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closeCorrection to "Phased Whole-Genome Genetic Risk in a Family Quartet Using a Major Allele Reference Sequence
Posted by rdewey on 02 Jul 2012 at 15:55 GMT
We used long-range phased haplotypes and an iterative search (described in full in Text S1) for the nearest HLA tag haplotype [32] to provide HLA types for each individual prior to downstream risk prediction
http://plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002280#article1.body1.sec2.sec8.p2
In PLoS Genetics, volume 7, issue 9: doi:10.1371/journal.pgen.1002280
Figure 4C included erroneously duplicated paternal imputed HLA haplotypes. Furthermore, review of the database of tag haplotypes used for imputation of HLA types1 revealed strand ambiguities contributing to ambiguous HLA type imputation. We manually reviewed all genotype information contributing to tag haplotype inference from de Bakker, et al, and mapped unambiguous strand orientations to the current dbSNP strand orientation. Application of these updated tag haplotypes to phased variant data (including phased genotype calls for homozygous reference positions), restricted to perfect match tag haplotypes, are presented in the revised Figure 4 below.
We also performed HLA typing of genomic DNA by Sanger fluorescent big dye terminator dideoxy nucleotide sequencing using PCR products amplified with locus-specific primers for HLA-A, B, C, DRB1, DQB1 and high resolution sequence specific priming (SSP) and oliqo probing (SSO) for DQA1. These results are displayed in the Figure 2 below. These results confirm a paternal recombination between HLA-B and DRB1 in the son, as previously identified by the inheritance state analysis and long range phasing. Manual review of tag haplotypes present in the database used for imputation revealed no tag haplotype for HLA-B*35:03 or *39:01, HLA-DRB1*14:54, or HLA-DQA1*01:04, all of which are HLA types present in the family. Two sequence genotyping errors contributed to inaccurate or missing HLA-type imputation. A sequencing error at rs3835309 contributed to lack of proper assignment of HLA-A*25:01 to mother, son, and daughter and a missing genotype at rs5875391 contributed to lack of proper assignment of HLA-DQB1*05:02 to mother and daughter.
These findings highlight the challenges inherent to imputation of HLA types in general, particularly rare HLA types, the need for fully sequenced, rather than intermediate typed, HLA databases, and the need for more comprehensive methods and data sources for HLA type imputation. The disease risk estimates on which these phased genotypes are based remain unchanged.
We regret any confusion this may have caused readers. We would like to acknowledge Dolly B. Tyan, Marcelo Fernandez-Vina, Matthew W. Anderson, Debra D. Hiraki for kind assistance in HLA typing and Neil Walker for commentary prompting this correction.
References
1. de Bakker PI, McVean G, Sabeti PC, Miretti MM, Green T, Marchini J, Ke X, Monsuur AJ, Whittaker P, Delgado M, Morrison J, Richardson A, Walsh EC, Gao X, Galver L, Hart J, Hafler DA, Pericak-Vance M, Todd JA, Daly MJ, Trowsdale J, Wijmenga C, Vyse TJ, Beck S, Murray SS, Carrington M, Gregory S, Deloukas P, Rioux JD. A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC. Nat Genet. 2006;38:1166-1172.
Figure Legends
Figure 1. Revised Figure 4. Ancestry and immunogenotyping using phased variant data. A, Ancestry analysis of maternal and paternal origins based on principle components analysis of SNP genotypes intersected with the Population Reference Sample dataset. B, The HMM identified a recombination between HLA-B and DRB1 and facilitated resolution of haplotype phase at HLA loci. Contig colors in the lower panel correspond to the inheritance state as depicted in Figure 3A. C, Imputed common HLA types for family quartet based on phased sequence data. *-- denotes no perfect-match tag haplotype present in family quartet.
Figure 2. HLA types for family quartet determined by di-deoxynucleotide sequence-based typing. X denotes likely homozygosity which, absent segregation, cannot be confirmed by descent.