Dataset Information

Long-range multilocus haplotype phasing of the MHC.

ABSTRACT: 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.

SUBMITTER: Guo Z

PROVIDER: S-EPMC1459002 | biostudies-literature | 2006 May

REPOSITORIES: biostudies-literature

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Long-range multilocus haplotype phasing of the MHC.

Guo Zhen Z Hood Leroy L Malkki Mari M Petersdorf Effie W EW

Proceedings of the National Academy of Sciences of the United States of America 20060421 18

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- ...[more]

PMID: 16632595

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Project description:BackgroundWe describe the latest improvements to the long-range phasing (LRP) and haplotype library imputation (HLI) algorithms for successful phasing of both datasets with one million individuals and datasets genotyped using different sets of single nucleotide polymorphisms (SNPs). Previous publicly available implementations of the LRP algorithm implemented in AlphaPhase could not phase large datasets due to the computational cost of defining surrogate parents by exhaustive all-against-all searches. Furthermore, the AlphaPhase implementations of LRP and HLI were not designed to deal with large amounts of missing data that are inherent when using multiple SNP arrays.MethodsWe developed methods that avoid the need for all-against-all searches by performing LRP on subsets of individuals and then concatenating the results. We also extended LRP and HLI algorithms to enable the use of different sets of markers, including missing values, when determining surrogate parents and identifying haplotypes. We implemented and tested these extensions in an updated version of AlphaPhase, and compared its performance to the software package Eagle2.ResultsA simulated dataset with one million individuals genotyped with the same 6711 SNPs for a single chromosome took less than a day to phase, compared to more than seven days for Eagle2. The percentage of correctly phased alleles at heterozygous loci was 90.2 and 99.9% for AlphaPhase and Eagle2, respectively. A larger dataset with one million individuals genotyped with 49,579 SNPs for a single chromosome took AlphaPhase 23 days to phase, with 89.9% of alleles at heterozygous loci phased correctly. The phasing accuracy was generally lower for datasets with different sets of markers than with one set of markers. For a simulated dataset with three sets of markers, 1.5% of alleles at heterozygous positions were phased incorrectly, compared to 0.4% with one set of markers.ConclusionsThe improved LRP and HLI algorithms enable AlphaPhase to quickly and accurately phase very large and heterogeneous datasets. AlphaPhase is an order of magnitude faster than the other tested packages, although Eagle2 showed a higher level of phasing accuracy. The speed gain will make phasing achievable for very large genomic datasets in livestock, enabling more powerful breeding and genetics research and application.

Dataset Information

Long-range multilocus haplotype phasing of the MHC.

Publications

Long-range multilocus haplotype phasing of the MHC.

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