Copyright © 2002 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 70, Issue 3, 686-707, 1 March 2002
doi:10.1086/339271
Fine-Scale Mapping of Disease Loci via Shattered Coalescent Modeling of Genealogies
A.P. Morris1, 2, 
, 
, J.C. Whittaker2, 3 and D.J. Balding2, 3
1 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford
2 Department of Applied Statistics, University of Reading, Reading, England
3 Department of Epidemiology and Public Health, Imperial College Faculty of Medicine, London
Address for correspondence and reprints: Dr. Andrew Morris, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, United KingdomAbstract
We present a Bayesian, Markov-chain Monte Carlo method for fine-scale linkage-disequilibrium gene mapping using high-density marker maps. The method explicitly models the genealogy underlying a sample of case chromosomes in the vicinity of a putative disease locus, in contrast with the assumption of a star-shaped tree made by many existing multipoint methods. Within this modeling framework, we can allow for missing marker information and for uncertainty about the true underlying genealogy and the makeup of ancestral marker haplotypes. A crucial advantage of our method is the incorporation of the shattered coalescent model for genealogies, allowing for multiple founding mutations at the disease locus and for sporadic cases of disease. Output from the method includes approximate posterior distributions of the location of the disease locus and population-marker haplotype proportions. In addition, output from the algorithm is used to construct a cladogram to represent genetic heterogeneity at the disease locus, highlighting clusters of case chromosomes sharing the same mutation. We present detailed simulations to provide evidence of improvements over existing methodology. Furthermore, inferences about the location of the disease locus are shown to remain robust to modeling assumptions.
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