How Accurate is Pure Parsimony Haplotype Inferencing

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Presentation transcript:

How Accurate is Pure Parsimony Haplotype Inferencing How Accurate is Pure Parsimony Haplotype Inferencing? Sharlee Climer Department of Computer Science and Engineering Department of Biology Washington University in Saint Louis sharlee@climer.us www.climer.us Joint work with Weixiong Zhang and Gerold Jaeger RECOMB SNPs Workshop/Jan 28, 2007

Pure Parsimony Pure Parsimony Haplotype Inferencing (PPHI) Find smallest set of unique haplotypes that can resolve a set of genotypes Suggested by Earl Hubbell in 2000 Cast as an Integer Linear Program (IP) by Dan Gusfield [CPM’03] Great research interest RECOMB SNPs Workshop/Jan 28, 2007

Overview Biological forces Haplotypes with low frequency Define haplotype classes Data sets Characteristics of real data RECOMB SNPs Workshop/Jan 28, 2007

Biological forces RECOMB SNPs Workshop/Jan 28, 2007

Biological forces RECOMB SNPs Workshop/Jan 28, 2007

Biological forces RECOMB SNPs Workshop/Jan 28, 2007

Biological forces RECOMB SNPs Workshop/Jan 28, 2007

Biological forces RECOMB SNPs Workshop/Jan 28, 2007

Biological forces RECOMB SNPs Workshop/Jan 28, 2007

Biological forces RECOMB SNPs Workshop/Jan 28, 2007

Biological forces Relatively few unique haplotypes Subset of haplotypes with low frequency Problems for PPHI Large number of optimal solutions True biological solution might not be parsimonious What are structural characteristics of optimal solutions? RECOMB SNPs Workshop/Jan 28, 2007

Classes of haplotypes Set of possible haplotypes is exponentially large Partition similar to Traveling Salesman Problem Backbone haplotypes Appear in every optimal solution Fat haplotypes Do not appear in any optimal solution Fluid haplotypes Appear in some, but not all, optimal solutions RECOMB SNPs Workshop/Jan 28, 2007

Backbone haplotypes Implicit backbones Explicit backbones All haplotypes that resolve unambiguous genotypes Explicit backbones Can identify by solving at most one IP for each haplotype in solution that isn’t implicit backbone RECOMB SNPs Workshop/Jan 28, 2007

Backbone haplotypes h3 h7 h15 h27 h39 h50 h55 h79 h91 bb bb bb bb RECOMB SNPs Workshop/Jan 28, 2007

Backbone graph RECOMB SNPs Workshop/Jan 28, 2007

Backbone graph RECOMB SNPs Workshop/Jan 28, 2007

An optimal solution RECOMB SNPs Workshop/Jan 28, 2007

Low frequency haplotype RECOMB SNPs Workshop/Jan 28, 2007

Low frequency haplotype RECOMB SNPs Workshop/Jan 28, 2007

Low frequency haplotype RECOMB SNPs Workshop/Jan 28, 2007

Low frequency haplotype RECOMB SNPs Workshop/Jan 28, 2007

Data sets 7 true haplotype data sets Orzack et al.[Genetics, 2003] 80 genotypes 9 sites ApoE Andres et al. [Genet. Epi., in press] 6 sets of complete data 39 genotypes 5 to 47 sites KLK13 and KLK14 RECOMB SNPs Workshop/Jan 28, 2007

Data sets HapMap data [Nature 2003, 2005] Phase unknown Random instance generator 20 unique genotypes 20 sites Three populations CEU YRI JPT+CHB 22 chromosomes RECOMB SNPs Workshop/Jan 28, 2007

Size of haplotype backbone RECOMB SNPs Workshop/Jan 28, 2007

Number of fluid haplotypes in each solution RECOMB SNPs Workshop/Jan 28, 2007

Number of optimal solutions RECOMB SNPs Workshop/Jan 28, 2007

Number of fluid haplotypes and solutions RECOMB SNPs Workshop/Jan 28, 2007

Biological correctness Data set # gen. # sites # BB hap. #fluid hap. # opt. sols. Avg. distance to real A 30 9 15 1 8 B 10 5 7 C 18 17 3 16 7.5 D 6 4 2.5 E 23 26 >1000 4.33 F 22 12 630 28.24 G 35 47 10.95 RECOMB SNPs Workshop/Jan 28, 2007

Biological correctness Data set Parsimony # of haplotypes True # of haplotypes A 15 17 B 7 C 12 D E 16 F 18 G 28 32 RECOMB SNPs Workshop/Jan 28, 2007

Biological correctness Accuracy of backbone haplotypes Two data sets (F and G) had errors One parsimony backbone haplotype not in real solution RECOMB SNPs Workshop/Jan 28, 2007

Number of solutions vs. number of genotypes RECOMB SNPs Workshop/Jan 28, 2007

Conclusions Biological forces tend to minimize cardinality, but also create low frequency haplotypes Low frequency in unique genotypes might not be low frequency in full set Low frequency haplotypes Large number of optimal solutions True solution not necessarily parsimonious Combinatorial nature can lead to errors in backbones Parsimony combined with other biological clues RECOMB SNPs Workshop/Jan 28, 2007

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