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Flashcards in Finding Disease Genes Deck (71)
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1

Candidate Gene Association Study

Hypothesis driven approach

Uses markers to test gene/causal variant indirectly

Depends on a priori biological or positional hypothesis (almost always wrong!)

Fatal flaws lead to false positives

2

Genome Wide Association Study

Hypothesis Free approach

Rather than look gene by gene (candidate gene association study) we could do whole genome at one time!

Search for SNPs with significantly different allele frequencies in cases verse controls

3

Genetic linkage study

Hypothesis free approach

Search for genome disproportionately coinherited along with disease in multiplex families

Assumes affected relatives within a family share disease susceptiblity genes "identical by descent"

4

Exome/Genome Sequencing Study

Sequence
Compare to reference
Look at common anomalies

5

Single gene sequencing

Sequence hypothesized gene

Most hypotheses wrong

6

What does genome mapping require?

Polymorphic DNA markers

7

Do we sequence the entire genome?

No... still too expensive

8

What do polymorphic DNA markers do for us?

They provide "Sign posts" where we can look at differences

9

Polymorphic DNA makers are surrogates for what?

Potential disease mutations;

10

What are three commonly used marker types?

Microsatellites
SNPs
CNVs

11

Gene Mapping: what are physical maps?

Maps that tell us absolute positions - this is here and this is here

12

Gene Mapping: what are genetic maps?

Relative maps based on recombination - across a whole population roughly how far apart are these two things/sequences from each other

13

Microsatellites

Simply a repeat sequence in the genome for which the copy number varies
Simple sequence repeats
Used in forensics
Multi-allelic

14

Single nucleotide polymorphisms

Bi-allelic
Used for association studies

Occurrence/allele frequencies differ in ethnic groups/populations

SNPs occur in local context (haplotype) of surrounding SNPs

15

How frequent are SNP?

1/50-300bp

16

SNP haplotypes

Recombination breaks macro-pattern of polymorphic genotypes on the same chromosome into blocks in which SNP alleles are in linkage disequilibrium (makers within blocks tend to be co-inherited because recombination within blocks is uncommon)

17

If you genotype enough SNPs to identify a haplotype you can impute other variation that wasn't genotyped and use this to infer ?

causal variation took place in this haplotype, even though SNP may not be causal variant

18

Copy Number variants

Common genomic deletions
Bi-allelic
Multi-allelic
Unique
Most not causal for human disease

19

If we have a common disease allele that has a small effect, what studies are best suited to hunt for the disease gene?

Association
Candidate gene or GWAS

20

If we have a rare disease allele that has a large effect, which studies are best suite to hunt for the disease gene?

Linkage
Sequencing
(track genes through families using linkage)

21

To track things that are common but have relatively little effect we use which type of studies?

Association

22

To track big effect genes that are relatively rare we use which kind of study?

Linkage in families

23

Hypothesis Driven Studies

Candidate DNA Sequencing
Candidate Gene association

24

Candidate gene DNA sequencing
Where do we come up with our candidate?

biological or positional
"hit" from GWAS or other mapping method

25

When do Candidate DNA studies work?

Single gene Mendelian diseases

26

Candidate DNA sequencing, are most hypotheses correct?

NO! most are wrong!

27

Which type of study uses markers to test gene/causal variant indirectly?

Candidate gene association studies

28

Which genetic study is the most common?

Candidate gene association

29

What do candidate gene association studies depend on?

A prior hypothesis

30

What are fatal flaws of candidate gene association studies and what do they lead to?

1. Multiple-testing correction impossible
2. Ethnically matched impossible
False positives!