title: HLA diversity in the 1000 genomes dataset.
abstract: The 1000 Genomes Project aims to provide a deep characterization of human genome sequence variation by sequencing at a level that should allow the genome-wide detection of most variants with frequencies as low as 1%. However, in the major histocompatibility complex (MHC), only the top 10 most frequent haplotypes are in the 1% frequency range whereas thousands of haplotypes are present at lower frequencies. Given the limitation of both the coverage and the read length of the sequences generated by the 1000 Genomes Project, the highly variable positions that define HLA alleles may be difficult to identify. We used classical Sanger sequencing techniques to type the HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1 genes in the available 1000 Genomes samples and combined the results with the 103,310 variants in the MHC region genotyped by the 1000 Genomes Project. Using pairwise identity-by-descent distances between individuals and principal component analysis, we established the relationship between ancestry and genetic diversity in the MHC region. As expected, both the MHC variants and the HLA phenotype can identify the major ancestry lineage, informed mainly by the most frequent HLA haplotypes. To some extent, regions of the genome with similar genetic or similar recombination rate have similar properties. An MHC-centric analysis underlines departures between the ancestral background of the MHC and the genome-wide picture. Our analysis of linkage disequilibrium (LD) decay in these samples suggests that overestimation of pairwise LD occurs due to a limited sampling of the MHC diversity. This collection of HLA-specific MHC variants, available on the dbMHC portal, is a valuable resource for future analyses of the role of MHC in population and disease studies.
authors.affiliation: Department of Neurology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Pierre-Antoine
authors.initials: PA
authors.lastname: Gourraud
authors.affiliation: Department of Neurology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Pouya
authors.initials: P
authors.lastname: Khankhanian
authors.affiliation: Histogenetics Inc., Ossining, New York, United States of America.
authors.forename: Nezih
authors.initials: N
authors.lastname: Cereb
authors.affiliation: Histogenetics Inc., Ossining, New York, United States of America.
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Yang
authors.affiliation: National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Feolo
authors.affiliation: National Marrow Donor Program, Minneapolis, Minnesota, United States of America.
authors.forename: Martin
authors.initials: M
authors.lastname: Maiers
authors.affiliation: Université de Montréal Institut de Cardiologie de Montréal, Montréal, Quebec, Canada.
authors.forename: John D
authors.initials: JD
authors.lastname: Rioux
authors.affiliation: Department of Neurology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Stephen
authors.initials: S
authors.lastname: Hauser
authors.affiliation: Department of Neurology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Jorge
authors.initials: J
authors.lastname: Oksenberg
mesh_terms: D000483:Alleles; D030541:Databases, Genetic; D014644:Genetic Variation; D015894:Genome, Human; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics*; D006239:Haplotypes; D006650:Histocompatibility Testing; D016045:Human Genome Project; D006801:Humans; D015810:Linkage Disequilibrium; D008285:Major Histocompatibility Complex / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D025341:Principal Component Analysis
chemical_list: D006680:HLA Antigens