Fine-scale mapping of disease loci via shattered coalescent modeling of genealogies

被引:100
作者
Morris, AP
Whittaker, JC
Balding, DJ
机构
[1] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England
[2] Univ Reading, Dept Appl Stat, Reading RG6 2AH, Berks, England
[3] Imperial Coll Fac Med, Dept Epidemiol & Publ Hlth, London, England
基金
英国惠康基金;
关键词
D O I
10.1086/339271
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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.
引用
收藏
页码:686 / 707
页数:22
相关论文
共 34 条
[1]  
Balding D., 2001, HDB STAT GENETICS, P179, DOI DOI 10.2307/2419615
[2]  
Bertranpetit J, 1996, CIBA F SYMP, V197, P97
[3]   Linkage disequilibrium mapping of disease susceptibility genes in human populations [J].
Clayton, D .
INTERNATIONAL STATISTICAL REVIEW, 2000, 68 (01) :23-43
[4]   Mapping a disease locus by allelic association [J].
Collins, A ;
Morton, NE .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (04) :1741-1745
[5]   A metric map of humans: 23,500 loci in 850 bands [J].
Collins, A ;
Frezal, J ;
Teague, J ;
Morton, NE .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1996, 93 (25) :14771-14775
[6]   Coalescents and genealogical structure under neutrality [J].
Donnelly, P ;
Tavare, S .
ANNUAL REVIEW OF GENETICS, 1995, 29 :401-421
[7]   Disequilibrium likelihoods for fine-scale mapping of a rare allele [J].
Graham, J ;
Thompson, EA .
AMERICAN JOURNAL OF HUMAN GENETICS, 1998, 63 (05) :1517-1530
[8]   Ancestral inference from samples of DNA sequences with recombination [J].
Griffiths, RC ;
Marjoram, P .
JOURNAL OF COMPUTATIONAL BIOLOGY, 1996, 3 (04) :479-502
[9]  
Griffiths RC, 1997, PROGR POPULATION GEN, P257
[10]  
Hudson R., 1991, OXFORD SURVEYS EVOLU, P1