Finding Disease Genes

Question 1

Functional cloning:

Answer 1

take disease with known biology and go find the gene (these types of diseases were rapidly exhausted)

Question 2

Positional Cloning:

Answer 2

Determine a gene then determine its function and relation to disease

Question 3

Hypothesis Driven approaches:

Answer 3

Candidate gene sequencing and Candidate gene association studies

Question 4

Hypothesis Free approaches:

Answer 4

Genetic linkage studies and genome wide association studies (GWAS)

Question 5

Understand the difference between genetic association study (gene-specific and genome-wide) versus genetic linkage study.

Answer 5

Association studies look for increased or decreased frequency of a particular allele (or set of alleles) in a sample group taken from the population. This can be done using a target gene or through GWAS. Gene specific linkage studies, search for regions of the genome that are inherited with a disease in a particular family.

Question 6

Linkage Studies

Answer 6

• Very effective for Mendelian traits
o With high power
• Can discover new, unknown genes 
• Fine localization
• Requires large, multiplex families with multiple affected individuals
• Not powerful for complex traits

Question 7

Candidate Gene Association Studies

Answer 7

• Most effective for common risk alleles
• Can detect common alleles with small effects
• Cheap and easy to perform
• Difficult to match ethnicity of cases and controls due to population stratification
o Leads to false positives
• Cannot apply multiple testing correction
• Publication bias of Positive results

Question 8

GWAS

Answer 8

• Can discover new, unknown genes
• Fine localization
• Best for complex traits
o Powerful
• Can correct for population stratification
• Tests very large numbers of SNPs
• Associations require confirmation by follow-up association study of specific SNPs

Question 9

Candidate Gene Sequencing Studies

Answer 9

• Most effective in Mendelian disorders

* Low yield in complex, multifactorial disorders

Question 10

Understand the basic statistical approaches used to test association and to test linkage.

Question 11

Microsatellites:

Answer 11

• stretches of DNA consisting of units of 2, 3, or 4 nucleotides that repeat
• Different alleles have different numbers of repeated nucleotide units

Question 12

Single Nucleotide Polymorphisms (SNPs):

Answer 12

a single base pair change to the DNA

Question 13

Copy Number Variations (CNVs):

Answer 13

changes in the number of copies of larger segments of the genome (200bp-2Mb)

Question 14

Be aware of the emerging use of genome/exome sequencing to discover disease genes and, in the future, genetic testing

Answer 14

Exome sequencing is no different than genome sequencing except that it specifically targets exons, not the other segments of DNA