2. A Primer on Genetic Variation Variety Lawrence Brody - NHGRI

3. Human Genetic Variation What is it? Where did it come from? How is it scored? What use is it?

6. D. Arbus, 1967

7. Annie Leibovitz

10. GATACAATGCATCATATGTA TCAGATGCAATATATCATTG TATCATGTATCATGTATCAT GTATCATGTATCATGTATCA TGTCTCCAGATGCTATGGAT CTTATGTATCATGTATCATGT ATCATGTATGATGTATC

11. DNA Self Replicating Molecule

12. Fidelity of DNA replication is nearly perfect Luckily for us, mistakes have been made

13. Mistakes in DNA The good, the bad and the indifferent

15. Time (generations) Frequency 100% 0 Fate of New Mutations

16. Genetic Variation SNP Single Nucleotide Polymorphism Duplications / Deletions

17. Why SNPs? Numerous Stable Easy to score In genes (sometimes)

18. GATACAATGCATCATA GATGCAATGTATCATA GATGCTATGCATCATA

19. Human SNPs 2 chromosomes differ ~1/1,000 bases more chromosomes more sites potential for 30 million variable sites

20. GATACAATGCATCATA GATGCAATGTATCATA Haplotype

21. Human Population History relatively young, ~ 100,000 years small populations isolated for long periods of time –estimated “effective breeding pool” - 10,000 individuals explosive expansion coincident with the spread of agriculture

22. Time (generations) Allele Frequency 1 0 4N e humans = 40,000 generations ~ 1 million years Fate of New Mutations

23. © 1999 Kenneth K Kidd, Yale University

26. Human Genetic Variation What is it? Where did it come from? How is it scored?

27. SNP Genotyping Tools 330,000-650,000 SNPs per array Affymetrix Illumina Courtesy, S. Gabriel

28. SNP Chip Image

30. * * **

31. When is a variant a polymorphism? Classical definition Two of more alleles Least frequent > 0.01 Functional consequences not relevant Popular definition Mutation = bad! Polymorphism = neutral Frequency not relevant

32. 100,000 years ago Cradle Lands