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The American Journal of Human Genetics
Article
License: Elsevier Non-Commercial
Data sources: UnpayWall
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The American Journal of Human Genetics
Article . 2000
License: Elsevier Non-Commercial
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The American Journal of Human Genetics
Article . 2000 . Peer-reviewed
License: Elsevier Non-Commercial
Data sources: Crossref
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Haplotype Fine Mapping by Evolutionary Trees

Authors: Lam, Johnny C.; Roeder, Kathryn; Devlin, B.;

Haplotype Fine Mapping by Evolutionary Trees

Abstract

To refine the location of a disease gene within the bounds provided by linkage analysis, many scientists use the pattern of linkage disequilibrium between the disease allele and alleles at nearby markers. We describe a method that seeks to refine location by analysis of "disease" and "normal" haplotypes, thereby using multivariate information about linkage disequilibrium. Under the assumption that the disease mutation occurs in a specific gap between adjacent markers, the method first combines parsimony and likelihood to build an evolutionary tree of disease haplotypes, with each node (haplotype) separated, by a single mutational or recombinational step, from its parent. If required, latent nodes (unobserved haplotypes) are incorporated to complete the tree. Once the tree is built, its likelihood is computed from probabilities of mutation and recombination. When each gap between adjacent markers is evaluated in this fashion and these results are combined with prior information, they yield a posterior probability distribution to guide the search for the disease mutation. We show, by evolutionary simulations, that an implementation of these methods, called "FineMap," yields substantial refinement and excellent coverage for the true location of the disease mutation. Moreover, by analysis of hereditary hemochromatosis haplotypes, we show that FineMap can be robust to genetic heterogeneity.

Keywords

Heterozygote, Linkage Disequilibrium, Genetic Heterogeneity, Gene Frequency, HLA Antigens, Linkage disequilibrium, Genetics, Humans, Genetics(clinical), Computer Simulation, Hemochromatosis Protein, Alleles, Bayesian probability model, Disease haplotype, Likelihood Functions, Models, Genetic, Histocompatibility Antigens Class I, Genetic Diseases, Inborn, Chromosome Mapping, Membrane Proteins, Europe, Haplotypes, Hereditary hemochromatosis, Multivariate Analysis, Hemochromatosis, Parsimony, Algorithms

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selected citations
These citations are derived from selected sources.
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
48
Average
Top 10%
Top 10%
hybrid