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
What is QTL?
- Quantitative trait locus
- Multiple additive genes, and each one confers modest relative risk
What are whole genome association studies?
- A direct study that detects an increased prevalence (association) of a particular functional variant in affected individuals within the coding region of a candidate gene
- More powerful than linkage studies
- Can use gene chips, 2M SNPs genotypes
Despite massive association studies, few high frequency SNPs have been found that account for genetic predisposition to disease, what is the “missing” heritability?
1) SNP density not sufficient
2) Interacting genes
3) Copy # variants
4) Rare variants
5) Imprinting
6) No environmental data
7) Overestimate of genetic impact
Why do we have high prevalence genetic disorders?
- Late onset allow affected individuals to have children
- Hypothesis: genes selected for in evolution when combined with environmental factors become deleterious
What are some overrepresented gene ontology categories?
Pathogen response, cell cycle, reproduction, neuronal function, protein metabolism, DNA metabolism
What is the a-actin-3 R577X mutation?
- -> In athletes, the frequency of this null mutation is lower in sprinting and power athletes, & higher in endurance athletes
- -> Shift in muscle metabolism toward aerobic pathway & increase endurance
