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. 2004 Aug;167(4):2003–2013. doi: 10.1534/genetics.103.023044

Simultaneous detection of linkage disequilibrium and genetic differentiation of subdivided populations.

Shuichi Kitada 1, Hirohisa Kishino 1
PMCID: PMC1470979  PMID: 15342536

Abstract

We propose a new method for simultaneously detecting linkage disequilibrium and genetic structure in subdivided populations. Taking subpopulation structure into account with a hierarchical model, we estimate the magnitude of genetic differentiation and linkage disequilibrium in a metapopulation on the basis of geographical samples, rather than decompose a population into a finite number of random-mating subpopulations. We assume that Hardy-Weinberg equilibrium is satisfied in each locality, but do not assume independence between marker loci. Linkage states remain unknown. Genetic differentiation and linkage disequilibrium are expressed as hyperparameters describing the prior distribution of genotypes or haplotypes. We estimate related parameters by maximizing marginal-likelihood functions and detect linkage equilibrium or disequilibrium by the Akaike information criterion. Our empirical Bayesian model analyzes genotype and haplotype frequencies regardless of haploid or diploid data, so it can be applied to most commonly used genetic markers. The performance of our procedure is examined via numerical simulations in comparison with classical procedures. Finally, we analyze isozyme data of ayu, a severely exploited fish species, and single-nucleotide polymorphisms in human ALDH2.

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Selected References

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  1. Ayres K. L., Balding D. J. Measuring gametic disequilibrium from multilocus data. Genetics. 2001 Jan;157(1):413–423. doi: 10.1093/genetics/157.1.413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Balding David J. Likelihood-based inference for genetic correlation coefficients. Theor Popul Biol. 2003 May;63(3):221–230. doi: 10.1016/s0040-5809(03)00007-8. [DOI] [PubMed] [Google Scholar]
  3. Brown A. H. Sample sizes required to detect linkage disequilibrium between two or three loci. Theor Popul Biol. 1975 Oct;8(2):184–201. doi: 10.1016/0040-5809(75)90031-3. [DOI] [PubMed] [Google Scholar]
  4. Excoffier L., Slatkin M. Incorporating genotypes of relatives into a test of linkage disequilibrium. Am J Hum Genet. 1998 Jan;62(1):171–180. doi: 10.1086/301674. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Excoffier L., Slatkin M. Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol Biol Evol. 1995 Sep;12(5):921–927. doi: 10.1093/oxfordjournals.molbev.a040269. [DOI] [PubMed] [Google Scholar]
  6. Hill W. G. Estimation of linkage disequilibrium in randomly mating populations. Heredity (Edinb) 1974 Oct;33(2):229–239. doi: 10.1038/hdy.1974.89. [DOI] [PubMed] [Google Scholar]
  7. Hill W. G. Tests for association of gene frequencies at several loci in random mating diploid populations. Biometrics. 1975 Dec;31(4):881–888. [PubMed] [Google Scholar]
  8. Jorde L. B. Linkage disequilibrium as a gene-mapping tool. Am J Hum Genet. 1995 Jan;56(1):11–14. [PMC free article] [PubMed] [Google Scholar]
  9. Kaplan N. L., Hill W. G., Weir B. S. Likelihood methods for locating disease genes in nonequilibrium populations. Am J Hum Genet. 1995 Jan;56(1):18–32. [PMC free article] [PubMed] [Google Scholar]
  10. Kitada S., Hayashi T., Kishino H. Empirical Bayes procedure for estimating genetic distance between populations and effective population size. Genetics. 2000 Dec;156(4):2063–2079. doi: 10.1093/genetics/156.4.2063. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Lander E. S., Schork N. J. Genetic dissection of complex traits. Science. 1994 Sep 30;265(5181):2037–2048. doi: 10.1126/science.8091226. [DOI] [PubMed] [Google Scholar]
  12. Lange K. Applications of the Dirichlet distribution to forensic match probabilities. Genetica. 1995;96(1-2):107–117. doi: 10.1007/BF01441156. [DOI] [PubMed] [Google Scholar]
  13. Lazzeroni L. C., Lange K. A conditional inference framework for extending the transmission/disequilibrium test. Hum Hered. 1998 Mar-Apr;48(2):67–81. doi: 10.1159/000022784. [DOI] [PubMed] [Google Scholar]
  14. Lewontin R C. The Interaction of Selection and Linkage. I. General Considerations; Heterotic Models. Genetics. 1964 Jan;49(1):49–67. doi: 10.1093/genetics/49.1.49. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Long J. C., Williams R. C., Urbanek M. An E-M algorithm and testing strategy for multiple-locus haplotypes. Am J Hum Genet. 1995 Mar;56(3):799–810. [PMC free article] [PubMed] [Google Scholar]
  16. Luo Z. W. Detecting linkage disequilibrium between a polymorphic marker locus and a trait locus in natural populations. Heredity (Edinb) 1998 Feb;80(Pt 2):198–208. doi: 10.1046/j.1365-2540.1998.00275.x. [DOI] [PubMed] [Google Scholar]
  17. Luo Z. W., Suhai S. Estimating linkage disequilibrium between a polymorphic marker locus and a trait locus in natural populations. Genetics. 1999 Jan;151(1):359–371. doi: 10.1093/genetics/151.1.359. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Luo Z. W., Tao S. H., Zeng Z. B. Inferring linkage disequilibrium between a polymorphic marker locus and a trait locus in natural populations. Genetics. 2000 Sep;156(1):457–467. doi: 10.1093/genetics/156.1.457. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Luo Z. W., Wu C. I. Modeling linkage disequilibrium between a polymorphic marker locus and a locus affecting complex dichotomous traits in natural populations. Genetics. 2001 Aug;158(4):1785–1800. doi: 10.1093/genetics/158.4.1785. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Meuwissen T. H., Goddard M. E. Fine mapping of quantitative trait loci using linkage disequilibria with closely linked marker loci. Genetics. 2000 May;155(1):421–430. doi: 10.1093/genetics/155.1.421. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Nei M., Li W. H. Linkage disequilibrium in subdivided populations. Genetics. 1973 Sep;75(1):213–219. doi: 10.1093/genetics/75.1.213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Ohta T. Linkage disequilibrium due to random genetic drift in finite subdivided populations. Proc Natl Acad Sci U S A. 1982 Mar;79(6):1940–1944. doi: 10.1073/pnas.79.6.1940. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Parra E. J., Marcini A., Akey J., Martinson J., Batzer M. A., Cooper R., Forrester T., Allison D. B., Deka R., Ferrell R. E. Estimating African American admixture proportions by use of population-specific alleles. Am J Hum Genet. 1998 Dec;63(6):1839–1851. doi: 10.1086/302148. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Peterson R. J., Goldman D., Long J. C. Effects of worldwide population subdivision on ALDH2 linkage disequilibrium. Genome Res. 1999 Sep;9(9):844–852. doi: 10.1101/gr.9.9.844. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Pritchard J. K., Stephens M., Rosenberg N. A., Donnelly P. Association mapping in structured populations. Am J Hum Genet. 2000 May 26;67(1):170–181. doi: 10.1086/302959. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Rannala B., Hartigan J. A. Estimating gene flow in island populations. Genet Res. 1996 Apr;67(2):147–158. doi: 10.1017/s0016672300033607. [DOI] [PubMed] [Google Scholar]
  27. Rosenberg Noah A., Pritchard Jonathan K., Weber James L., Cann Howard M., Kidd Kenneth K., Zhivotovsky Lev A., Feldman Marcus W. Genetic structure of human populations. Science. 2002 Dec 20;298(5602):2381–2385. doi: 10.1126/science.1078311. [DOI] [PubMed] [Google Scholar]
  28. Slatkin M., Excoffier L. Testing for linkage disequilibrium in genotypic data using the Expectation-Maximization algorithm. Heredity (Edinb) 1996 Apr;76(Pt 4):377–383. doi: 10.1038/hdy.1996.55. [DOI] [PubMed] [Google Scholar]
  29. Spielman R. S., Ewens W. J. A sibship test for linkage in the presence of association: the sib transmission/disequilibrium test. Am J Hum Genet. 1998 Feb;62(2):450–458. doi: 10.1086/301714. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Spielman R. S., McGinnis R. E., Ewens W. J. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet. 1993 Mar;52(3):506–516. [PMC free article] [PubMed] [Google Scholar]
  31. Thornsberry J. M., Goodman M. M., Doebley J., Kresovich S., Nielsen D., Buckler E. S., 4th Dwarf8 polymorphisms associate with variation in flowering time. Nat Genet. 2001 Jul;28(3):286–289. doi: 10.1038/90135. [DOI] [PubMed] [Google Scholar]
  32. Weir B. S., Cockerham C. C. Testing Hypotheses about Linkage Disequilibrium with Multiple Alleles. Genetics. 1978 Mar;88(3):633–642. doi: 10.1093/genetics/88.3.633. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Wright S. The Differential Equation of the Distribution of Gene Frequencies. Proc Natl Acad Sci U S A. 1945 Dec;31(12):382–389. doi: 10.1073/pnas.31.12.382. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Wu R., Zeng Z. B. Joint linkage and linkage disequilibrium mapping in natural populations. Genetics. 2001 Feb;157(2):899–909. doi: 10.1093/genetics/157.2.899. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Xiong M., Guo S. W. Fine-scale genetic mapping based on linkage disequilibrium: theory and applications. Am J Hum Genet. 1997 Jun;60(6):1513–1531. doi: 10.1086/515475. [DOI] [PMC free article] [PubMed] [Google Scholar]

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