High-resolution multipoint linkage-disequilibrium mapping in the context of a human genome sequence.
A new method is presented for fine-scale linkage disequilibrium (LD) mapping of a disease mutation; it uses multiple linked single-nucleotide polymorphisms, restriction-fragment-length polymorphisms, or microsatellite markers and incorporates information from an annotated human genome sequence (HGS) and from a human mutation database. The method takes account of population demographic effects, using Markov chain Monte Carlo methods to integrate over the unknown gene genealogy and gene coalescence times. Information about the relative frequency of disease mutations in exons, introns, and other regions, from mutational databases, as well as assumptions about the completeness of the gene annotation, are used with an annotated HGS, to generate a prior probability that a mutation lies at any particular position in a specified region of the genome. This information is updated with information about mutation location, from LD at a set of linked markers in the region, to generate the posterior probability density of the mutation location. The performance of the method is evaluated by simulation and by analysis of a data set for diastrophic dysplasia (DTD) in Finland. The DTD disease gene has been positionally cloned, so the actual location of the mutation is known and can be compared with the position predicted by our method. For the DTD data, the addition of information from an HGS results in disease-gene localization at a resolution that is much higher than that which would be possible by LD mapping alone. In this case, the gene would be found by sequencing a region < or =7 kb in size.
Rannala
B
B
Department of Medical Genetics, University of Alberta, Edmonton, Alberta T6G 2H7, Canada. brannala@ualberta.ca
Reeve
J P
JP
D000465:Algorithms; D027321:Anion Transport Proteins; D001499:Bayes Theorem; D001848:Bone Diseases, Developmental / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D002874:Chromosome Mapping / Q000379:methods* / Q000706:statistics & numerical data; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D003198:Computer Simulation; D019992:Databases as Topic; D005387:Finland; D005787:Gene Frequency / Q000235:genetics; D030342:Genetic Diseases, Inborn / Q000235:genetics; D015894:Genome, Human; D023281:Genomics; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics*; D008390:Markov Chains; D026901:Membrane Transport Proteins; D018895:Microsatellite Repeats / Q000235:genetics; D009010:Monte Carlo Method; D009154:Mutation / Q000235:genetics; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D012984:Software; D016008:Statistical Distributions; D000076988:Sulfate Transporters
D027321:Anion Transport Proteins; D002352:Carrier Proteins; D026901:Membrane Transport Proteins; C089651:SLC26A2 protein, human; D000076988:Sulfate Transporters