Reconstructing ancestral haplotypes with a dictionary model

Abstract

We propose a dictionary model for haplotypes. According to the model, a haplotype is constructed by randomly concatenating haplotype segments from a given dictionary of segments. A haplotype block is defined as a set of haplotype segments that begin and end with the same pair of markers. In this framework, haplotype blocks can overlap, and the model provides a setting for testing the accuracy of simpler models invoking only nonoverlapping blocks. Each haplotype segment in a dictionary has an assigned probability and alternate spellings that account for genotyping errors and mutation. The model also allows for missing data, unphased genotypes, and prior distribution of parameters. Likelihood evaluations rely on forward and backward recurrences similar to the ones encountered in hidden Markov models. Parameter estimation is carried out with an EM algorithm. The search for the optimal dictionary is particularly difficult because of the variable dimension of the model space. We define a minimum description length criteria to evaluate each dictionary and use a combination of greedy search and careful initialization to select a best dictionary for a given dataset. Application of the model to simulated data gives encouraging results. In a real dataset, we are able to reconstruct a parsimonious dictionary that captures patterns of linkage disequilibrium well.