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A fast and practical approach to genotype phasing and imputation on a pedigree with erroneous and incomplete information
Nov.-Dec. 2012 (vol. 9 no. 6)
pp. 1582-1594
Y. Pirola, Dipt. di Inf. Sist. e Comun. (DISCo), Univ. degli Studi di Milano-Bicocca, Milan, Italy
G. D. Vedova, Dipt. di Statistica, Univ. degli Studi di Milano-Bicocca, Milan, Italy
S. Biffani, Centro Ric. e Studi Agroalimentari (CeRSA), Lodi, Italy
A. Stella, Centro Ric. e Studi Agroalimentari (CeRSA), Lodi, Italy
P. Bonizzoni, Dipt. di Inf. Sist. e Comun. (DISCo), Univ. degli Studi di Milano-Bicocca, Milan, Italy
The MINIMUM-RECOMBINANT HAPLOTYPE CONFIGURATION problem (MRHC) has been highly successful in providing a sound combinatorial formulation for the important problem of genotype phasing on pedigrees. Despite several algorithmic advances that have improved the efficiency, its applicability to real data sets has been limited since it does not take into account some important phenomena such as mutations, genotyping errors, and missing data. In this work, we propose the MINIMUM-RECOMBINANT HAPLOTYPE CONFIGURATION WITH BOUNDED ERRORS problem (MRHCE), which extends the original MRHC formulation by incorporating the two most common characteristics of real data: errors and missing genotypes (including untyped individuals). We describe a practical algorithm for MRHCE that is based on a reduction to the well-known Satisfiability problem (SAT) and exploits recent advances in the constraint programming literature. An experimental analysis demonstrates the biological soundness of the phasing model and the effectiveness (on both accuracy and performance) of the algorithm under several scenarios. The analysis on real data and the comparison with state-of-the-art programs reveals that our approach couples better scalability to large and complex pedigrees with the explicit inclusion of genotyping errors into the model.
Index Terms:
genomics,bioinformatics,computability,constraint handling,incomplete information,genotype phasing,genotype imputation,combinatorial formulation,pedigrees,minimum-recombinant haplotype configuration with bounded errors problem,MRHCE,satisfiability problem,constraint programming literature,biological soundness,phasing model,genotyping errors,erroneous information,Bioinformatics,Genetics,Algorithm design and analysis,Computational biology,Genomics,recombinations,Haplotype inference,pedigrees,genotyping errors,missing data
Citation:
Y. Pirola, G. D. Vedova, S. Biffani, A. Stella, P. Bonizzoni, "A fast and practical approach to genotype phasing and imputation on a pedigree with erroneous and incomplete information," IEEE/ACM Transactions on Computational Biology and Bioinformatics, vol. 9, no. 6, pp. 1582-1594, Nov.-Dec. 2012, doi:10.1109/TCBB.2012.100
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