Positional Cloning

LO

D

Sib pairs Chromosome Region Association Study

Genetics

GenomicsPhysical Mapping/Sequencing

Candidate Gene Selection/Polymorphism Detection

Mutation Characterization/Functional Annotation

Netherton Syndrome Linkage

Chavanas et al., Am J Hum Genet, 66:914-921, 2000

Netherton Syndrome Haplotypes

Chavanas et al., Am J Hum Genet, 66:914-921, 2000

Chavanas et al. 2000, Nature Genetics

Inflammatory Bowel Disease Genome Screen

Hampe et al., Am J Hum Genet, 64:808-816, 1999

Inflammatory Bowel Disease Genome Screen

Hampe et al., Am J Hum Genet, 64:808-816, 1999

Allelic AssociationAllelic AssociationA Special Type of LinkageA Special Type of Linkage

3/5 2/6

3/2 5/2

3/5 2/6

3/6 5/6

Both families are ‘linked’ with the marker, but a different allele is involved.

This is Linkage but no Association

Allelic AssociationAllelic AssociationA Special Type of LinkageA Special Type of Linkage

3/6 2/4

3/2 6/2

3/5 2/6

3/6 5/6

All families are ‘linked’ with the markerAllele 6 is ‘associated’ with disease

4/6 2/6

6/6 6/6

Linkage is just association within families

Allelic AssociationAllelic AssociationA Special Type of LinkageA Special Type of Linkage

3/6

2/43/2

6/23/5

2/6

3/6 5/6

Allele 6 is ‘associated’ with disease

4/62/6

6/6

6/6

3/4

5/2

Controls Cases

Association study: UsesAssociation study: Uses

Pharmacogeneticsgenotyping clinically relevant samples (toxicity vs efficacy)

Insurance purposescontentious, but likely at some point

Candidate genes for specific diseasescommon practice in medicine/genetics

Positional cloningthe most frequent source of new loci at present

Genome-wide association with 2-3 million SNPs, can search whole genome exhaustively