ArticlePLoS computational biology2017
HLA class I haplotype diversity is consistent with selection for frequent existing haplotypes.
Article in PLoS computational biology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 49 citations in OpenAlex.
- Unlocking Ethiopia's genomic landscape and its global significance: a call for inclusive genomics research.Human genomics · 2026Review
- Clinical settings in which human leukocyte antigen typing is still useful in the diagnosis of celiac disease.World journal of gastroenterology · 2025Review
- A Tool for the Assessment of HLA-DQ Heterodimer Variation in Hematopoietic Cell Transplantation.Transplantation and cellular therapy · 2024Article
- Polygenic polymorphism is associated with NKG2A repertoire and influences lymphocyte phenotype and function.Blood advances · 2024Article
- HLA Genetic Diversity and Chronic Hepatitis B Virus Infection: Effect of Heterozygosity Advantage.Medical sciences (Basel, Switzerland) · 2024Article
- The Impact of Patterns in Linkage Disequilibrium and Sequencing Quality on the Imprint of Balancing Selection.Genome biology and evolution · 2024Article
- Graph-Based Imputation Methods and Their Applications to Single Donors and Families.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Combined imputation of HLA genotype and self-identified race leads to better donor-recipient matching.Human immunology · 2023Article
- Expanding the MAPPs Assay to Accommodate MHC-II Pan Receptors for Improved Predictability of Potential T Cell Epitopes.Biology · 2023Article
- COVID-19 annual update: a narrative review.Human genomics · 2023Review
- Bw4 ligand and direct T-cell receptor binding induced selection on HLA A and B alleles.Frontiers in immunology · 2023Article
- Type 1 diabetes in diverse ancestries and the use of genetic risk scores.The lancet. Diabetes & endocrinology · 2022Review
- High Resolution HLA ∼A, ∼B, ∼C, ∼DRB1, ∼DQA1, and ∼DQB1 Diversity in South African Populations.Frontiers in genetics · 2022Article
- MHC Haplotyping of SARS-CoV-2 Patients: HLA Subtypes Are Not Associated with the Presence and Severity of COVID-19 in the Israeli Population.Journal of clinical immunology · 2021Article
- Exome Sequencing Reveals a Putative Role for HLA-C*03:02 in Control of HIV-1 in African Pediatric Populations.Frontiers in genetics · 2021Article
- Comprehensive Analysis of CD4Frontiers in immunology · 2020Article
- Evolution of the human MHC: New haplotype frequency analysis is not informative.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Reply to Hedrick and Klitz: High haplotype discovery rate in the HLA locus.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- MHC haplotype diversity in Icelandic horses determined by polymorphic microsatellites.Genes and immunity · 2019Article
- Single haplotype admixture models using large scale HLA genotype frequencies to reproduce human admixture.Immunogenetics · 2019Article
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The major histocompatibility complex (MHC) contains the most polymorphic genetic system in humans, the human leukocyte antigen (HLA) genes of the adaptive immune system. High allelic diversity in HLA is argued to be maintained by balancing selection, such as negative frequency-dependent selection or heterozygote advantage. Selective pressure against immune escape by pathogens can maintain appreciable frequencies of many different HLA alleles. The selection pressures operating on combinations of HLA alleles across loci, or haplotypes, have not been extensively evaluated since the high HLA polymorphism necessitates very large sample sizes, which have not been available until recently. We aimed to evaluate the effect of selection operating at the HLA haplotype level by analyzing HLA A~C~B~DRB1~DQB1 haplotype frequencies derived from over six million individuals genotyped by the National Marrow Donor Program registry. In contrast with alleles, HLA haplotype diversity patterns suggest purifying selection, as certain HLA allele combinations co-occur in high linkage disequilibrium. Linkage disequilibrium is positive (Dij'>0) among frequent haplotypes and negative (Dij'<0) among rare haplotypes. Fitting the haplotype frequency distribution to several population dynamics models, we found that the best fit was obtained when significant positive frequency-dependent selection (FDS) was incorporated. Finally, the Ewens-Watterson test of homozygosity showed excess homozygosity for 5-locus haplotypes within 23 US populations studied, with an average Fnd of 28.43. Haplotype diversity is most consistent with purifying selection for HLA Class I haplotypes (HLA-A, -B, -C), and was not inferred for HLA Class II haplotypes (-DRB1 and-DQB1). We discuss our empirical results in the context of evolutionary theory, exploring potential mechanisms of selection that maintain high linkage disequilibrium in MHC haplotype blocks.
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