Blockwise HMM computation for large-scale population genomic inference

Abstract

A promising class of methods for large-scale population genomic inference use the conditional sampling distribution (CSD), which approximates the probability of sampling an individual with a particular DNA sequence, given that a collection of sequences from the population has already been observed. The CSD has a wide range of applications, including imputing missing sequence data, estimating recombination rates, inferring human colonization history and identifying tracts of distinct ancestry in admixed populations. Most well-used CSDs are based on hidden Markov models (HMMs). Although computationally efficient in principle, methods resulting from the common implementation of the relevant HMM techniques remain intractable for large genomic datasets. To address this issue, a set of algorithmic improvements for performing the exact HMM computation is introduced here, by exploiting the particular structure of the CSD and typical characteristics of genomic data. It is empirically demonstrated that these improvements result in a speedup of several orders of magnitude for large datasets and that the speedup continues to increase with the number of sequences. The optimized algorithms can be adopted in methods for various applications, including the ones mentioned above and make previously impracticable analyses possible. Software available upon request. Supplementary data are available at Bioinformatics online. yss@eecs.berkeley.edu.