PMID- 31345698 OWN - NLM STAT- MEDLINE DCOM- 20200226 LR - 20221207 IS - 1879-1166 (Electronic) IS - 0198-8859 (Print) IS - 0198-8859 (Linking) VI - 80 IP - 10 DP - 2019 Oct TI - Next-generation sequencing reveals new information about HLA allele and haplotype diversity in a large European American population. PG - 807-822 LID - S0198-8859(19)30952-8 [pii] LID - 10.1016/j.humimm.2019.07.275 [doi] AB - The human leukocyte antigen (HLA) genes are extremely polymorphic and are useful molecular markers to make inferences about human population history. However, the accuracy of the estimation of genetic diversity at HLA loci very much depends on the technology used to characterize HLA alleles; high-resolution genotyping of long-range HLA gene products improves the assessment of HLA population diversity as well as other population parameters compared to lower resolution typing methods. In this study we examined allelic and haplotype HLA diversity in a large healthy European American population sourced from the UCSF-DNA bank. A high-resolution next-generation sequencing method was applied to define non-ambiguous 3- and 4-field alleles at the HLA-A, HLA-C, HLA-B, HLA-DRB1, HLA-DRB3/4/5, HLA-DQA1, HLA-DQB1, HLA-DPA1, and HLA-DPB1 loci in samples provided by 2248 unrelated individuals. A number of population parameters were examined including balancing selection and various measurements of linkage disequilibrium were calculated. There were no detectable deviations from Hardy-Weinberg proportions at HLA-A, HLA-DRB1, HLA-DQA1 and HLA-DQB1. For the remaining loci moderate and significant deviations were detected at HLA-C, HLA-B, HLA-DRB3/4/5, HLA-DPA1 and HLA-DPB1 loci mostly from population substructures. Unique 4-field associations were observed among alleles at 2 loci and haplotypes extending large intervals that were not apparent in results obtained using testing methodologies with limited sequence coverage and phasing. The high diversity at HLA-DPA1 results from detection of intron variants of otherwise well conserved protein sequences. It may be speculated that divergence in exon sequences may be negatively selected. Our data provides a valuable reference source for future population studies that may allow for precise fine mapping of coding and non-coding sequences determining disease susceptibility and allo-immunogenicity. CI - Copyright (c) 2019 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved. FAU - Creary, Lisa E AU - Creary LE AD - Department of Pathology, Stanford University School of Medicine, Palo Alto, CA, USA; Histocompatibility, Immunogenetics and Disease Profiling Laboratory, Stanford Blood Center, Palo Alto, CA, USA. Electronic address: lcreary@stanford.edu. FAU - Gangavarapu, Sridevi AU - Gangavarapu S AD - Histocompatibility, Immunogenetics and Disease Profiling Laboratory, Stanford Blood Center, Palo Alto, CA, USA. FAU - Mallempati, Kalyan C AU - Mallempati KC AD - Histocompatibility, Immunogenetics and Disease Profiling Laboratory, Stanford Blood Center, Palo Alto, CA, USA. FAU - Montero-Martin, Gonzalo AU - Montero-Martin G AD - Department of Pathology, Stanford University School of Medicine, Palo Alto, CA, USA; Histocompatibility, Immunogenetics and Disease Profiling Laboratory, Stanford Blood Center, Palo Alto, CA, USA. FAU - Caillier, Stacy J AU - Caillier SJ AD - Department of Neurology, School of Medicine, University of California San Francisco, San Francisco, CA, USA. FAU - Santaniello, Adam AU - Santaniello A AD - Department of Neurology, School of Medicine, University of California San Francisco, San Francisco, CA, USA. FAU - Hollenbach, Jill A AU - Hollenbach JA AD - Department of Neurology, School of Medicine, University of California San Francisco, San Francisco, CA, USA. FAU - Oksenberg, Jorge R AU - Oksenberg JR AD - Department of Neurology, School of Medicine, University of California San Francisco, San Francisco, CA, USA. FAU - Fernandez-Vina, Marcelo A AU - Fernandez-Vina MA AD - Department of Pathology, Stanford University School of Medicine, Palo Alto, CA, USA; Histocompatibility, Immunogenetics and Disease Profiling Laboratory, Stanford Blood Center, Palo Alto, CA, USA. LA - eng GR - U19 NS095774/NS/NINDS NIH HHS/United States PT - Journal Article DEP - 20190722 PL - United States TA - Hum Immunol JT - Human immunology JID - 8010936 RN - 0 (HLA Antigens) SB - IM MH - Adolescent MH - Adult MH - Aged MH - Aged, 80 and over MH - Alleles MH - Cohort Studies MH - Europe/ethnology MH - Female MH - Gene Frequency/*genetics MH - Genetic Loci/genetics MH - Genetics, Population/*methods MH - HLA Antigens/*genetics MH - Haplotypes/*genetics MH - *High-Throughput Nucleotide Sequencing MH - Histocompatibility Testing MH - Humans MH - Linkage Disequilibrium/genetics MH - Male MH - Middle Aged MH - United States MH - White People/ethnology/*genetics MH - Young Adult PMC - PMC6778037 MID - NIHMS1535883 OTO - NOTNLM OT - Allele frequency OT - European Americans OT - Haplotype blocks OT - Haplotype frequency OT - Human leukocyte antigen OT - Linkage disequilibrium OT - Next-generation sequencing OT - Population genetics COIS- Conflict of interest disclosure The authors declare no competing financial or other interests. EDAT- 2019/07/28 06:00 MHDA- 2020/02/27 06:00 PMCR- 2020/10/01 CRDT- 2019/07/27 06:00 PHST- 2018/12/24 00:00 [received] PHST- 2019/06/21 00:00 [revised] PHST- 2019/07/06 00:00 [accepted] PHST- 2019/07/28 06:00 [pubmed] PHST- 2020/02/27 06:00 [medline] PHST- 2019/07/27 06:00 [entrez] PHST- 2020/10/01 00:00 [pmc-release] AID - S0198-8859(19)30952-8 [pii] AID - 10.1016/j.humimm.2019.07.275 [doi] PST - ppublish SO - Hum Immunol. 2019 Oct;80(10):807-822. doi: 10.1016/j.humimm.2019.07.275. Epub 2019 Jul 22.