Abstract
Genetic linkage studies based on pedigree data have limited resolution, because of the relatively small number of segregations. Disequilibrium mapping, which uses population associations to infer the location of a disease mutation, provides one possible strategy for narrowing the candidate region. The coalescent process provides a model for the ancestry of a sample of disease alleles, and recombination events between disease locus and marker may be placed on this ancestral phylogeny. These events define the recombinant classes, the sets of sampled disease copies descending from the meiosis at which a given recombination occurred. We show how Monte Carlo generation of the recombinant classes leads to a linkage likelihood for fine-scale mapping from disease haplotypes. We compare single-marker disequilibrium mapping with interval-disequilibrium mapping and discuss how the approach may be extended to multipoint-disequilibrium mapping. The method and its properties are illustrated with an example of simulated data, constructed to be typical of fine-scale mapping of a rare disease in the Japanese population. The method can take into account known features of population history, such as changing patterns of population growth.
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- Arnason A., Larsen B., Marshall W. H., Edwards J. H., Macintosh P., Olaisen B., Teisberg P. Very close linkage between HLA-B and Bf inferred from allelic association. Nature. 1977 Aug 11;268(5620):527–528. doi: 10.1038/268527a0. [DOI] [PubMed] [Google Scholar]
- Felsenstein J. The rate of loss of multiple alleles in finite haploid populations. Theor Popul Biol. 1971 Dec;2(4):391–403. doi: 10.1016/0040-5809(71)90028-1. [DOI] [PubMed] [Google Scholar]
- Goddard K. A., Yu C. E., Oshima J., Miki T., Nakura J., Piussan C., Martin G. M., Schellenberg G. D., Wijsman E. M. Toward localization of the Werner syndrome gene by linkage disequilibrium and ancestral haplotyping: lessons learned from analysis of 35 chromosome 8p11.1-21.1 markers. Am J Hum Genet. 1996 Jun;58(6):1286–1302. [PMC free article] [PubMed] [Google Scholar]
- Hästbacka J., Kaitila I., Sistonen P., de la Chapelle A. Diastrophic dysplasia gene maps to the distal long arm of chromosome 5. Proc Natl Acad Sci U S A. 1990 Oct;87(20):8056–8059. doi: 10.1073/pnas.87.20.8056. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- 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]
- 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]
- Matsumoto T., Imamura O., Yamabe Y., Kuromitsu J., Tokutake Y., Shimamoto A., Suzuki N., Satoh M., Kitao S., Ichikawa K. Mutation and haplotype analyses of the Werner's syndrome gene based on its genomic structure: genetic epidemiology in the Japanese population. Hum Genet. 1997 Jul;100(1):123–130. doi: 10.1007/s004390050477. [DOI] [PubMed] [Google Scholar]
- 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]
- 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]
- Thompson E. A., Neel J. V. Allelic disequilibrium and allele frequency distribution as a function of social and demographic history. Am J Hum Genet. 1997 Jan;60(1):197–204. [PMC free article] [PubMed] [Google Scholar]
- Thompson E. A., Neel J. V., Smouse P. E., Barrantes R. Microevolution of the Chibcha-speaking peoples of lower Central America: rare genes in an Amerindian complex. Am J Hum Genet. 1992 Sep;51(3):609–626. [PMC free article] [PubMed] [Google Scholar]
- Thompson E. A. The number of ancestral genes contributing to a sample of B8 alleles. Nature. 1978 Mar 16;272(5650):288–288. doi: 10.1038/272288a0. [DOI] [PubMed] [Google Scholar]
- 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]
- Yu C. E., Oshima J., Fu Y. H., Wijsman E. M., Hisama F., Alisch R., Matthews S., Nakura J., Miki T., Ouais S. Positional cloning of the Werner's syndrome gene. Science. 1996 Apr 12;272(5259):258–262. doi: 10.1126/science.272.5259.258. [DOI] [PubMed] [Google Scholar]