Why have linkage studies got a low success rate in detecting complex traits?
Linkage studies have a low success rate in detecting complex traits. A greater statistical power is needed to detect them and therefore association studies are used.
What are the potential causes of associations(ref the definition from previous lecture)?
Associations have several potential causes: direct causation, epistatic effects, popn. stratification, type 1 statistical errors, and linkage disequilibrium.
- Type 1 statistical errors – rejection of a true null hypothesis.
- Linkage disequilibrium – the nonrandom association between variants within a haplotype.
Explain shared a certain chromosome segments.
- Two unrelated people inherit a disease susceptibility allele from a common ancestor.
- Repeated recombination during meioses over generations reduces size of the shared segment to a very small region and only alleles tightly linked to the susceptibility locus will still be shared.
What is meant by decay of LD over time?
- In the absence of selection in a large, random mating popn., LD decreases exponentially each generation
- LD is reduced by a factor equal to the recombination rate between the two loci
- For example, the LD between two loci 10cM apart will be reduced by 10% per generation.
LD is rare beyond… what might this information be used for?
- LD rare beyond 100 kb or so; and almost zero LD beyond 500 kb.
- This information is used for mapping by association testing: If there is a strong association (a signature of LD), it means those markers must be within 100 kb of each other.
Outline the international HapMap Project.
International HapMap Project launched in 2002 to provide a genome-wide database of common sequence variation.
- Unlike the earlier maps using RFLPs or microsatellites, HapMap is a high density map generated by using SNPs.
Define direct association and indirect association.
- Direct association: SNP influencing a phenotype is directly
genotyped in a study and found to be associated with trait- Sometimes referred to as the functional SNP
- Indirect association: a tag SNP in high LD with the functional
SNP is genotyped and is associated with the phenotype- A significant association should not be assumed to be the
causal variant – further studies need to map functional SNP
- A significant association should not be assumed to be the
Define Tag SNPs and how they are used(research).
- Suppose two SNPS have r2 = 1, they are completely correlated with each other.
- In a genome-wide association study would only need to genotype one of them (known as a tag SNP).
What has since happened to the HapMap?
- The HapMap site was taken down in 2016.
- Buchanan et al (2012) states a possible decline in usage of HapMap over the previous 5 years as the 1,000 Genomes Project (launched in 2007 and final results published in 2015) established itself as a standard for population genetics and genomics.
