Haplotype Inference

Part of the Methods in Molecular Biology book series (MIMB, volume 1666)


Haplotypes, as they specify linkage patterns between individual nucleotide variants, confer critical information for understanding the genetics of human diseases. However, haplotype information is not directly obtainable from high-throughput genotyping platforms. In this chapter, we introduce four representative methods to reconstruct haplotypes from unphased genotype data, two of them are for unrelated individuals and the other two are for families.

Key words

Haplotype Genotype Pedigree Population Mendelian law Linkage disequilibrium PedPhase 3.0 Merlin FASTPHASE MACH 



This work was supported in part by NIH R03 HG008632.


  1. 1.
    Bonizzoni P, Della Vedova G, Dondi R, Li J (2003) The haplotyping problem: an overview of computational models and solutions. J Comput Sci Technol 18:675–688CrossRefGoogle Scholar
  2. 2.
    Gusfield D (2004) An overview of combinatorial methods for haplotype inference. In: Computational methods for SNPs and haplotype inference, pp 599–600Google Scholar
  3. 3.
    Halldorsson B, Bafna V, Edwards N, Lippert R, Yooseph S, Istrail S (2004) A survey of computational methods for determining haplotypes. In: Computational methods for SNPs and haplotype inference, pp 613–614Google Scholar
  4. 4.
    Zhang X, Wang R, Wu L, Chen L (2006) Models and algorithms for haplotyping problem. Curr Bioinforma 1:105–114CrossRefGoogle Scholar
  5. 5.
    Li J, Jiang T (2008) A survey on haplotyping algorithms for tightly linked markers. J Bioinforma Comput Biol 6:241–259CrossRefGoogle Scholar
  6. 6.
    Browning SR, Brownig BL (2011) Haplotype phasing: existing methods and new developments. Nat Rev Genet 12:703–714CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Scheet P, Stephens M (2006) A fast and flexible statistical model for large-scale population genotype data: applications to inferring missing genotypes and haplotypic phase. Am J Hum Genet 78:629–644CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Li Y, Willer CJ, Ding J, Scheet P, Abecasis GR (2010) MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet Epidemiol 34:816–834CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Li Y, Willer CJ, Sanna S, Abecasis GR (2009) Genotype imputation. Annu Rev Genomics Hum Genet 10:387–406CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Li X, Li J (2009) An almost linear time algorithm for a general haplotype solution on tree pedigrees with no recombination and its extensions. J Bioinforma Comput Biol 7:521–545CrossRefGoogle Scholar
  11. 11.
    Li X, Li J (2011) Haplotype reconstruction in large pedigrees with untyped individuals through IBD inference. J Comput Biol 8(11):1411–1421CrossRefGoogle Scholar
  12. 12.
    Abecasis G, Cherny S, Cookson W, Cardon L (2001) Merlin – rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 30:97–101CrossRefPubMedGoogle Scholar
  13. 13.
    Stephens M, Smith N, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68:978–989CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    The International HapMap Consortium (2003) The international HapMap project. Nature 426:789–796CrossRefGoogle Scholar
  15. 15.
    Excoffier L, Slatkin M (1995) Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol Biol Evol 12:921–927PubMedGoogle Scholar
  16. 16.
    Hawley M, Kidd K (1995) HAPLO: a program using the EM algorithm to estimate the frequencies of multi-site haplotypes. J Hered 86:409–411CrossRefPubMedGoogle Scholar
  17. 17.
    Niu T, Qin Z, Xu X, Liu J (2002) Bayesian haplotype inference for multiple linked single-nucleotide polymorphisms. Am J Hum Genet 70:157–169CrossRefPubMedGoogle Scholar
  18. 18.
    Qin Z, Niu T, Liu J (2002) Partition-ligation-expectation-maximization algorithm for haplotype inference with single-nucleotide polymorphisms. Am J Hum Genet 71:1242–1247CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Sun S, Greenwood C, Neal R (2007) Haplotype inference using a Bayesian hidden Markov model. Genet Epidemiol 31:937–948CrossRefPubMedGoogle Scholar
  20. 20.
    Browning S, Browning B (2007) Rapid and accurate haplotype phasing and missing-data inference for whole-genome association studies by use of localized haplotype clustering. Am J Hum Genet 81:1084–1097CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Howie BN, Donnelly P, Marchini J (2009) A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet 5(6):e1000529CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    O’Connell J (2000) Zero-recombinant haplotyping: applications to fine mapping using SNPs. Genet Epidemiol 19:S64–S70CrossRefPubMedGoogle Scholar
  23. 23.
    Qian D, Beckmann L (2002) Minimum-recombinant haplotyping inpedigrees. Am J Hum Genet 70:1434–1445CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Tapadar P, Ghosh S, Majumder P (2000) Haplotyping in pedigreesvia a genetic algorithm. Hum Hered 50:43–56CrossRefPubMedGoogle Scholar
  25. 25.
    Zhang K, Sun F, Zhao H (2005) HAPLORE: a program for haplotype reconstruction in general pedigrees without recombination. Bioinformatics 21:90–103CrossRefPubMedGoogle Scholar
  26. 26.
    Chan M, Chan W, Chin F, Fung S, Kao M (2006) Linear-timehaplotype inference on pedigrees without recombinations. In: Algorithms in bioinformatics, pp 56–67Google Scholar
  27. 27.
    Xiao J, Liu L, Xia L, Jiang T (2007) Fast elimination of redundant linear equations and reconstruction of recombination-free Mendelian inheritance on a pedigree. In: Proceedings of the eighteenth annual ACM-SIAM symposium on discrete algorithms, pp 655–664Google Scholar
  28. 28.
    Li X, Chen Y, Li J (2010) Detecting genome-wide haplotype polymorphism by combined use of Mendelian constraints and local population structure. Pac Symp Biocomput 15:348–358Google Scholar
  29. 29.
    Liu L, Xi C, Xiao J, Jiang T (2007) Complexity and approximation of the minimum recombinant haplotype configuration problem. Theor Comput Sci 378:316–330CrossRefGoogle Scholar
  30. 30.
    Elston R, Stewart J (1971) A general model for the genetic analysis of pedigree data. Hum Hered 21:523–542CrossRefPubMedGoogle Scholar
  31. 31.
    Lander E, Green P (1987) Construction of multilocus genetic linkage maps in humans. Proc Natl Acad Sci U S A 84:2363–2367CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Sobel E, Lange K (1996) Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker-sharing statistics. Am J Hum Genet 58:1323–1327PubMedPubMedCentralGoogle Scholar
  33. 33.
    Kruglyak L, Daly M, Reeve-Daly M, Lander E (1996) Parametric and nonparametric linkage analysis: a unified multipoint approach. Am J Hum Genet 58:1347–1363PubMedPubMedCentralGoogle Scholar
  34. 34.
    Gudbjartsson D, Jonasson K, Frigge M, Kong A (2000) Allegro, a new computer program for multipoint linkage analysis. Nat Genet 25:12–13CrossRefPubMedGoogle Scholar
  35. 35.
    Abecasis G, Wigginton J (2005) Handling marker-marker linkage disequilibrium: pedigree analysis with clustered markers. Am J Hum Genet 77:754–767CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Li J, Jiang T (2003) Efficient inference of haplotypes from genotypes on a pedigree. Int J Bioinforma Comput Biol 1:41–70CrossRefGoogle Scholar
  37. 37.
    Doi K, Li J, Jiang T (2003) Minimum recombinant haplotype configuration on tree pedigrees. In: Algorithms in bioinformatics, pp 339–353Google Scholar
  38. 38.
    Li J, Jiang T (2005) Computing the minimum recombinant haplotype configuration from incomplete genotype data on a pedigree by integer linear programming. J Comput Biol 12:719–739CrossRefPubMedGoogle Scholar
  39. 39.
    Li X, Li J (2007) Comparison of haplotyping methods using families and unrelated individuals on simulated rheumatoid arthritis data. BMC Proc 1:S55CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media LLC 2017

Authors and Affiliations

  1. 1.Case Western Reserve UniversityClevelandUSA

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