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Vol. 60, No. 2, 2005
Issue release date: 2005
Section title: Original Paper
Hum Hered 2005;60:119–122
(DOI:10.1159/000088914)

SimPed: A Simulation Program to Generate Haplotype and Genotype Data for Pedigree Structures

Leal S.M.a · Yan K.a · Müller-Myhsok B.b
aDepartment of Molecular and Human Genetic, Baylor College of Medicine, Houston, Tex., USA; bComputational Genetics Group, Max-Planck-InstituteofPsychiatry, Munich, Germany
email Corresponding Author

Abstract

With the widespread availability of SNP genotype data, there is great interest in analyzing pedigree haplotype data. Intermarker linkage disequilibrium for microsatellite markers is usually low due to their physical distance; however, for dense maps of SNP markers, there can be strong linkage disequilibrium between marker loci. Linkage analysis (parametric and nonparametric) and family-based association studies are currently being carried out using dense maps of SNP marker loci. Monte Carlo methods are often used for both linkage and association studies; however, to date there are no programs available which can generate haplotype and/or genotype data consisting of a large number of loci for pedigree structures. SimPed is a program that quickly generates haplotype and/or genotype data for pedigrees of virtually any size and complexity. Marker data either in linkage disequilibrium or equilibrium can be generated for greater than 20,000 diallelic or multiallelic marker loci. Haplotypes and/or genotypes are generated for pedigree structures using specified genetic map distances and haplotype and/or allele frequencies. The simulated data generated by SimPed is useful for a variety of purposes, including evaluating methods that estimate haplotype frequencies for pedigree data, evaluating type I error due to intermarker linkage disequilibrium and estimating empirical p values for linkage and family-based association studies.

© 2005 S. Karger AG, Basel


  

Key Words

  • Simulation
  • Pedigree structure
  • Type I error
  • Empirical p values

References

  1. Murray SS, Oliphant A, Shen R, McBride C, Steeke RJ, Shannon SG, Rubano T, Kermani BG, Fan JB, Chee MS, Hansen MST: A highly informative SNP linkage panel for human genetic studies. Nat Methods 2004;1:113–117.
  2. Matsuzaki H, Dong S, Loi H, Di X, Liu G, Hubbell E, Law J, Berntsen T, Chadha M, Hui H, Yang G, Webster T, Cawley S, Walsh P, Jones KW, Mei R: Genotyping over 100,000 SNPs on a pair of oligonucleotide arrays. Nat Methods 2004;1:109–111.
  3. Kong X, Murphy K, Raj T, He C, White PS, Matise TC: A combined linkage-physical map of the human genome. Am J Hum Genet 2004;75:1143–1148.
  4. Kennedy GC, Matsuzaki H, Dong S, Liu WM, Huang J, Liu G, Su X, Cao M, ChenW, Zhang J, Liu W, Yang G, Di X, Ryder T, He Z, Surti U, Phillips MS, Boyce-Jacino MT, Fodor SP, Jones KW: Large-scale genotyping of complex DNA. Nat Biotechnol 2003;21:1233–1237.
  5. Boehnke M: Estimating the power of a proposed linkage study: a practical computer simulation approach. Am J Hum Genet 1986;39:513–527.
  6. Gudbjartsson DF, Jonasson K, Frigge ML, Kong A: Allegro, a new computer program for multipoint linkage analysis. Nat Genet 2002;25:12–13.
  7. Weeks DE, Ott J, Lathrop GM: A general simulation program for linkage analysis. Am J Hum Genet 1994;47(suppl):A204.
  8. Terwilliger JD, Speer M, Ott J: Chromosome-based method for rapid computer simulation in human genetic linkage analysis. Genet Epidemiol 1993;10:217–224.
  9. Terwilliger JD, Ott J: Handbook of Human Genetic Linkage. Baltimore, Johns Hopkins University Press, 1994.
  10. Abecasis GR, Cherny SS, Cookson WO, Cardon LR: Merlin – rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 2002;30:97–101.
  11. Bass MP, Martin ER, Hauser ER: Software for Simulation Studies of Complex Traits: SIMLA. Am J Hum Genet 2002;71(suppl):A2341.
  12. Broman KW, Murray JC, Sheffield VC, White RL, Weber JL: Comprehensive human genetic maps: individual and sex-specific variation in recombination. Am J Hum Genet. 1998;63:861–869.
  13. Kong A, Gudbjartsson DF, Sainz J, Jonsdottir GM, Gudjonsson SA, Richardsson B, Sigurdardottir S, Barnard J, Hallbeck B, Masson G, Shlien A, Palsson ST, Frigge ML, Thorgeirsson TE, Gulcher JR, Stefansson K: A high-resolution recombination map of the human genome. Nat Genet 2002;31:241–247.
  14. The International HapMap Consortium: The International HapMap Project. Nature 2003;426:789–796.
  15. Nievergelt CM, Smith DW, Kohlenberg JB, Schork NJ: Large-scale integration of human genetic and physical maps. Genome Res 2004;14:1199–1205.
  16. Kruglyak L, Daly MJ, Reeve-Daly MP, Lander ES: Parametric and nonparametric linkage analysis: A unified multipoint approach. Am J Hum Genet 1996;51:1347–1363.

    External Resources

  17. Cottingham RWJ, Indury RM, Schaffer AA: Faster sequential genetic linkage computations. Am J Hum Genet 1993;53:252–263.
  18. Weeks DE, Sobel E, O’Connell JR, Lange K: Computer programs for multilocus haplotyping of general pedigrees. Am J Hum Genet 1995;56:1506–1507.
  19. Sobel E, Lange K: Descent graphs in pedigree analysis: Applications to haplotyping, location scores, and marker-sharing statistics. Am J Hum Genet 1996;58:1323–1337.
  20. Huang Q, Shete S, Amos CI: Ignoring linkage disequilibrium among tightly linked markers induces false-positive evidence of linkage for affected sib pair analysis. Am J Hum Genet 2004;75:1106–1112.

  

Author Contacts

Suzanne M. Leal, PhD
Baylor College of Medicine, Department of Molecular and Human Genetics
One Baylor Plaza, N1619.01
Houston, TX 77025 (USA)
Tel. +1 713 798 4011, Fax +1 713 798 5373, E-Mail sleal@bcm.tmc.edu

  

Article Information

Received: July 25, 2005
Accepted: August 8, 2005
Published online: October 13, 2005
Number of Print Pages : 4
Number of Figures : 0, Number of Tables : 1, Number of References : 20

  

Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 60, No. 2, Year 2005 (Cover Date: 2005)

Journal Editor: Devoto, M. (Wilmington, Del.)
ISSN: 0001–5652 (print), 1423–0062 (Online)

For additional information: http://www.karger.com/hhe


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

With the widespread availability of SNP genotype data, there is great interest in analyzing pedigree haplotype data. Intermarker linkage disequilibrium for microsatellite markers is usually low due to their physical distance; however, for dense maps of SNP markers, there can be strong linkage disequilibrium between marker loci. Linkage analysis (parametric and nonparametric) and family-based association studies are currently being carried out using dense maps of SNP marker loci. Monte Carlo methods are often used for both linkage and association studies; however, to date there are no programs available which can generate haplotype and/or genotype data consisting of a large number of loci for pedigree structures. SimPed is a program that quickly generates haplotype and/or genotype data for pedigrees of virtually any size and complexity. Marker data either in linkage disequilibrium or equilibrium can be generated for greater than 20,000 diallelic or multiallelic marker loci. Haplotypes and/or genotypes are generated for pedigree structures using specified genetic map distances and haplotype and/or allele frequencies. The simulated data generated by SimPed is useful for a variety of purposes, including evaluating methods that estimate haplotype frequencies for pedigree data, evaluating type I error due to intermarker linkage disequilibrium and estimating empirical p values for linkage and family-based association studies.

© 2005 S. Karger AG, Basel


  

Author Contacts

Suzanne M. Leal, PhD
Baylor College of Medicine, Department of Molecular and Human Genetics
One Baylor Plaza, N1619.01
Houston, TX 77025 (USA)
Tel. +1 713 798 4011, Fax +1 713 798 5373, E-Mail sleal@bcm.tmc.edu

  

Article Information

Received: July 25, 2005
Accepted: August 8, 2005
Published online: October 13, 2005
Number of Print Pages : 4
Number of Figures : 0, Number of Tables : 1, Number of References : 20

  

Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 60, No. 2, Year 2005 (Cover Date: 2005)

Journal Editor: Devoto, M. (Wilmington, Del.)
ISSN: 0001–5652 (print), 1423–0062 (Online)

For additional information: http://www.karger.com/hhe


Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: 7/25/2005
Accepted: 8/8/2005
Published online: 11/2/2005
Issue release date: 2005

Number of Print Pages: 4
Number of Figures: 0
Number of Tables: 1

ISSN: 0001-5652 (Print)
eISSN: 1423-0062 (Online)

For additional information: http://www.karger.com/HHE


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Murray SS, Oliphant A, Shen R, McBride C, Steeke RJ, Shannon SG, Rubano T, Kermani BG, Fan JB, Chee MS, Hansen MST: A highly informative SNP linkage panel for human genetic studies. Nat Methods 2004;1:113–117.
  2. Matsuzaki H, Dong S, Loi H, Di X, Liu G, Hubbell E, Law J, Berntsen T, Chadha M, Hui H, Yang G, Webster T, Cawley S, Walsh P, Jones KW, Mei R: Genotyping over 100,000 SNPs on a pair of oligonucleotide arrays. Nat Methods 2004;1:109–111.
  3. Kong X, Murphy K, Raj T, He C, White PS, Matise TC: A combined linkage-physical map of the human genome. Am J Hum Genet 2004;75:1143–1148.
  4. Kennedy GC, Matsuzaki H, Dong S, Liu WM, Huang J, Liu G, Su X, Cao M, ChenW, Zhang J, Liu W, Yang G, Di X, Ryder T, He Z, Surti U, Phillips MS, Boyce-Jacino MT, Fodor SP, Jones KW: Large-scale genotyping of complex DNA. Nat Biotechnol 2003;21:1233–1237.
  5. Boehnke M: Estimating the power of a proposed linkage study: a practical computer simulation approach. Am J Hum Genet 1986;39:513–527.
  6. Gudbjartsson DF, Jonasson K, Frigge ML, Kong A: Allegro, a new computer program for multipoint linkage analysis. Nat Genet 2002;25:12–13.
  7. Weeks DE, Ott J, Lathrop GM: A general simulation program for linkage analysis. Am J Hum Genet 1994;47(suppl):A204.
  8. Terwilliger JD, Speer M, Ott J: Chromosome-based method for rapid computer simulation in human genetic linkage analysis. Genet Epidemiol 1993;10:217–224.
  9. Terwilliger JD, Ott J: Handbook of Human Genetic Linkage. Baltimore, Johns Hopkins University Press, 1994.
  10. Abecasis GR, Cherny SS, Cookson WO, Cardon LR: Merlin – rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 2002;30:97–101.
  11. Bass MP, Martin ER, Hauser ER: Software for Simulation Studies of Complex Traits: SIMLA. Am J Hum Genet 2002;71(suppl):A2341.
  12. Broman KW, Murray JC, Sheffield VC, White RL, Weber JL: Comprehensive human genetic maps: individual and sex-specific variation in recombination. Am J Hum Genet. 1998;63:861–869.
  13. Kong A, Gudbjartsson DF, Sainz J, Jonsdottir GM, Gudjonsson SA, Richardsson B, Sigurdardottir S, Barnard J, Hallbeck B, Masson G, Shlien A, Palsson ST, Frigge ML, Thorgeirsson TE, Gulcher JR, Stefansson K: A high-resolution recombination map of the human genome. Nat Genet 2002;31:241–247.
  14. The International HapMap Consortium: The International HapMap Project. Nature 2003;426:789–796.
  15. Nievergelt CM, Smith DW, Kohlenberg JB, Schork NJ: Large-scale integration of human genetic and physical maps. Genome Res 2004;14:1199–1205.
  16. Kruglyak L, Daly MJ, Reeve-Daly MP, Lander ES: Parametric and nonparametric linkage analysis: A unified multipoint approach. Am J Hum Genet 1996;51:1347–1363.

    External Resources

  17. Cottingham RWJ, Indury RM, Schaffer AA: Faster sequential genetic linkage computations. Am J Hum Genet 1993;53:252–263.
  18. Weeks DE, Sobel E, O’Connell JR, Lange K: Computer programs for multilocus haplotyping of general pedigrees. Am J Hum Genet 1995;56:1506–1507.
  19. Sobel E, Lange K: Descent graphs in pedigree analysis: Applications to haplotyping, location scores, and marker-sharing statistics. Am J Hum Genet 1996;58:1323–1337.
  20. Huang Q, Shete S, Amos CI: Ignoring linkage disequilibrium among tightly linked markers induces false-positive evidence of linkage for affected sib pair analysis. Am J Hum Genet 2004;75:1106–1112.