Presentation on theme: "Inferring Local Tree Topologies for SNP Sequences Under Recombination in a Population Yufeng Wu Dept. of Computer Science and Engineering University of."— Presentation transcript:
Inferring Local Tree Topologies for SNP Sequences Under Recombination in a Population Yufeng Wu Dept. of Computer Science and Engineering University of Connecticut, USA MIEP 2008
2 Genetic Variations Single-nucleotide polymorphism (SNP): a site (genomic location) where two types of nucleotides occur frequently in the population. –Haplotype, a binary vector of SNPs (encoded as 0/1). Haplotypes: offer hints on genealogy. AATGTAGCCGA AATATAACCTA AATGTAGCCGT AATGTAACCTA CATATAGCCGT AATGTAGCCGA AATATAACCTA AATGTAGCCGT AATGTAACCTA CATATAGCCGT DNA sequences Sites 00100 01010 00101 00010 11101 Haplotypes Sites Each SNP induces a split
Genealogy: Evolutionary History of Genomic Sequences Tells how individuals in a population are related Helps to explain diseases: disease mutations occur on branches and all descendents carry the mutations Problem: How to determine the genealogy for “unrelated” individuals? Complicated by recombination Individuals in current population Diseased (case) Healthy (control) Disease mutation 3
4 Recombination One of the principle genetic forces shaping sequence variations within species Two equal length sequences generate a third new equal length sequence in genealogy Spatial order is important: different parts of genome inherit from different ancestors. 110001111111001 000110000001111 Prefix Suffix 110000000001111 Breakpoint
Ancestral Recombination Graph (ARG) 100100 S1 = 00 S2 = 01 S3 = 10 S4 = 10 Mutations S1 = 00 S2 = 01 S3 = 10 S4 = 11 10010011 Recombination Assumption: At most one mutation per site 1 00 1 1 0 1010 5
Local Trees ARG represents a set of local trees. Each tree for a continuous genomic region. No recombination between two sites same local trees for the two sites Local tree topology: informative and useful ARG Local tree near sites 1 and 2 Local tree near site 2Local tree to the right of site 3 6
Inference of Local Tree Topologies 7 Question: given SNP haplotypes, infer local tree topologies (one tree for each SNP site, ignore branch length) –Hein (1990, 1993) Enumerate all possible tree topologies at each site –Song and Hein (2003,2005) –Parsimony-based Local tree reconstruction can be formulated as inference on a hidden Markov model.
Local Tree Topologies 8 Key technical difficulty –Brute-force enumeration of local tree topologies: not feasible when number of sequences > 9 Can not enumerate all tree topologies Trivial solution: create a tree for a SNP containing the single split induced by the SNP. –Always correct (assume one mutation per site) –But not very informative: need more refined trees! A: 0 B: 0 C: 1 D: 0 E: 1 F: 0 G: 1 H: 0 C E G A B D F H
How to do better? Neighboring Local Trees are Similar! Nearby SNP sites provide hints! –Near-by local trees are often topologically similar –Recombination often only alters small parts of the trees Key idea: reconstructing local trees by combining information from multiple nearby SNPs 9
RENT: REfining Neighboring Trees Maintain for each SNP site a (possibly non- binary) tree topology –Initialize to a tree containing the split induced by the SNP Gradually refining trees by adding new splits to the trees –Splits found by a set of rules (later) –Splits added early may be more reliable Stop when binary trees or enough information is recovered 10
11 0 0 0 1 0 1 0 0 1 0 0 0 1 0 0 1 0 1 0 0 0 1 1 0 0 0 1 1 0 1 0 0 1 0 1 1 2 3 4 5 abcdefgabcdefg M A Little Background: Compatibility Two sites (columns) p, q are incompatible if columns p,q contains all four ordered pairs (gametes): 00, 01, 10, 11. Otherwise, p and q are compatible. Easily extended to splits. A split s is incompatible with tree T if s is incompatible with any one split in T. Two trees are compatible if their splits are pairwise compatible. Sites 1 and 2 are compatible, but 1 and 3 are incompatible.
Fully-Compatible Region: Simple Case A region of consecutive SNP sites where these SNPs are pairwise compatible. –May indicate no topology-altering recombination occurred within the region Rule: for site s, add any such split to tree at s. –Compatibility: very strong property and unlikely arise due to chance. 12
Split Propagation: More General Rule Three consecutive sites 1,2 and 3. Sites 1 and 2 are incompatible. Does site 3 matter for tree at site 1? –Trees at site 1 and 2 are different. –Suppose site 3 is compatible with sites 1 and 2. Then? –Site 3 may indicate a shared subtree in both trees at sites 1 and 2. Rule: a split propagates to both directions until reaching a incompatible tree. 13
Unique Refinement Consider the subtree with leaves 1,2 and 3. – Which refinement is more likely? – Add split of 1 and 2: the only split that is compatible with neighboring T2. Rule: refine a non-binary node by the only compatible split with neighboring trees 13 2 ? 14
One Subtree-Prune-Regraft (SPR) Event Recombination: simulated by SPR. –The rest of two trees (without pruned subtrees) remain the same Rule: find identical subtree T s in neighboring trees T1 and T2, s.t. the rest of T1 and T2 (T s removed) are compatible. Then joint refine T1- T s and T2- T s before adding back T s. Subtree to prune 15 More complex rules possible.
Simulation Hudson’s program MS (with known coalescent local tree topologies): 100 datasets for each settings. –Data much larger and perform better or similarly for small data than Song and Hein’s method. Test local tree topology recovery scored by Song and Hein’s shared- split measure = 15 = 50 16
17 Acknowledgement Software available upon request. More information available at: http://www.engr.uconn.edu/~ywu I want to thank –Yun S. Song –Dan Gusfield