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Detection of sharing by descent, long-range phasing and haplotype imputation

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Abstract

Uncertainty about the phase of strings of SNPs creates complications in genetic analysis, although methods have been developed for phasing population-based samples. However, these methods can only phase a small number of SNPs effectively and become unreliable when applied to SNPs spanning many linkage disequilibrium (LD) blocks. Here we show how to phase more than 1,000 SNPs simultaneously for a large fraction of the 35,528 Icelanders genotyped by Illumina chips. Moreover, haplotypes that are identical by descent (IBD) between close and distant relatives, for example, those separated by ten meioses or more, can often be reliably detected. This method is particularly powerful in studies of the inheritance of recurrent mutations and fine-scale recombinations in large sample sets. A further extension of the method allows us to impute long haplotypes for individuals who are not genotyped.

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Figure 1: The concept of surrogate parenthood.
Figure 2: The relationship between sample size and the yield of LRP.
Figure 3: Applying long-range phasing to determine a recombination event.
Figure 4: The inheritance of a chromosome associated with a deletion.
Figure 5: Imputing haplotypes into an untyped proband P.

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Authors and Affiliations

  1. deCODE genetics, Sturlugata 8, Reykjavík, 101, Iceland

    Augustine Kong, Gisli Masson, Michael L Frigge, Arnaldur Gylfason, Pasha Zusmanovich, Gudmar Thorleifsson, Pall I Olason, Andres Ingason, Stacy Steinberg, Thorunn Rafnar, Patrick Sulem, Magali Mouy, Frosti Jonsson, Unnur Thorsteinsdottir, Daniel F Gudbjartsson, Hreinn Stefansson & Kari Stefansson

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  1. Augustine Kong
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  2. Gisli Masson
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  3. Michael L Frigge
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  4. Arnaldur Gylfason
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  5. Pasha Zusmanovich
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  6. Gudmar Thorleifsson
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  15. Daniel F Gudbjartsson
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  16. Hreinn Stefansson
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  17. Kari Stefansson
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Contributions

A.K. and K.S. planned and supervised the research. A.K. wrote the first draft of the paper and together with K.S. and G.M. did most of the writing for the final version. The idea of long range phasing (LRP) originated from A.K. and G.M., motivated by a problem posed by H.S. G.M. and P.I.O. coded the LRP algorithm. A.K., M.L.F., A.G. and P.Z. contributed to the study of the population characteristics of Iceland. A.K., G.T. and M.L.F. contributed to the recombination study. A.K., H.S., S.S. and A.I. contributed to the study of the deletion at 15q11. A.K., D.F.G., T.R., P.S. and M.L.F. contributed to the haplotype imputation study. U.T., M.M. and F.J. contributed to genotyping.

Corresponding authors

Correspondence to Augustine Kong or Kari Stefansson.

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Competing interests

The authors from deCode genetics declare competing financial interests as stock holders in deCode genetics.

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Supplementary Note, Supplementary Tables 1–3 (PDF 162 kb)

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Kong, A., Masson, G., Frigge, M. et al. Detection of sharing by descent, long-range phasing and haplotype imputation. Nat Genet 40, 1068–1075 (2008). https://doi.org/10.1038/ng.216

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