Moyzis3/4-gene-discovery Flashcards
What is linkage analysis?
-Method for mapping the location of disease-causing loci by identifying genetic markers that are co-inherited with a phenotype of interest
What is positional cloning?
- Identification of genes based on their position in the genome (genetic mapping) rather than by its function
- A single sib pair can localize a “disease” gene to 50% of the genome
- Cannot resolve region below 1Mb
What is Allelic heterogeneity?
- Multiple DNA changes in one gene all lead to a single disorder
- Many different alleles that predispose you to the disorder
- Ex. Cystic fibrosis
What is HD?
- Huntington’s disease is an autosomal dominant progressive neurodegenerative disorder
- Exhibit movement, cognitive, and psychiatric abnormalities
- Expansion of CAG repeat in Huntingtin protein
- Single site DNA change, rare
What is linkage disequilibrium?
- A measure of order vs disorder in genomic variation. It refers to a part of DNA that is unusually not scrambled. All or most people have the same DNA segment in the same position.
- Indirect study that detects increased prevalence of a particular set of SNP alleles in affected individuals
- Used to further define region of candidate gene after use of positional cloning
Why does linkage disequilibrium work?
- Because diseases caused by specific mutations are passed on along with adjacent DNA from generation to generation.
- Works only within populations where most of the people are closely related
What is done after a candidate region of 1cM is defined?
- Genes are prioritized for analysis
- Mutations are looked for (ex. early termination codon)
What is cystic fibrosis?
- Defect in Cl- transport protein
- Build up of mucous in airways, malabsorption, blocked pancreatic ducts, sinusitis, lung bacterial infections common
What is done after a mutation has been identified?
- Use in diagnostic tests, “gene chips”
- Intervention approaches are developed: environmental (PKU), pharmacological (GH), & gene therapy (expression vectors)
How are common and rare variants tested for?
- Common variants: SNP arrays, directed sequencing
- Rare variants: directed re-sequencing or genomic re-sequencing
What is DALY?
Disability adjusted life-years (to take into account the deleterious effects in life quality as result of chronic disorders)
What are CVCD and RVCD?
- Common Variant-Common disorder (CVCD) hypothesis: if a common allele is predisposing, only a moderate increase in frequency is expected
- Rare variant-common disorder (RVCD) hypothesis: allelic heterogeneity hypothesis; many infrequent predisposing alleles bc humans collect junk DNA
What is heritability?
- Measure of the relative contribution of genetics & environment on variability, at the time the measurement is made. h^2 = 2(Mz-Dz)
- h=0.6 means that 60% of variance is genetic
- Only if h=1, the genetic mutation is the cause, & environment has no role
- High heritability: behavioral disorders
- Low heritability: cancer
What are some problems with twin studies?
- Their DNA is not exactly identical
- Environment is not necessarily the same
What is locus heterogeneity?
- Different regions of the genome, so different genes can be mutated to cause the same disorder
- Problem: may not be the same, just poor phenotyping
