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Merlin—rapid analysis of dense genetic maps using sparse gene flow trees

Nature Genetics volume 30, pages 97101 (2002) | Download Citation

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Abstract

Efforts to find disease genes using high-density single-nucleotide polymorphism (SNP) maps will produce data sets that exceed the limitations of current computational tools. Here we describe a new, efficient method for the analysis of dense genetic maps in pedigree data that provides extremely fast solutions to common problems such as allele-sharing analyses and haplotyping. We show that sparse binary trees represent patterns of gene flow in general pedigrees in a parsimonious manner, and derive a family of related algorithms for pedigree traversal. With these trees, exact likelihood calculations can be carried out efficiently for single markers or for multiple linked markers. Using an approximate multipoint calculation that ignores the unlikely possibility of a large number of recombinants further improves speed and provides accurate solutions in dense maps with thousands of markers. Our multipoint engine for rapid likelihood inference (Merlin) is a computer program that uses sparse inheritance trees for pedigree analysis; it performs rapid haplotyping, genotype error detection and affected pair linkage analyses and can handle more markers than other pedigree analysis packages.

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References

  1. 1.

    et al. An SNP map of human chromosome 22. Nature 407, 516–520 (2000).

  2. 2.

    et al. An SNP map of the human genome generated by reduced representation shotgun sequencing. Nature 407, 513–516 (2000).

  3. 3.

    , , & Multilocus linkage analysis in humans: detection of linkage and estimation of recombination. Am. J. Hum. Genet. 37, 482–498 (1985).

  4. 4.

    & Complete multipoint sib-pair analysis of qualitative and quantitative traits. Am. J. Hum. Genet. 57, 439–454 (1995).

  5. 5.

    & The VITESSE algorithm for rapid exact multilocus linkage analysis via genotype set-recoding and fuzzy inheritance. Nature Genet. 11, 402–408 (1995).

  6. 6.

    , & Faster sequential genetic linkage computations. Am. J. Hum. Genet. 53, 252–263 (1993).

  7. 7.

    & Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker-sharing statistics. Am. J. Hum. Genet. 58, 1323–1337 (1996).

  8. 8.

    Markov chain Monte Carlo segregation and linkage analysis for oligogenic models. Am. J. Hum. Genet. 61, 748–760 (1997).

  9. 9.

    , , & Allegro, a new computer program for multipoint linkage analysis. Nature Genet. 25, 12–13 (2000).

  10. 10.

    & A general model for the genetic analysis of pedigree data. Hum. Hered. 21, 523–542 (1971).

  11. 11.

    & Construction of multilocus genetic linkage maps in humans. Proc. Natl Acad. Sci. USA 84, 2363–2367 (1987).

  12. 12.

    & A Monte Carlo method for combined segregation and linkage analysis. Am. J. Hum. Genet. 51, 1111–1126 (1992).

  13. 13.

    , & A multipoint method for detecting genotyping errors and mutations in sibling-pair linkage data. Am. J. Hum. Genet. 66, 1287–1297 (2000).

  14. 14.

    , & The impact of genotyping error on linkage and association analysis of quantitative traits. Eur. J. Hum. Genet. 9, 130–134 (2001).

  15. 15.

    , & True pedigree errors more frequent than apparent errors for single nucleotide polymorphisms. Hum. Hered. 49, 65–70 (1999).

  16. 16.

    , & Efficient multipoint linkage analysis through reduction of inheritance space. Am. J. Hum. Genet. 68, 963–977 (2001).

  17. 17.

    , , & Numerical Recipes in C. (Cambridge University Press, New York, 1992).

  18. 18.

    & A faster and more general hidden Markov model algorithm for multipoint likelihood calculations. Hum. Hered. 47, 197–202 (1997).

  19. 19.

    & Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol. Biol. Evol. 12, 921–927 (1995).

  20. 20.

    et al. Measured haplotype analysis of the angiotensin-I converting enzyme gene. Hum. Mol. Genet. 7, 1745–1751 (1998).

  21. 21.

    Pulse Code Communication. in Patent 2,632,058 (USA, 1953).

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Acknowledgements

This work was supported by the Wellcome Trust through a Prize Studentship (G.R.A.) Senior Research Fellowship (W.O.C.) and a Principal Research Fellowship (L.R.C.), and by the National Eye Institute (S.S.C. and L.R.C.).

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Author notes

    • Gonçalo R. Abecasis

    Present address: Center for Statistical Genetics, Department for Biostatistics, School of Public Health, 1420 Washington Heights, Ann Arbor, Michigan 48109-2029, USA.

Affiliations

  1. The Wellcome Trust Center for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.

    • Gonçalo R. Abecasis
    • , Stacey S. Cherny
    • , William O. Cookson
    •  & Lon R. Cardon

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Correspondence to Gonçalo R. Abecasis.

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DOI

https://doi.org/10.1038/ng786

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