Long-range multilocus haplotype phasing of the MHC.

Haplotypes are a powerful tool for identifying the genetic basis of common complex diseases. Disease-association mapping requires molecular methods for haplotyping biallelic SNP variation and highly complex polymorphisms. We developed a method for phasing HLA-A, HLA-B, and HLA-DRB1 alleles on chromosome 6 in unrelated individuals. This method uses the highly polymorphic HLA-B locus to discriminate the two HLA haplotypes in heterozygous individuals and its ideal location 1.4 Mbp telomeric to HLA-DRB1 and 1.2 Mbp centromeric to HLA-A to capture 2-Mbp-long genomic DNA. Genomic DNA representing a single HLA-B-captured haplotype is genotyped for HLA-A and HLA-DRB1 alleles and linkage to HLA-B is established. Proof of principle was established in a large blinded study of phase-known samples. Availability of an efficient method for MHC haplotype phase determination will facilitate the mapping of causative MHC-resident genes in many human diseases and has the potential to be broadened to other polymorphic gene complexes.

[1]  Minjie Luo,et al.  A genotyping system capable of simultaneously analyzing >1000 single nucleotide polymorphisms in a haploid genome. , 2005, Genome research.

[2]  S. Wallenstein,et al.  Molecular haplotyping by linking emulsion PCR: analysis of paraoxonase 1 haplotypes and phenotypes , 2005, Nucleic acids research.

[3]  A. Thiel,et al.  Direct fluorescence analysis of genetic polymorphisms by hybridization with oligonucleotide arrays on glass supports. , 1994, Nucleic acids research.

[4]  N. Schork,et al.  Accuracy of haplotype frequency estimation for biallelic loci, via the expectation-maximization algorithm for unphased diploid genotype data. , 2000, American journal of human genetics.

[5]  K K Kidd,et al.  The accuracy of statistical methods for estimation of haplotype frequencies: an example from the CD4 locus. , 2000, American journal of human genetics.

[6]  Shirley A. Miller,et al.  A simple salting out procedure for extracting DNA from human nucleated cells. , 1988, Nucleic acids research.

[7]  Jennifer Wessel,et al.  A comprehensive literature review of haplotyping software and methods for use with unrelated individuals , 2005, Human Genomics.

[8]  Charles M. Lieber,et al.  Structural and functional imaging with carbon nanotube AFM probes. , 2001, Progress in biophysics and molecular biology.

[9]  J. Apgar,et al.  Single-molecule dilution and multiple displacement amplification for molecular haplotyping. , 2005, BioTechniques.

[10]  M. Uhlén,et al.  Molecular haplotyping by Pyrosequencing (TM) , 2002 .

[11]  Luigi Luca Cavalli-Sforza,et al.  The genetics of human populations. , 1972, Scientific American.

[12]  K. Boucher,et al.  HLA gene and haplotype frequencies in the North American population: the National Marrow Donor Program Donor Registry. , 1997, Transplantation.

[13]  Charles R Cantor,et al.  Direct molecular haplotyping of long-range genomic DNA with M1-PCR , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[14]  M. Boehnke,et al.  Experimentally-derived haplotypes substantially increase the efficiency of linkage disequilibrium studies , 2001, Nature Genetics.

[15]  R S Judson,et al.  Complex promoter and coding region beta 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[16]  Pui-Yan Kwok,et al.  Single‐molecule analysis for molecular haplotyping , 2004, Human mutation.

[17]  L. Excoffier,et al.  Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. , 1995, Molecular biology and evolution.

[18]  Stephan Beck,et al.  A high-resolution linkage-disequilibrium map of the human major histocompatibility complex and first generation of tag single-nucleotide polymorphisms. , 2005, American journal of human genetics.

[19]  Oligonucleotide arrays for high-throughput SNPs detection in the MHC class I genes: HLA-B as a model system. , 2002, Genome research.

[20]  B. Storer,et al.  Major-histocompatibility-complex class I alleles and antigens in hematopoietic-cell transplantation. , 2001, The New England journal of medicine.

[21]  Matthias Wjst,et al.  Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. , 2005, Methods in molecular biology.

[22]  Yun-Shien Lee,et al.  Linear allele‐specific long‐range amplification: a novel method of long‐range molecular haplotyping , 2005, Human mutation.

[23]  B. Devlin,et al.  ADLAPH: A molecular haplotyping method based on allele-discriminating long-range PCR. , 2004, Genomics.

[24]  Jerzy K. Kulski,et al.  An update of the HLA genomic region, locus information and disease associations: 2004. , 2004, Tissue antigens.

[25]  Sue Povey,et al.  Gene map of the extended human MHC , 2004, Nature Reviews Genetics.

[26]  A. Alderborn,et al.  Molecular haplotype determination using allele-specific PCR and pyrosequencing technology. , 2003, Genomics.

[27]  M. Carrington,et al.  Recombination within the human MHC , 1999, Immunological reviews.

[28]  P. Kwok,et al.  SNP genotyping and molecular haplotyping of DNA pools. , 2003, Cold Spring Harbor symposia on quantitative biology.

[29]  Jay Shendure,et al.  Long-range polony haplotyping of individual human chromosome molecules , 2006, Nature Genetics.

[30]  L. Hood,et al.  Oligonucleotide arrays for high-throughput SNPs detection in the MHC class I genes: HLA-B as a model system. , 2002, Genome research.

[31]  Hans Lehrach,et al.  Clone-based systematic haplotyping (CSH): a procedure for physical haplotyping of whole genomes. , 2003, Genome research.

[32]  Charles M. Lieber,et al.  Direct haplotyping of kilobase-size DNA using carbon nanotube probes , 2000, Nature Biotechnology.

[33]  Rainer Lehtonen,et al.  A novel functionally deficient MYH variant in individuals with colorectal adenomatous polyposis , 2005, Human mutation.

[34]  Roger E Bumgarner,et al.  PART-1: a novel human prostate-specific, androgen-regulated gene that maps to chromosome 5q12. , 2000, Cancer research.

[35]  D C Ward,et al.  Visualization of oligonucleotide probes and point mutations in interphase nuclei and DNA fibers using rolling circle DNA amplification , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[36]  Dan Geiger,et al.  Maximum Likelihood Haplotyping for General Pedigrees , 2005, Human Heredity.

[37]  David E. Housman,et al.  Digital genotyping and haplotyping with polymerase colonies , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[38]  D. Labie,et al.  Hematologically and genetically distinct forms of sickle cell anemia in Africa. The Senegal type and the Benin type. , 1985, The New England journal of medicine.

[39]  Anajane G. Smith,et al.  Optimizing outcome after unrelated marrow transplantation by comprehensive matching of HLA class I and II alleles in the donor and recipient. , 1998, Blood.

[40]  J. Hansen,et al.  A comprehensive approach for typing the alleles of the HLA-B locus by automated sequencing. , 1995, Tissue antigens.

[41]  M. Carrington,et al.  High-resolution patterns of meiotic recombination across the human major histocompatibility complex. , 2002, American journal of human genetics.

[42]  Anajane G. Smith,et al.  Ten HLA-DR4 alleles defined by sequence polymorphisms within the DRB1 first domain , 2004, Immunogenetics.

[43]  P I Terasaki,et al.  Twelve years' experience with national sharing of HLA-matched cadaveric kidneys for transplantation. , 2000, The New England journal of medicine.

[44]  Benjamin Yakir,et al.  An efficient haplotyping method with DNA pools. , 2002, Nucleic acids research.