1. Mapping human disease genes with Affymetrix 10K SNP chips and the HMS Orchestra Shared Research Cluster Steve DePalma, Ph.D. Seidman lab, HMS Genetics depalma@rascal.med.harvard.edu 3/31/2005

2. Full genome scan, the old way family size of 20 people marker type#markers#PCR’s effective resolution time to genotype family # lod scores micro- satellites 4008,00010 cM weeks to months 400

3. Genotype: microsatellite marker 5 / 6 5 / 45 / 25 / 4 5 / 15 / 3 6 / 26 / 4 2 / 4 1 / 3 4 / 1 Two-point Lod at 0% = +2.4 (dominant inheritance) = affected = unaffected

4. Full genome scan, old vs. new family size of 20 people marker type#markers#PCR’s effective resolution time to genotype family # lod scores micro- satellites 4008,00010 cM weeks to months 400 SNP10,00080~3 cM days to weeks 10,000

5. Genotype: SNP marker G / T G / G T / GG / G T / T Two-point Lod at 0% = +0.90

6. Haplotype: SNP markers G/G A/C G/C T/G T/G A/CG/G G/G A/CG/G T/T C/CG/G G/T C/C C/G G/G G/T C/C C/G G/G G/T A/C G/G T/G G/T A/C G/G T/G G/T A/C G/G T/G G/G A/A G/G T/G G/G A/A G/G T/G Multipoint Lod = +2.0

7. Multipoint calculations, sliding window of 4 SNPs * * * * * SNP 159131721 1 2 3 4 5

8. Example of a result Family N1, chromosome 1, 6-snp window lod

9. Calculations per chromosome Family N1, 6-snp window

10. SNP multipoints: sliding window Family N2, chromosome X Lod

11. Window size vs. CPU time Family N1, using Vitesse on Orchestra SNPs seconds/ calculation time/ genome Memory usage (MB RAM) 40.175 min.3 64018 hr.7 813,000220 days59 102,000,000+2,400+ yr.1829

12. The Future Affymetrix 100K SNP chip Affymetrix 500K SNP chip?

13. Thanks to: Sumy Mathew Okan Toka Yami Nicolau Meredith Moore Jon and Kricket Seidman Marcos Athanasoulis and the ORCHESTRA team