluster encodes…
subunits of the nicotinic acetylcholine receptor (smoking)
What percentage of SCZ smoke?
Like, 80%
Does the association between CHRNAS-A3-B4 and smoking mean that heavy smoking may contribute to smoking risk?
Yep
What are the other nice things that GWAS can do?
- raise new possibilities
- point to environmental risk factors
- provide new evidence for existing hypothesis
What is the test with the dot where you have to look to the opposite side of the screen to the dot?
Antisaccade oculomotor task
What is the Antisaccade oculomotor task
The test with the dot where you have to look to the opposite side of the screen to the dot
Disturbances of visual sensitivity are associated with what two disorders?
SCZ
Autism
SCZ and Autism are associated with disturbances in the sensitivity of which sense?
Vision
What did a gene-wide association study (GWAS) find was strongly associated with the 1q21.1?
Visual sensitivity… also it’s a known risk region for SCZ and Autism
A gene-wide association study (GWAS) found that visual sensitivity was strongly associated with the 1q21.1. Where was that marker located?
In the 5’-untranslated region of the gene PDZK1
What do PDZ proteins do? (Hint: something to do with the surface of cells…)
Hold other proteins in appropriate configuration fr localisation on the surface of cells
Does the PDZK1 thingo interact with NMDA receptions?
What even are NMDA receptors?
Yes!
Do NMDA receptors play a role in contrast control in the retina?
Yes!
Does the PDZK1 thingo interact with DLG4?receptions?
Yes!
What happens if you take a mouse and fiddle with its Dlg4?
You get ASD-related phenotype
So is it possible that perceptual abnormalities observed in SCZ and ASD may be linked by common genetic elements affecting synaptic function?
Yes
Neural complexity and lengthy of life are negatively correlated, T/F
FALSE
In animal models, what’s the name for when you induce random mutations?
‘Forward genetic approach’
What are the four steps in the FORWARD GENETIC approach to animal models
- random mutations induced
- MUTAGENISED animals cross with a WILD TYPE strain over several generations.
- Animals are screened for target phenotype
- Animals with target phenotype are genotyped
What happens in REVERSE GENETICS animal models?
TARGETED mutations are introduced and the effect on the phenotype is measured,
What is the CRISPR-Cas9 system all about?
Bacterium’s defence against invading viruses.
Cas9 is a NUCLEASE protein. What can nuclease proteins do?
Cut chains of nucleotides
How does CRISPR-Cas9 get involved in targeted mutations?
‘Guide RNA’ directs Cas9 protein to desired DNA sequence, where the Cas9 snips the DNA - during the repair process, random stuff happens, or targeted sequences are introduced
What process uses microbial OPSINS to excite or inhibit neutrons by light?
Optogenetics
Do different microbial opsin respond to light of particular wavelengths?
You bet they do - for instance, some respond to yellow whereas others respond to blue light
The Adeo-Associated Virus (AAV) is commonly used to introduce genetic material in which process?
Optogenetics
In the context of Optogenetics, the CHANNELRHODOPSIN-2 (ChR2) pump responds to what coloured light, and allows what type of ions into the cell… and creates what nueural response
Blue light
Positive ions
Excitation
In the context of Optogenetics, the HALORHODOPSIN (NpHR) pump responds to what coloured light, and allows what type of ions into the cell
Yellow light
Negative ions
Inhibition
What happens in mice when you stimulate ChR2 in mouse amygdala
Predatory response
What two things become possible when combining an ontogenetic system with a CRISPR-Cas9 system?
Light-controlled protein transcription
Light-controlled genome editing
When doing animal models, what is the technique we use to identify and target genes that are homologous (equivalent) to the ones we care about in humans.
Bioinformatics
When using bioinformatics, using model organisms allow direct measurement at what 3 levels
SFB
Structure
Function
Behaviour
SFB
HTR1A is the human gene encoding the ___-1A receptor
Serotonin
If a FUNCTIONAL SNP is situated in the promotor region it affects protein ___ rather than protein ____
Transcription
Structure
SNP rs6295 in the promotor region of HTR1A is associated with trait ____
Anxiety
‘Individuals with one or two copies of the G allele showed lower trait anxiety than individuals homozygous for the C allele’ (What does this even mean?)
HTR1A SNP rs6295 is associated with ___ binding potential
Serotonin
Additional copies of G allele are associated with INCREASED binding potential
In the context of the HTR1A SNP rs6295, the G allele does what to the TRANSCRIPTIONAL REPRESSION of the promoter?
Impairs
It causes INCREASED expression of the 5-HT 1A receptor
Positron emission tomography (PET) is red to measure ___ potential
Binding
PET stands for
Positron emission tomography (PET)
How does Positron Emission Tomography (PET) work?
- Detects radiation from an injected TRACER wth a high affinity for5-HT 1A receptors
- Higher density of receptors leads to higher binding potential
5-HT 1A receptor is a ___ receptor
An AUTOreceptor
5-HT 1A receptor is a AUTOreceptor that is located on the presynaptic or postsynaptic membrane?
Presynaptic
Is the 5-HT 1A receptor a key part of regulating neurotransmitter release
Oh yes it is
____ capacity for regulation of 5-HT release is associated with ____ amygdala reactivity
Reduced.. and…. increased
In the contest of HTR1A SNP rs6295, additional copies of the G allele are associated with ___ amygdala reactivity
Decreased
If you increase the serotonin-binding potential throughout the brain which way does anxiety go…
Lower!
Let’s tie this all together
- PRESENCE of G allele of rs6295 IMPAIRS repression of HTR1A transcription
- this leads to ____ receptor density, indexed by binding potential
- this leads to DECREASED amygdala reactivity
- this predisposes to ___ anxiety
increased (receptor density)
and
low (anxiety)
And also…
ABSENCE of G allele of rs6295 PROMOTES repression of HTR1A transcription
- this leads to ___ receptor density, indexed by binding potential
- this leads to INCREASED amygdala reactivity
- this predisposes to ___ anxiety
Decreased (receptor density)
and
high (anxiety)
By comparing measurements across multiple levels, we can reveal the likely biological pathway linking a genetic variant to a behavioural phenotype
If you say so
What is it called when reuse light to control brain activity?
Optogenetics
What is REVERSE GENETICS about?
Discovering the effect of a gene on a phenotype
What is FORWARD GENETICS about
Discovering which genes contribute to a phenotype
Ona pedigree map, if you have an unaffected father and an affected daughter, what does this tell you?
Can be X-linked, but it cannot be recessive
What approach should you use when assessing
- check to see if fathers have passed on to sons. If this is the case, it’s not X-linked
- Check to see if it has skipped generations. If it hasn’t, then it is most LIKELY dominant
- Look for two parents with unaffected children (confirms it is dominant)
What are the three advantages of using endophenotypes when undertaking GWAS?
- Avoids difficulties assigning diagnostic categories
- Allows testing of psychologically normal participants
- Underlying biological mechanisms are likely to be simpler than for psychological disorders
