Neurogenetics

Question 1

How many base pairs in the human genome?

Answer 1

~3.2 billion

Question 2

How many genes in the human genomes?

Answer 2

~23,000

Question 3

Does one gene code for only one protein?

Answer 3

No - many isoforms

Question 4

What percentage of DNA encodes proteins?

Answer 4

1-2%

Question 5

What does the rest of DNA that doesn’t code proteins do?

Answer 5

We don’t know

Question 6

What types of mutations (changes in DNA - not necessarily “mutations”) are there?

Answer 6

SNP
single nucleotide variants
Indel
Copy number variants
short tandem repeats

Question 7

What is a SNP?

Answer 7

changes in DNA which don’t cause disease

Question 8

What is an SNV?

Answer 8

“point mutation”, one base substituted by another

Question 9

What are the types of SNVs?

Answer 9

Missense mutation (amino acid change)

Nonsense mutation (generates stop codon)

Splicing mutation (in exon / intron junction) - leads to unstructured protein

Question 10

What are indels?

Answer 10

insertion or deletion of <50 bases

Question 11

Why are indels bad?

Answer 11

Alters mRNA reading frame –> frameshift, unless multiple of 3
The RNA might be degraded if a stop codon is made??

Question 12

What is a CNV?

Answer 12

Gain or loss of >50 bases

Question 13

How large can a CNV be?

Answer 13

a megabase (very large)

Question 14

TRUE or FALSE? - CNVs only affect one gene

Answer 14

FALSE - multiple genes can be affected

Question 15

When are short tandem repeats bad?

Answer 15

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

Question 16

Give examples of short tandem repeats which cause diseases?

Answer 16

Coding: CAG –> glutamine eg Huntington’s

Non- coding: eg C9ORF72 –> ALS and related phenotypes
In non-coding regions it can also cause damage

Question 17

What is the most common mechanism of Gain-of-function mutations?

Answer 17

aggregation

Question 18

How can mutations cause aggregation? - give examples

Answer 18

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)

Question 19

How do mutations cause loss-of-function mutations?

Answer 19

Early stop codon (nonsense mutation or frameshift)

Protein is not functional, or not produced at all (mRNA unstable)

Question 20

What is are the normal inheritance patterns for gain and loss of function mutations?

Answer 20

Dominant –> gain of function

Recessive –> loss of function

Question 21

what is an exception to the normal inheritance patterns of gain or loss of function mutations?

Answer 21

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)

Question 22

Are all neurodegenerative diseases inheritied like HD?

Answer 22

No

AD,ALS,PD have only some familial cases

Question 23

What is the difference between eukaryotic and mitochondrial DNA?

Answer 23

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

Question 24

How many base pairs in mtDNA?

Answer 24

16.5 kb

Question 25

What does mtDNA do?

Answer 25

encodes proteins of respiratory chain

Question 26

What kinds of mutations do you find in mtDNA?

Answer 26

SNVs or deletions

Question 27

What part of the body is most affected by mtDNA mutations and why?

Answer 27

Can affect all body, but neurons sensitive - Due to energy demands

Question 28

What are the easiest cases when you are testing for mutations? - examples

Answer 28

testing for a specific mutation Huntington’s: CAG expansion A specific mutation in family member eg Parkinson’s or Alzheimer’s gene

Question 29

What are harder cases when testing for mutations?

Answer 29

looking for any mutation that may cause this disease

Question 30

What do you use to look for any mutation (not a specific one)?

Answer 30

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

Question 31

What is the disadvantage of just sequencing the exome?

Answer 31

what if the mutation is in the non-coding region?

Question 32

What is the problem with the 100,000 genome project?

Answer 32

1. the analysis is really tricky 2. 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?

Question 33

CNV analysis is easy - TRUE or FALSE?

Answer 33

FALSE

Question 34

What kinds of tests are there?

Answer 34

Diagnostic Predictive Risk alleles

Question 35

give examples of diagnostic tests?

Answer 35

Most straightforward eg “do I have Huntington’s?” | Family risks eg “is my PD due to a mutation?” are a bit less straightforward

Question 36

give examples of predictive tests

Answer 36

will i get HD? - looking for the CAG expansion

Question 37

what are the problems with predictive tests?

Answer 37

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

Question 38

give examples of risk alleles we can test for

Answer 38

Carrying GBA increases risk of PD 5-10x | apoE: number of ε4 alleles influences risk of Alzheimer’s

Question 39

what does GBA encode?

Answer 39

glucocerebrosidase

Question 40

what disease does GBA mutation cause and how is it inherited?

Answer 40

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

Question 41

Is gaucher's disease a gain or loss of function disease?

Answer 41

unclear - Is it because lysosomes don’t work well or because the GBA mutation leads to increased aggregation

Question 42

what are the problems with checking for risk alleles

Answer 42

what if you can't cure the disease | can you explain/understand/quantify risk?

Question 43

Name and discribe patterns of inheritance

Answer 43

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

Question 44

what are points to remember in clinic when doing genetic tests?

Answer 44

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

Question 45

name mutations that cause PD, what they code for and their inheritance

Answer 45

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

Question 46

what is an example of a gene mutation that causes variable phenotypes?

Answer 46

C9ORF72 - ALS

Question 47

compare the penetrance of two different PD mutations

Answer 47

SNCA mutations: essentially complete (PD) LRRK2 G2019S: incomplete, ~70% by age 70 (PD) Penetrance is high but not full

Question 48

Give an example of anticipation

Answer 48

HD: More repeats - earlier onset (each generation gets it earlier)

Question 49

TRUE or FALSE? - effect size is high for common mutations

Answer 49

FALSE | Effect size is higher for rare alleles and lower for common alleles usually

Question 50

Can Sporadic disorders have a genetic components?

Answer 50

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)

Question 51

In how many chromosomes (according to GWAS) is there a PD risk allele?

Answer 51

all of them

Question 52

What is the use of PD genetics in clinic and how is PD genetics NOT used in clinic?

Answer 52

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

Question 53

what is the use of genetics in neurology out of clinics? - examples

Answer 53

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

Question 54

what if you see a genetic disease but can't find mutations in the blood?

Answer 54

You might have a mutation in the brain or another place (somatic mutations) which will not be found in blood