Lectures 29 30 Statistical Evaluation of Genetic Linkage Phase Lod scores genetic linkage mapping We genotype the six members of the family for SSRs scattered throughout the genome which spans 3300 cM one SSR must be within 10 cM of the Huntington s gene HD SSR12 SSR112 20 cM SSR31 SSR37 SSR5 LOD0 06 family 1 log10 0 024 0 0039 log10 6 25 0 796 Same for families 2 and 3 LOD0 06 families 1 2 3 3 x 0 796 2 388 Family 4 Maternal alleles HD SSR37 P if linked at 0 06 HD D HD D D HD D 1 2 P if phase 1 1 2 P if phase 2 1 2 0 47 x 0 47 x 0 03 x 0 47 1 2 0 03 x 0 03 x 0 47 x 0 03 0 0016 LOD0 06 family 4 log10 0 0016 0 0039 log10 0 41 0 387 LOD0 06 families 1 2 3 4 2 388 0 387 2 001 Still not sufficient to publish What to do 1 It s tempting to ignore family 4 to declare it to be irrelevant for some reason or another But this would not be an acceptable solution 2 Calculate LOD scores for other values 2 5 2 1 5 LOD 1 0 5 0 0 0 5 0 1 0 2 0 3 0 4 0 5 0 6 3 Get more families always a good idea 4 Determine phase in affected parents In each of the four families we were uncertain about phase and our LOD calculations embodied those uncertainties Family 4 Phase 1 Phase 2 HD SSR37 HD D B HD B D two possible arrangements of alleles on mother s chromosomes Typing the maternal grandparents for SSR37 Family 4 A SSR37 B C D E Locus Now we can deduce the phase in the mother Phase 1 Phase 2 HD SSR37 HD D B HD B D Here is a more realistic version of the genotypic information we might obtain dead Family 4 A SSR37 refused consent B C D E or inferred Before we had written P if linked at 0 06 1 2 P if phase 1 1 2 P if phase 2 1 2 0 47 x 0 47 x 0 03 x 0 47 1 2 0 03 x 0 03 x 0 47 x 0 03 0 0016 But we now know that phase 1 was correct P if linked at 0 06 1 2 P if phase 1 1 2 P if phase 2 1 2 0 47 x 0 47 x 0 03 x 0 47 1 2 0 03 x 0 03 x 0 47 x 0 03 LOD0 06 family 4 log10 0 0032 0 0039 log10 0 82 0 086 We can sum the LOD0 06 scores for all four families LOD0 06 family 1 2 3 4 2 388 0 086 2 302 phase known 0 0032 Overall effect of determining phase in all four families Add increment of log10 2 0 301 to each family s LOD score LOD0 06 families 1 2 3 4 all phased LOD0 06 families 1 2 3 4 unphased 4 log10 2 2 001 4 0 301 3 205 Publish What if we had not been able to obtain samples from any grandparents Try more markers Search for SSR marker showing no recombination with HD Where to look SSR34 Chr 4 SSR35 SSR36 SSR37 SSR38 20 cM or Marker showing no recombination with HD HD LOD0 families 1 2 3 4 unphased 4 x 0 903 3 609 Very strong conclusion
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