Finding Disease Genes

Question 1

What is the rationale for finding disease genes?

Answer 1

• Disease genes and environmental factors underpin almost all diseases
  => since we can’t systematically discover environmental risk factors, we can systematically discover disease genes
• Disease genes provide clues to pathogenic mechanisms
  => new approaches to treatments, inference of environmental factors, disease prevention

Question 2

What are the strengths, weaknesses, and typical (and optimal) applications of genome wide association studies?

Answer 2

Strengths: best for complex traits, no hypothesis, can discover new genes, gets right answer

Weaknesses: need independent verification of case control studies, super expensive, need many cases and controls

Application: search for regions of genome associated with disease; most effective for common alleles with small to moderate effect sizes

Question 3

What are the strengths, weaknesses, and typical (and optimal) applications of candidate gene association studies?

Answer 3

Strengths: detect common alleles with small effects, tests gene/casual variant directly by tagging nearby markers

Weaknesses: almost always wrong, its a horrible approach

Application: common risk alleles; only successful approach for complex disease

Question 4

What are the the basic statistical approaches used to test association and to test linkage?

Answer 4

simple statistics (chi squared, fischer)
multiple testing correction

real association does not imply causation

Question 5

What are the three most commonly used types of DNA polymorphisms?

Answer 5

1. Microsatelites –used mostly in forensics; repeating 1-6 bp
2. SNPs (single nucleotide polymorphisms) –single base changes anywhere in genome; allele frequencies differ across ethnic groups and populations; can result in aa changes
3. CNVs (copy number variations) –common genetic deletions; 100s-10,000s of bp; differ across groups; individually rare, collectively common; inside or outside of genes, or include genes; uncertain how often these are causal for human disease

Question 6

What are the strengths, weaknesses, and typical (and optimal) applications of genetic linkage studies?

Answer 6

Strengths: Mendelian traits, powerful, can discover new genes, can provide fine localization

Weaknesses: complex traits, requires multiplex families, expensive; less powerful for complex traits

Application: search for regions of genome systematically co-inherited along with disease through families; best for uncommon alleles with strong effects