1. NCSU Summer Institute of Statistical Genetics, Raleigh 2004: Genome Science Session 3: Genomic Variation

2. Human Regulatory SNPs

3. Polymorphism and LD

4. Human LD Nature 411, 199 - 204 (2001)

5. 9.7 kb Human LPL African Finnish Minnesota

6. LD in Human ApoE

7. International HapMap Project http://www.hapmap.org/

8. Tests of Neutrality Neutral evolution (most genes)Neutral evolution (Ras genes) Recent selective sweep (Ksr)Balanced polymorphism (Adh)

9. Interval Mapping

10. Pedigree Mapping

11. Linkage Disequilibrium Mapping Heritability / relative risk Number of genes and distribution of effects Penetrance and Expressivity Distribution of linkage disequilibrium (LD) Genetic heterogeneity Population stratification Hidden environmental structure Genotype-by-environment interaction Incomplete genotyping

12. Population stratification Population 1 Population 2 f(A) = 0.8 f(A) = 0.2 f(a) = 0.2 f(a) = 0.8 diabetics = 20%diabetics = 10% P(A)diabetic = (.8x20 +.2x10) = 18% P(a)diabetic = (.2x20 +.8x10) = 12% Stratification may be environmental, cultural or genetic

13. Case-control and family designs Observed Expected Allele M Allele m Allele M Allele m Affected 34278 61265 Unaffected 69256 62269  2 = 14.0 P <0.01 Transmitted Allele Mm Observed7846 Expected6262  2 = 8.2 P < 0.0001

14. Hierarchical Association Mapping

15. Genetic Association Database http://geneticassociationdb.nih.gov

16. SNPs Online http://www.ncbi.nlm.nih.gov/SNP/ Seattle SNPs http://pga.mbt.washington.edu/welcome.html The SNP Consortium http://snp.cshl.org/

17. VDAs: Variant Detector Arrays

18. Gel-based SBE

19. Allele-specific primer extension

20. Pyrosequencing

21. Homogeneous Assays

22. The Invader Assay