1. Inferring Haplotypes Dr. Russell Thomson

2. A Haplotype. …AGCTATATTA…..GGCTGCTC…..AGCAGCGA… …AGCTAAATTA…..GGCTCCTC…..AGCAGCGA… One individual. Marker 1Marker 2Marker 3 T G G A C G

3. Recombination Hotspots. Recombinations do NOT occur at random positions across the genome. Instead they are more likely to occur at “recombination hotspots”. “Recombination hotspots” are positions where recombinations are more likely To occur. Reed & Tishkoff, Genetics (2006).

4. Haplotype Blocks A haplotype block occurs between recombination hotspots. Within a haplotype block, there is LD between all the markers. Not all markers need to be genotyped within a haplotype block.

5. Defining Haplotype Blocks Many Proposed Rules. For example: Solid Spine of LD “the first and last markers in a block are in strong LD with all intermediate markers” LD can be defined using r 2, D ’ and/or LOD. VarFlow and Haploview can be used to define haplotype blocks

6. A Haplotype. …AGCTATATTA…..GGCTGCTC…..AGCAGCGA… …AGCTAAATTA…..GGCTCCTC…..AGCAGCGA… One individual. Marker 1Marker 2Marker 3 T G G A C G You can associate disease risk to a haplotype, instead of an allele.

7. A Haplotype. …AGCTATATTA…..GGCTGCTC…..AGCAGCGA… …AGCTAAATTA…..GGCTCCTC…..AGCAGCGA… One individual. Marker 1Marker 2Marker 3 T G G A C G Marker 1:T/A Marker 2:C/G Marker 3:G/G Genotypic Data:

8. Haplotype or Phase Inference Marker 1:T/A Marker 2:C/G Marker 3:G/G T G G A C G

9. Haplotype Inference using pedigrees G/C A/T C/C A/A G/C A/T mother father daughter This family structure is sometimes called a TRIO

10. Haplotype Inference using pedigrees G/C A/T C/C A/A G/C A/T CACA CACA

11. Haplotype Inference using pedigrees G/C A/T C/C A/A G/C A/T CACA CACA CACA

12. Haplotype Inference using pedigrees G/C A/T C/C A/A G/C A/T CACA GTGT CACA CACA

13. Haplotype Inference using pedigrees G/C A/T C/C A/A G/C A/T CACA GTGT CACA GTGT CACA CACA

14. Programs to conduct Haplotype Inference using pedigrees Haploview – using trios only. Merlin, Allegro and other linkage analysis software – any type of pedigree.

15. Haplotype Inference using population data. G/C A/A G/G A/A C/C T/T G/G A/T G/C A/T

16. Haplotype Inference using population data. G/C A/A G/G A/A C/C T/T G/G A/T G/C A/T GAGA CACA GAGA GAGA CTCT CTCT GAGA GTGT

17. Haplotype Inference using population data. G/C A/A G/G A/A C/C T/T G/G A/T G/C A/T GAGA CACA GAGA GAGA CTCT CTCT GAGA GTGT Probably GAGA CTCT

18. Haplotype Inference using population data. There are many algorithms to do this. They assign haplotype probabilities, given genotypes. Haploview implements one and VarFlow implements many Haplotype inference algorithms.