Finding Disease Genes Flashcards
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
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
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”
Exome/Genome Sequencing Study
Sequence
Compare to reference
Look at common anomalies
Single gene sequencing
Sequence hypothesized gene
Most hypotheses wrong
What does genome mapping require?
Polymorphic DNA markers
Do we sequence the entire genome?
No… still too expensive
What do polymorphic DNA markers do for us?
They provide “Sign posts” where we can look at differences
Polymorphic DNA makers are surrogates for what?
Potential disease mutations;
What are three commonly used marker types?
Microsatellites
SNPs
CNVs
Gene Mapping: what are physical maps?
Maps that tell us absolute positions - this is here and this is here
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
Microsatellites
Simply a repeat sequence in the genome for which the copy number varies
Simple sequence repeats
Used in forensics
Multi-allelic
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
How frequent are SNP?
1/50-300bp
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)
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
Copy Number variants
Common genomic deletions Bi-allelic Multi-allelic Unique Most not causal for human disease
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
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)
To track things that are common but have relatively little effect we use which type of studies?
Association
To track big effect genes that are relatively rare we use which kind of study?
Linkage in families
Hypothesis Driven Studies
Candidate DNA Sequencing
Candidate Gene association
Candidate gene DNA sequencing
Where do we come up with our candidate?
biological or positional
“hit” from GWAS or other mapping method
When do Candidate DNA studies work?
Single gene Mendelian diseases
Candidate DNA sequencing, are most hypotheses correct?
NO! most are wrong!
Which type of study uses markers to test gene/causal variant indirectly?
Candidate gene association studies
Which genetic study is the most common?
Candidate gene association
