SpeedHap: An Accurate Heuristic for the Single Individual SNP Haplotyping Problem with Many Gaps, High Reading Error Rate and Low Coverage

Single nucleotide polymorphism (SNP) is the most frequent form of DNA variation. The set of SNP's present in a chromosome (called the haplotype) is of interest in a wide area of applications in molecular biology and biomedicine, including diagnostic and medical therapy. In this paper we propose a new heuristic method for the problem of haplotype reconstruction for (portions of) a pair of homologous human chromosomes from a single individual (SIH). The problem is well known in literature and exact algorithms have been proposed for the case when no (or few) gaps are allowed in the input fragments. These algorithms, though exact and of polynomial complexity, are slow in practice. When gaps are considered no exact method of polynomial complexity is known. The problem is also hard to approximate with guarantees. Therefore fast heuristics have been proposed. In this paper we describe SpeedHap, a new heuristic method that is able to tackle the case of many gapped fragments and retains its effectiveness even when the input fragments have high rate of reading errors (up to 20%) and low coverage (as low as 3). We test SpeedHap on real data from the HapMap Project.

[1]  Paola Bonizzoni,et al.  The Haplotyping problem: An overview of computational models and solutions , 2003, Journal of Computer Science and Technology.

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

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

[4]  John J. Grefenstette,et al.  Application of machine learning in SNP discovery , 2006, BMC Bioinformatics.

[5]  Ying Wang,et al.  A clustering algorithm based on two distance functions for MEC model , 2007, Comput. Biol. Chem..

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

[7]  P. Deloukas,et al.  The impact of SNP density on fine-scale patterns of linkage disequilibrium. , 2004, Human molecular genetics.

[8]  M. Daly,et al.  High-resolution haplotype structure in the human genome , 2001, Nature Genetics.

[9]  Hwan-Gue Cho,et al.  FASIM : Fragments assembly simulation using biased-sampling model and assembly simulation for microbial genome shotgun sequencing , 2006 .

[10]  Russell Schwartz,et al.  Haplotypes and informative SNP selection algorithms: don't block out information , 2003, RECOMB '03.

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

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

[13]  Michael P Weiner,et al.  Introduction to SNPs: discovery of markers for disease. , 2002, BioTechniques.

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

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

[16]  Jong Hyun Kim,et al.  Haplotype reconstruction from SNP alignment , 2003, RECOMB '03.

[17]  M. Daly,et al.  A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms , 2001, Nature.

[18]  Eugene W. Myers,et al.  A Dataset Generator for Whole Genome Shotgun Sequencing , 1999, ISMB.

[19]  Gonzalo Navarro,et al.  Compressed full-text indexes , 2007, CSUR.

[20]  Leo van Iersel,et al.  The Complexity of the Single Individual SNP Haplotyping Problem , 2005, Algorithmica.

[21]  Eugene W. Myers,et al.  The fragment assembly string graph , 2005, ECCB/JBI.

[22]  E. Lander,et al.  Genomic mapping by fingerprinting random clones: a mathematical analysis. , 1988, Genomics.

[23]  J. Roach,et al.  Pairwise end sequencing: a unified approach to genomic mapping and sequencing. , 1995, Genomics.

[24]  Luonan Chen,et al.  A Markov chain model for haplotype assembly from SNP fragments. , 2006, Genome informatics. International Conference on Genome Informatics.

[25]  Roberto Grossi,et al.  High-order entropy-compressed text indexes , 2003, SODA '03.

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

[27]  Zhaohui S. Qin,et al.  A second generation human haplotype map of over 3.1 million SNPs , 2007, Nature.

[28]  Yongjian Guo,et al.  The distribution of SNPs in human gene regulatory regions , 2005, BMC Genomics.

[29]  J. Pritchard,et al.  Linkage disequilibrium in humans: models and data. , 2001, American journal of human genetics.