Skip to main content
PMC home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1995 Jan;56(1):18–32.

Likelihood methods for locating disease genes in nonequilibrium populations.

N L Kaplan 1, W G Hill 1, B S Weir 1
PMCID: PMC1801340  PMID: 7825575

Abstract

Until recently, attempts to map disease genes on the basis of population associations with linked markers have been based on expected values of linkage disequilibrium. These methods suffer from the large variances imposed on disequilibrium measures by the evolutionary process, but a more serious problem for many diseases is that they assume an equilibrium population. For diseases that arose only a few hundred generations ago, it is more appropriate to concentrate on the initial growth phase of the disease. We invoke a Poisson branching process for this early growth, and estimate the likelihood for the recombination fraction between marker and disease loci, on the basis of simulated disease populations. The limits of the resulting support intervals for the recombination fraction vary inversely with the age of the disease in generations. We illustrate the procedure with data on cystic fibrosis and diastrophic dysplasia, for which the method appears appropriate, and for Friedreich ataxia and Huntington disease, for which it does not. A valuable aspect of the method is the ability in some cases to compare likelihoods of the three orders for a disease locus and two linked marker loci.

Full text

PDF
20

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adam S., Theilmann J., Buetow K., Hedrick A., Collins C., Weber B., Huggins M., Hayden M. Linkage disequilibrium and modification of risk for Huntington disease. Am J Hum Genet. 1991 Mar;48(3):595–603. [PMC free article] [PubMed] [Google Scholar]
  2. Andrew S. E., Goldberg Y. P., Kremer B., Squitieri F., Theilmann J., Zeisler J., Telenius H., Adam S., Almquist E., Anvret M. Huntington disease without CAG expansion: phenocopies or errors in assignment? Am J Hum Genet. 1994 May;54(5):852–863. [PMC free article] [PubMed] [Google Scholar]
  3. Andrew S., Theilmann J., Hedrick A., Mah D., Weber B., Hayden M. R. Nonrandom association between Huntington disease and two loci separated by about 3 Mb on 4p16.3. Genomics. 1992 Jun;13(2):301–311. doi: 10.1016/0888-7543(92)90246-o. [DOI] [PubMed] [Google Scholar]
  4. Beaudet A. L., Feldman G. L., Fernbach S. D., Buffone G. J., O'Brien W. E. Linkage disequilibrium, cystic fibrosis, and genetic counseling. Am J Hum Genet. 1989 Mar;44(3):319–326. [PMC free article] [PubMed] [Google Scholar]
  5. Beaudet A., Bowcock A., Buchwald M., Cavalli-Sforza L., Farrall M., King M. C., Klinger K., Lalouel J. M., Lathrop G., Naylor S. Linkage of cystic fibrosis to two tightly linked DNA markers: joint report from a collaborative study. Am J Hum Genet. 1986 Dec;39(6):681–693. [PMC free article] [PubMed] [Google Scholar]
  6. Chakravarti A., Buetow K. H., Antonarakis S. E., Waber P. G., Boehm C. D., Kazazian H. H. Nonuniform recombination within the human beta-globin gene cluster. Am J Hum Genet. 1984 Nov;36(6):1239–1258. [PMC free article] [PubMed] [Google Scholar]
  7. Chamberlain S., Farrall M., Shaw J., Wilkes D., Carvajal J., Hillerman R., Doudney K., Harding A. E., Williamson R., Sirugo G. Genetic recombination events which position the Friedreich ataxia locus proximal to the D9S15/D9S5 linkage group on chromosome 9q. Am J Hum Genet. 1993 Jan;52(1):99–109. [PMC free article] [PubMed] [Google Scholar]
  8. Chamberlain S., Shaw J., Rowland A., Wallis J., South S., Nakamura Y., von Gabain A., Farrall M., Williamson R. Mapping of mutation causing Friedreich's ataxia to human chromosome 9. Nature. 1988 Jul 21;334(6179):248–250. doi: 10.1038/334248a0. [DOI] [PubMed] [Google Scholar]
  9. Cutting G. R., Antonarakis S. E., Buetow K. H., Kasch L. M., Rosenstein B. J., Kazazian H. H., Jr Analysis of DNA polymorphism haplotypes linked to the cystic fibrosis locus in North American black and Caucasian families supports the existence of multiple mutations of the cystic fibrosis gene. Am J Hum Genet. 1989 Mar;44(3):307–318. [PMC free article] [PubMed] [Google Scholar]
  10. Estivill X., Farrall M., Scambler P. J., Bell G. M., Hawley K. M., Lench N. J., Bates G. P., Kruyer H. C., Frederick P. A., Stanier P. A candidate for the cystic fibrosis locus isolated by selection for methylation-free islands. 1987 Apr 30-May 6Nature. 326(6116):840–845. doi: 10.1038/326840a0. [DOI] [PubMed] [Google Scholar]
  11. Estivill X., Farrall M., Williamson R., Ferrari M., Seia M., Giunta A. M., Novelli G., Potenza L., Dallapicolla B., Borgo G. Linkage disequilibrium between cystic fibrosis and linked DNA polymorphisms in Italian families: a collaborative study. Am J Hum Genet. 1988 Jul;43(1):23–28. [PMC free article] [PubMed] [Google Scholar]
  12. Fujita R., Hanauer A., Sirugo G., Heilig R., Mandel J. L. Additional polymorphisms at marker loci D9S5 and D9S15 generate extended haplotypes in linkage disequilibrium with Friedreich ataxia. Proc Natl Acad Sci U S A. 1990 Mar;87(5):1796–1800. doi: 10.1073/pnas.87.5.1796. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gilliam T. C., Tanzi R. E., Haines J. L., Bonner T. I., Faryniarz A. G., Hobbs W. J., MacDonald M. E., Cheng S. V., Folstein S. E., Conneally P. M. Localization of the Huntington's disease gene to a small segment of chromosome 4 flanked by D4S10 and the telomere. Cell. 1987 Aug 14;50(4):565–571. doi: 10.1016/0092-8674(87)90029-8. [DOI] [PubMed] [Google Scholar]
  14. Hanauer A., Chery M., Fujita R., Driesel A. J., Gilgenkrantz S., Mandel J. L. The Friedreich ataxia gene is assigned to chromosome 9q13-q21 by mapping of tightly linked markers and shows linkage disequilibrium with D9S15. Am J Hum Genet. 1990 Jan;46(1):133–137. [PMC free article] [PubMed] [Google Scholar]
  15. Hill W. G., Weir B. S. Variances and covariances of squared linkage disequilibria in finite populations. Theor Popul Biol. 1988 Feb;33(1):54–78. doi: 10.1016/0040-5809(88)90004-4. [DOI] [PubMed] [Google Scholar]
  16. Hästbacka J., de la Chapelle A., Kaitila I., Sistonen P., Weaver A., Lander E. Linkage disequilibrium mapping in isolated founder populations: diastrophic dysplasia in Finland. Nat Genet. 1992 Nov;2(3):204–211. doi: 10.1038/ng1192-204. [DOI] [PubMed] [Google Scholar]
  17. Hästbacka J., de la Chapelle A., Mahtani M. M., Clines G., Reeve-Daly M. P., Daly M., Hamilton B. A., Kusumi K., Trivedi B., Weaver A. The diastrophic dysplasia gene encodes a novel sulfate transporter: positional cloning by fine-structure linkage disequilibrium mapping. Cell. 1994 Sep 23;78(6):1073–1087. doi: 10.1016/0092-8674(94)90281-x. [DOI] [PubMed] [Google Scholar]
  18. Kaplan N., Weir B. S. Expected behavior of conditional linkage disequilibrium. Am J Hum Genet. 1992 Aug;51(2):333–343. [PMC free article] [PubMed] [Google Scholar]
  19. Kerem B., Rommens J. M., Buchanan J. A., Markiewicz D., Cox T. K., Chakravarti A., Buchwald M., Tsui L. C. Identification of the cystic fibrosis gene: genetic analysis. Science. 1989 Sep 8;245(4922):1073–1080. doi: 10.1126/science.2570460. [DOI] [PubMed] [Google Scholar]
  20. MacDonald M. E., Lin C., Srinidhi L., Bates G., Altherr M., Whaley W. L., Lehrach H., Wasmuth J., Gusella J. F. Complex patterns of linkage disequilibrium in the Huntington disease region. Am J Hum Genet. 1991 Oct;49(4):723–734. [PMC free article] [PubMed] [Google Scholar]
  21. MacDonald M. E., Novelletto A., Lin C., Tagle D., Barnes G., Bates G., Taylor S., Allitto B., Altherr M., Myers R. The Huntington's disease candidate region exhibits many different haplotypes. Nat Genet. 1992 May;1(2):99–103. doi: 10.1038/ng0592-99. [DOI] [PubMed] [Google Scholar]
  22. Morral N., Bertranpetit J., Estivill X., Nunes V., Casals T., Giménez J., Reis A., Varon-Mateeva R., Macek M., Jr, Kalaydjieva L. The origin of the major cystic fibrosis mutation (delta F508) in European populations. Nat Genet. 1994 Jun;7(2):169–175. doi: 10.1038/ng0694-169. [DOI] [PubMed] [Google Scholar]
  23. Pandolfo M., Sirugo G., Antonelli A., Weitnauer L., Ferretti L., Leone M., Dones I., Cerino A., Fujita R., Hanauer A. Friedreich ataxia in Italian families: genetic homogeneity and linkage disequilibrium with the marker loci D9S5 and D9S15. Am J Hum Genet. 1990 Aug;47(2):228–235. [PMC free article] [PubMed] [Google Scholar]
  24. Rodius F., Duclos F., Wrogemann K., Le Paslier D., Ougen P., Billault A., Belal S., Musenger C., Brice A., Dürr A. Recombinations in individuals homozygous by descent localize the Friedreich ataxia locus in a cloned 450-kb interval. Am J Hum Genet. 1994 Jun;54(6):1050–1059. [PMC free article] [PubMed] [Google Scholar]
  25. Romeo G., Menozzi P., Ferlini A., Fadda S., Di Donato S., Uziel G., Lucci B., Capodaglio L., Filla A., Campanella G. Incidence of Friedreich ataxia in Italy estimated from consanguineous marriages. Am J Hum Genet. 1983 May;35(3):523–529. [PMC free article] [PubMed] [Google Scholar]
  26. Serre J. L., Simon-Bouy B., Mornet E., Jaume-Roig B., Balassopoulou A., Schwartz M., Taillandier A., Boué J., Boué A. Studies of RFLP closely linked to the cystic fibrosis locus throughout Europe lead to new considerations in populations genetics. Hum Genet. 1990 Apr;84(5):449–454. doi: 10.1007/BF00195818. [DOI] [PubMed] [Google Scholar]
  27. Sirugo G., Keats B., Fujita R., Duclos F., Purohit K., Koenig M., Mandel J. L. Friedreich ataxia in Louisiana Acadians: demonstration of a founder effect by analysis of microsatellite-generated extended haplotypes. Am J Hum Genet. 1992 Mar;50(3):559–566. [PMC free article] [PubMed] [Google Scholar]
  28. Skraastad M. I., Van de Vosse E., Belfroid R., Höld K., Vegter-van der Vlis M., Sandkuijl L. A., Bakker E., van Ommen G. J. Significant linkage disequilibrium between the Huntington disease gene and the loci D4S10 and D4S95 in the Dutch population. Am J Hum Genet. 1992 Oct;51(4):730–735. [PMC free article] [PubMed] [Google Scholar]
  29. Snell R. G., Lazarou L. P., Youngman S., Quarrell O. W., Wasmuth J. J., Shaw D. J., Harper P. S. Linkage disequilibrium in Huntington's disease: an improved localisation for the gene. J Med Genet. 1989 Nov;26(11):673–675. doi: 10.1136/jmg.26.11.673. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Theilmann J., Kanani S., Shiang R., Robbins C., Quarrell O., Huggins M., Hedrick A., Weber B., Collins C., Wasmuth J. J. Non-random association between alleles detected at D4S95 and D4S98 and the Huntington's disease gene. J Med Genet. 1989 Nov;26(11):676–681. doi: 10.1136/jmg.26.11.676. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Weir B. S., Hill W. G. Effect of mating structure on variation in linkage disequilibrium. Genetics. 1980 Jun;95(2):477–488. doi: 10.1093/genetics/95.2.477. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Whaley W. L., Michiels F., MacDonald M. E., Romano D., Zimmer M., Smith B., Leavitt J., Bucan M., Haines J. L., Gilliam T. C. Mapping of D4S98/S114/S113 confines the Huntington's defect to a reduced physical region at the telomere of chromosome 4. Nucleic Acids Res. 1988 Dec 23;16(24):11769–11780. doi: 10.1093/nar/16.24.11769. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. de la Chapelle A. Disease gene mapping in isolated human populations: the example of Finland. J Med Genet. 1993 Oct;30(10):857–865. doi: 10.1136/jmg.30.10.857. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES