Genetics of Common Diseases Flashcards
Can you identify which TWO of the following types of genetic variation are unlikely to be associated with a monogenic disease that is lethal in early childhood?
- Rare missense variation
- Deletion in the DNA sequence that encodes a protein
- Rare single nucleotide variation in intergenic region of genome
- Common missense variation
- Change in the non-coding DNA that interferes with splicing
- Rare insertion in the DNA sequence that encodes a protein.
3 and 4
Researchers identify a missense variant in the gene that encodes dystrophin, and find that 30% of the European population have this variant. Which of the following statements about the variant is FALSE:
- It is a SNP
- It is likely to cause muscular dystrophy
- It results in a change in amino acid sequence
- The minor allele frequency is 0.3
2
Define the genetic term “penetrance”
A measure of the proportion of those who have the trait genotype and show the trait phenotype
Define Heritability.
Measure of how well differences in individual genes account for differences in their traits.
A heritability close to 1 indicates almost all variability comes from genetic differences.
How is heritability measured?
Using twin studies
- Monozygotic twins share 100% germ-line genetic variation
- Dizygotic twins share 50% of germ line genetic variation
Comparing data from monozygotic twins with dizygotic twins and compare the correlation (r value) in a scatter graph.
h2 = 2 x (MZ correlation – DZ correlation)
Heritability is scored between 0 and 1.
A trait highly influenced by genes will have a heritability value greater than…
h2>0.8
What steps should be taken next after identifying a rare allele causing a mendelian disease?
Linkage analysis
What steps should be taken next after identifying a common variant implicated in a common disease?
Genome Wide Association Study
There are millions of SNPs in the genome. How are they efficiently captured?
Through probe-based SNP array platforms like illumina at large quantities.
How does an SNP Microarray work?
- DNA is amplified and fragmented into single stranded DNA.
- Sample DNA is captured onto a chip and a complementary strand is formed.
- double stranded DNA is ligated off the chip.
- The sample DNA is then stained and and imaged to give off a signal.
Explain Linkage disequilibrium / SNP-SNP association.
This is the difference between observed frequency at a particular combination of allels at 2 loci and the frequency expercted fro random association.
So if LD between SNP4 and 7 is high, then they are co-inherited more often than SNPs that are unlinked. So if SNP 4 is heterozygous we can determine that SNP 7 is also heterozygous.
What is the relationship between Linkage disequilibrium between 2 SNPs and physical distance?
An increase in distance decreases the strength of linkage disequilibrium.
If linkage disequilibrium is strong then fewer SNPs are needed to be capture variation in a region for analysis.
A GWAS study cannot use a p value of 0.05 because it causes multiple testing issues. Why is this an issue? How can this be resolved?
GWAS studies multiple SNPs so using a p value of 0.05 would mean a large number of SNPs being false positives.
Bonferroni correction is a solution to this by dividing the p-value by the no. of SNPs to reduce the chances of false positives in our findings.
So the results after would be either due to a causal relationship or a marker for linkage disequilibrium indicating there is a causal locus nearby.
What is the difference between intergenic regions and intronic regions?
Intergenic regions are non-coding regions that are found between genes.
Intronic regions are also non-coding regions but they are found in between protein coding regions. They are removed before the protein is made.
Fill the blank
Most GWAs studies have found association between ______ regions and human diseases.
Most GWAs studies have found association between Non-coding regions and human diseases.
