HapCUT: an efficient and accurate algorithm for the haplotype assembly problem

MOTIVATION The goal of the haplotype assembly problem is to reconstruct the two haplotypes (chromosomes) for an individual using a mix of sequenced fragments from the two chromosomes. This problem has been shown to be computationally intractable for various optimization criteria. Polynomial time algorithms have been proposed for restricted versions of the problem. In this article, we consider the haplotype assembly problem in the most general setting, i.e. fragments of any length and with an arbitrary number of gaps. RESULTS We describe a novel combinatorial approach for the haplotype assembly problem based on computing max-cuts in certain graphs derived from the sequenced fragments. Levy et al. have sequenced the complete genome of a human individual and used a greedy heuristic to assemble the haplotypes for this individual. We have applied our method HapCUTto infer haplotypes from this data and demonstrate that the haplotypes inferred using HapCUT are significantly more accurate (20-25% lower maximum error correction scores for all chromosomes) than the greedy heuristic and a previously published method, Fast Hare. We also describe a maximum likelihood based estimator of the absolute accuracy of the sequence-based haplotypes using population haplotypes from the International HapMap project. AVAILABILITY A program implementing HapCUT is available on request.

[1]  Zhaohui S. Qin,et al.  A comparison of phasing algorithms for trios and unrelated individuals. , 2006, American journal of human genetics.

[2]  Timothy B. Stockwell,et al.  The Diploid Genome Sequence of an Individual Human , 2007, PLoS biology.

[3]  Giuseppe Lancia,et al.  Polynomial and APX-hard cases of the individual haplotyping problem , 2005, Theor. Comput. Sci..

[4]  Teofilo F. Gonzalez,et al.  P-Complete Problems and Approximate Solutions , 1974, SWAT.

[5]  Xiang-Sun Zhang,et al.  Haplotype reconstruction from SNP fragments by minimum error correction , 2005, Bioinform..

[6]  Alessandro Panconesi,et al.  Fast Hare: A Fast Heuristic for Single Individual SNP Haplotype Reconstruction , 2004, WABI.

[7]  M. Olivier.  A haplotype map of the human genome , 2003, Nature.

[8]  David S. Johnson,et al.  Computers and Intractability: A Guide to the Theory of NP-Completeness , 1978 .

[9]  Giuseppe Lancia,et al.  Practical Algorithms and Fixed-Parameter Tractability for the Single Individual SNP Haplotyping Problem , 2002, WABI.

[10]  P. Donnelly,et al.  A new statistical method for haplotype reconstruction from population data. , 2001, American journal of human genetics.

[11]  M. Olivier.  A haplotype map of the human genome. , 2003, Nature.

[12]  Russell Schwartz,et al.  SNPs Problems, Complexity, and Algorithms , 2001, ESA.

[13]  A. Halpern,et al.  An MCMC algorithm for haplotype assembly from whole-genome sequence data. , 2008, Genome research.

[14]  Leo van Iersel,et al.  On the Complexity of Several Haplotyping Problems , 2005, WABI.

[15]  Russell Schwartz,et al.  Algorithmic strategies for the single nucleotide polymorphism haplotype assembly problem , 2002, Briefings Bioinform..

[16]  Dan Gusfield,et al.  Haplotyping as perfect phylogeny: conceptual framework and efficient solutions , 2002, RECOMB '02.

[17]  Shibu Yooseph,et al.  Haplotyping as Perfect Phylogeny: A Direct Approach , 2003, J. Comput. Biol..

[18]  Michael S Waterman,et al.  Diploid genome reconstruction of Ciona intestinalis and comparative analysis with Ciona savignyi. , 2007, Genome research.

[19]  Jong Hyun Kim,et al.  Haplotype Reconstruction from SNP Alignment , 2004, J. Comput. Biol..

[20]  R. Karp,et al.  Efficient reconstruction of haplotype structure via perfect phylogeny. , 2002, Journal of bioinformatics and computational biology.