Haplotype Analysis. 02 November 2003 Mendel Short IGES Slide 1
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1 Haplotype Analysis Specifies the genetic information descending through a pedigree Useful visualization of the gene flow through a pedigree A haplotype for a given individual and set of loci is defined as the set of alleles inherited, one per locus, from the same parent 0 November 00 Mendel Short IGES Slide
2 Inferred Haplotype DS7 DS DS DS DS DS8 DS DS Figure.. Example of of a haplotyped pedigree in in which each founder haplotype has has been uniquely colored. This fully-typed pedigree comes from a study of of Krabbe disease: the the full-black symbol indicates an an affected; half-black indicates obligate carriers; half-gray indicates carriers identified by by an an enzyme assay. 0 November 00 Mendel Short IGES Slide
3 Standard Pedigree Likelihood Function L = G Gn j Prior(G j ) {m,k,l} Trans(G m G k G l ) i Pen(X i G i ) Haplotypes scored by their Likelihood Gp runs through all possible multilocus-genotypes at person p X i is the phenotype (or observed genotype) at person i j runs over all founders; i runs over all people; {k,l,m} runs over all parent offspring triples 0 November 00 Mendel Short IGES Slide
4 Combining Loci (a) a/b / e/e a/b / f/f (b) ae/be af/bf a/b / e/f ae/bf Figure.. Part (a) (a) shows unordered genotypes at at three loci. Each locus is is uninformative in in this this mating. In In part (b) (b) the the three loci loci have been haplotyped and and combined into into one one super-locus that that is is informative. 0 November 00 Mendel Short IGES Slide
5 Mistyping a b d e c d e f a d d f Figure.. Haplotyping results that that suggest that that the the child s typing may be be in in error at at the the allele. The arrows indicate flanking recombination events. However, there are are now programs (e.g., Mendel and and SimWalk) that that perform mistyping analysis by, by, in in essence, averaging over all all possible haplotypes weighting each by by their likelihood. The right way to to do do mistyping analysis! 0 November 00 Mendel Short IGES Slide
6 Founder Effects S8 S8 S S centromere 0 kb 00 kb 0 kb telomere 00 kb A-T support interval from linkage analysis Figure.. Map of of four loci on on chromosome that are closely linked to to the Ataxia-Telangiectasia (A-T) gene. The 00 kb kb support interval for for the A-T locus found using multipoint linkage analysis is is indicated. 0 November 00 Mendel Short IGES Slide
7 0 November 00 Mendel Short IGES Slide 7 Haplotyping results of 7 seemingly unrelated Costa Rican A-T patients. The individuals are labeled above the haplotypes; the haplotypes are labeled beneath the haplotypes. The haplotypes of common ancestral origin are similarly colored. Unique haplotypes (G, H, I & J) are not colored. Haplotyping results of 7 seemingly unrelated Costa Rican A-T patients. The individuals are labeled above the haplotypes; the haplotypes are labeled beneath the haplotypes. The haplotypes of common ancestral origin are similarly colored. Unique haplotypes (G, H, I & J) are not colored. S8 S87 S S8 S8 B7 S S S88 S0 S7 S00 S [A][A] [A][A] [A][A] [A][A] [H][A] [E][A] [A][G] [A][A] [A][A] S8 S87 S S8 S8 B7 S S S88 S0 S7 S00 S [A][A] [B][A] [B][A] [B][B] [B][A/B] [B][B] [A][B] [B][B] [A][C] S8 S87 S S8 S8 B7 S S S88 S0 S7 S00 S [C][A] [C][C] [J][C] [D][C] [C][D] [D][D] [A][D] [F][F] [I][E]
8 Conclusions Programs will always output a single most likely haplotype, but what is the confidence level? There may be many other haplotypes that are equally, or only slightly less, likely The true haplotype may not even be among the most likely! There are some ways to trick the software into providing multiple likely haplotypes 0 November 00 Mendel Short IGES Slide 8
9 Conclusions Rather than look at one haplotype, a better analysis would be to average over all possible haplotypes, weighting each by their likelihood One can be more confident in haplotype results when using a dense map and informative markers However, all current software assumes all markers are in Linkage Equilibrium! 0 November 00 Mendel Short IGES Slide
10 EA Haplotype Example pterm. DS DS00 CACNLA DS7 py/ py/ KCNA DS DS cen ? November 00 Mendel Short IGES Slide 0
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