Neurogenetics Flashcards
How many base pairs in the human genome?
~3.2 billion
How many genes in the human genomes?
~23,000
Does one gene code for only one protein?
No - many isoforms
What percentage of DNA encodes proteins?
1-2%
What does the rest of DNA that doesn’t code proteins do?
We don’t know
What types of mutations (changes in DNA - not necessarily “mutations”) are there?
SNP single nucleotide variants Indel Copy number variants short tandem repeats
What is a SNP?
changes in DNA which don’t cause disease
What is an SNV?
“point mutation”, one base substituted by another
What are the types of SNVs?
Missense mutation (amino acid change)
Nonsense mutation (generates stop codon)
Splicing mutation (in exon / intron junction) - leads to unstructured protein
What are indels?
insertion or deletion of <50 bases
Why are indels bad?
Alters mRNA reading frame –> frameshift, unless multiple of 3
The RNA might be degraded if a stop codon is made??
What is a CNV?
Gain or loss of >50 bases
How large can a CNV be?
a megabase (very large)
TRUE or FALSE? - CNVs only affect one gene
FALSE - multiple genes can be affected
When are short tandem repeats bad?
If it’s a coding region it’s bad, if it’s non-coding it’s not so bad
Extra copies beyond a threshold can be pathogenic
Give examples of short tandem repeats which cause diseases?
Coding: CAG –> glutamine eg Huntington’s
Non- coding: eg C9ORF72 –> ALS and related phenotypes
In non-coding regions it can also cause damage
What is the most common mechanism of Gain-of-function mutations?
aggregation
How can mutations cause aggregation? - give examples
Protein altered: missense mutations in alpha-synuclein (PD), extra glutamines in huntingtin
Too much of a good thing: SNCA CNVs (extra copies of whole gene)
How do mutations cause loss-of-function mutations?
Early stop codon (nonsense mutation or frameshift)
Protein is not functional, or not produced at all (mRNA unstable)
What is are the normal inheritance patterns for gain and loss of function mutations?
Dominant –> gain of function
Recessive –> loss of function
what is an exception to the normal inheritance patterns of gain or loss of function mutations?
haploinsufficiency - Usually with loss-of-function one gene is enough to stay healthy but if both alleles need to be healthy then you get disease if only one is mutated (dominant inheritance)
Are all neurodegenerative diseases inheritied like HD?
No
AD,ALS,PD have only some familial cases
What is the difference between eukaryotic and mitochondrial DNA?
Tiny circular genome Numerous copies per cell They may have differences between diff DNA molecules, diff mitochondria, diff cells, diff tissues (heteroplasmy) Inheritance is only maternal
How many base pairs in mtDNA?
16.5 kb
What does mtDNA do?
encodes proteins of respiratory chain
What kinds of mutations do you find in mtDNA?
SNVs or deletions
What part of the body is most affected by mtDNA mutations and why?
Can affect all body, but neurons sensitive - Due to energy demands
What are the easiest cases when you are testing for mutations? - examples
testing for a specific mutation
Huntington’s: CAG expansion
A specific mutation in family member eg Parkinson’s or Alzheimer’s gene
What are harder cases when testing for mutations?
looking for any mutation that may cause this disease
What do you use to look for any mutation (not a specific one)?
NGS or sanger
Mostly next gen is used bc high throughput. But, Sanger is used for simple genes bc it’s fast and cheap.
You could use a gene panel to look for a group of common mutations
What is the disadvantage of just sequencing the exome?
what if the mutation is in the non-coding region?
What is the problem with the 100,000 genome project?
- the analysis is really tricky
- Ethics: what if you find a mutation which is unconnected to what you are studying? Save someone’s life by telling them or tell them and mess up their life?
CNV analysis is easy - TRUE or FALSE?
FALSE
What kinds of tests are there?
Diagnostic
Predictive
Risk alleles
give examples of diagnostic tests?
Most straightforward eg “do I have Huntington’s?”
Family risks eg “is my PD due to a mutation?” are a bit less straightforward
give examples of predictive tests
will i get HD? - looking for the CAG expansion
what are the problems with predictive tests?
Complex… ethics, counseling
Should we test someone who might have a genetic cause of PD, if you’re not sure?
Example: My grandpa had hand tremors before dying of a heart attack at 70 and my dad did too but he never got diagnosed.
Survivors guilt with a negative result
Getting a positive result - psychological issues
give examples of risk alleles we can test for
Carrying GBA increases risk of PD 5-10x
apoE: number of ε4 alleles influences risk of Alzheimer’s
what does GBA encode?
glucocerebrosidase
what disease does GBA mutation cause and how is it inherited?
Causes Gaucher disease (recessive), a lysosomal storage disorder,
If you have 2 mutations, you get Gaucher but if you have 1 your get no disease but your risk of Parkinson’s will increase
Is gaucher’s disease a gain or loss of function disease?
unclear - Is it because lysosomes don’t work well or because the GBA mutation leads to increased aggregation
what are the problems with checking for risk alleles
what if you can’t cure the disease
can you explain/understand/quantify risk?
Name and discribe patterns of inheritance
Autosomal dominant: risk 50% to offspring
autosomal recessive: 25% if both parents carriers
This is why there is inbreeding depression
X-linked (recessive): male only?
Mitochondrial: maternal
what are points to remember in clinic when doing genetic tests?
Is there a family history?
“censored” : parent died before age of onset
Consanguinity? (same village?) -inbreeding
One condition can result from mutations in different genes
Genes are there nt to cause the disease but to do important things in the body
can get variable phenotype from same gene
what kind of penetrance does the gene have
anticipation
name mutations that cause PD, what they code for and their inheritance
SNCA - alpha synuclein - dominant
PRKN - Parkin - recessive
PINK1 - PTEN-induced putative kinase1 - recessive
DJ-1 - Protein DJ-1 - recessive
LRRK2 - leucine rich repeat kinase 2 - dominant
what is an example of a gene mutation that causes variable phenotypes?
C9ORF72 - ALS
compare the penetrance of two different PD mutations
SNCA mutations: essentially complete (PD)
LRRK2 G2019S: incomplete, ~70% by age 70 (PD)
Penetrance is high but not full
Give an example of anticipation
HD: More repeats - earlier onset (each generation gets it earlier)
TRUE or FALSE? - effect size is high for common mutations
FALSE
Effect size is higher for rare alleles and lower for common alleles usually
Can Sporadic disorders have a genetic components?
YES
Rare cases carry causative Mendelian mutations (~1%)
Dominant: alpha-synuclein (SNCA), LRRK2
Recessive: parkin, DJ1, PINK1
heritability: ~30% (the 29% comes from more common low impact variants)
In how many chromosomes (according to GWAS) is there a PD risk allele?
all of them
What is the use of PD genetics in clinic and how is PD genetics NOT used in clinic?
USES:
GBA carriers more likely to get dementia- but you can’t prevent it!
GBA carriers should avoid deep brain stimulation - some people do worse
Predict risk to children
NOT:
confirm diagnosis
NO evidence can target treatment based on mutation presence
GWAS
what is the use of genetics in neurology out of clinics? - examples
Genetics helps us understand pathogenesis -
PD LLRK2 - maybe involved in vesicular trafficking
ALS - trying to find out why some get ALS and others get other diseases from C9ORF72
HD - showing that repeat size increases through paternal transmission due to instability in the sperm
what if you see a genetic disease but can’t find mutations in the blood?
You might have a mutation in the brain or another place (somatic mutations) which will not be found in blood
