Rare diseases

Question 1

Why are rare diseases so hard to cure

Answer 1

1. They are hard to diagnose – really hard to treat because really hard to diagnose
2. Small population size
3. Limited funding

Question 2

Diagnosing rare disease

Answer 2

Rare disease = really hard to diagnose
- Really hard to treat rare disease because really hard to diagnose
- People = trained to find the most likely reason but rare disease might be the most likley trait = hard to diagnose

“When you hear hooves sometimes its a zebra” – rare because you think hooves (not always most common thing)

Question 3

Mascot for rare disease

Answer 3

Zebra

Question 4

Issue with Population size for rare diseases

Answer 4

1. Harder to collect information
2. Not enough cases/controls for GWAS study

Because of population size – hard to find what genes control it
- Can’t do GWAS to find what genes control it because there are few people = not enough to do GWAS

Question 5

Funding for studying rare diseases

Answer 5

Federal grant monies are given to projects that will make the biggest impact
- Want to fund things that help the most people
- Hard to get people to help 1/2 families when can help 1000s = rare diseases get overlooked

Low profitability for corporations
- Companies won’t make money on drugs –> not enough people will buy it = companies won’t make it

Question 6

Example Rare disease

Answer 6

Chronic Tubuliontersyitial Kidney Disease

Question 7

Chronic Tubuliontersyitial Kidney Disease

Answer 7

Rare disease – A group of kidney diseases afefcteing tubules of kidney
- Chronic kidney disease
- Requires Dialysis
- Requires Kidney transplants

Rare – 500 US families

Question 8

Answer 8

Answer: Autosomal Dominant

NOT X-linked because II.1 is affected if X linked = III.1 would have to be affected

Question 9

Answer 9

Answer: 1 – because having one dominant allele is all you need to get the disease

If was controlled by two genes = you would need 2 dominant alleles –> would be in 1/16 kids

Question 10

How can you identify the disease allele

Answer 10

1. Sequencey entire genome
2. Look at candidate genes
3. Linkage

Question 11

Why do we want to know the gene

Answer 11

If we know the gene = we can tailor treatment for disease

Question 12

Issue with sequencing (Challeneges)

Answer 12

1. Cost of sequencing (not as big of an issue now)
2. Time and cost of sequence analysis –> we have the technology BUT need to anaylyze it
   
   • Need to put small sequcnes together and compare it to others – takes time
3. Accuracey – have a 99.99% accuracey BUT that would mean 300,000 inaccruacies when looking at 3 Billion BP genome
   
   • If looking for one gene –> how will you find the one gene if it might have inaacuracies

Can do sequencing to find gene BUT it is not always productive

Question 13

Using candidate genes Ex.

Answer 13

2018 – 500 US families had sequencing of candidate genes –> found mutations in different genes (MUC1, REN, SEC61A, UMOD1)

Looked at genes they knew were involved in kidney function

Question 14

Using linkage to identify gene in rare disease

Answer 14

Don’t always need to find a gene mutation that causes disease –> can find something linked to the gene that has mutations
- Can see what SNP co-segragtes with disease THEN the SNP is a marker that is inherited with the disease

Most SNPs = not linked to gene just looking for ones that are

FINDING SNP = can show you region of the disease causing gene –> can then look for the gene more easily
- If use linkage – see SNP that is linked to the disease gene = know where to look for the disease gene

Question 15

Answer 15

Answer: DA and dG –> If linked only get the parental gametes (same phase as parents) because no recombination

Question 16

Answer 16

Answer: True –> unlinked means have Independent Assortment = get all 4 possible gametes

Question 17

Gametic Phase

Answer 17

The allele combinations inherited from each parent

Question 18

What does linkage lead to

Answer 18

Linkage leads to more parental phases in offspring

Example – AB/ab
AB and ab – parental (Non-recombinant) – if linked = they are more abundant

Ab and aB – Non-parental (recombinant) – require a recombination event

Question 19

Answer 19

Answer: Parental (non-recombinant)

Maternal = need to be DA – because only can ge D from mom
- DA = parental

dA = paternal

Question 20

Answer 20

Answer: Not possible to determine

DA = has to be maternal (can only get D from mom)

dA = paternal –> don’t know if recombinant or non-recombinant because can get dA with or without recombination

Question 21

What do you need in order to know if something is parental or non-parental

Answer 21

Parents MUST be heterozygous at BOTH loci in order to deduce whether the offspring contains a parental or non-parental phase of alleles

Question 22

Answer 22

Pedigree 1:
Mom = don’t know
Dad = don’t know
- Neither are heterozygous at both loci = can’t know
- Homozygous at one loci = can’t tell

Pedigree 2:
Mom = Parental
Dad = Don’t know

Pedigree 3:
Mom = Parental
Dad = Non-parental
- Don’t know which parent gave which gamete (could have been either giving them) BUT doesn’t matter (either way one is parental and one is non-parental)

Question 23

First step in using linkage to find disease causing loci

Answer 23

Genotype each family member at markers all across the genome

Question 24

Answer 24

Question 25

Is the SNP linked to disease?

Answer 25

NOT LINKED

If linked = expect more parental than recombinant

Here:
2 Gametes parental
2 Gametes recombinant
(LOOK at ALL not just disease gametes)

Since equal recombinant and not recombinant = this SNP is NOT linked to disease causing allele – NOT linked to the Disease locus)