ArticleProceedings of the National Academy of Sciences of the United States of America2019
Multiplicative fitness, rapid haplotype discovery, and fitness decay explain evolution of human MHC.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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10 citing papers in PubMed.
- GRIMM-II: A two-stage real-time algorithm for nine-locus HLA imputation and matching with up to three mismatches.Human immunology · 2026Article
- Bw4 ligand and direct T-cell receptor binding induced selection on HLA A and B alleles.Frontiers in immunology · 2023Article
- Polymorphism and varying selection within the MHC class I of four Anas species.Immunogenetics · 2021Article
- 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
- The giant axolotl genome uncovers the evolution, scaling, and transcriptional control of complex gene loci.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Comprehensive Analysis of CD4Frontiers in immunology · 2020Article
- SNP-Density Crossover Maps of Polymorphic Transposable Elements and HLA Genes Within MHC Class I Haplotype Blocks and Junction.Frontiers in genetics · 2020Article
- 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
- 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
- Single haplotype admixture models using large scale HLA genotype frequencies to reproduce human admixture.Immunogenetics · 2019Article
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Abstract
The major histocompatibility complex (MHC) is a central component of the vertebrate immune system and hence evolves in the regime of a host-pathogen evolutionary race. The MHC is associated with quantitative traits which directly affect fitness and are subject to selection pressure. The evolution of haplotypes at the MHC HLA (HLA) locus is generally thought to be governed by selection for increased diversity that is manifested in overdominance and/or negative frequency-dependent selection (FDS). However, recently, a model combining purifying selection on haplotypes and balancing selection on alleles has been proposed. We compare the predictions of several population dynamics models of haplotype frequency evolution to the distributions derived from 6.59-million-donor HLA typings from the National Marrow Donor Program registry. We show that models that combine a multiplicative fitness function, extremely high haplotype discovery rates, and exponential fitness decay over time produce the best fit to the data for most of the analyzed populations. In contrast, overdominance is not supported, and population substructure does not explain the observed haplotype frequencies. Furthermore, there is no evidence of negative FDS. Thus, multiplicative fitness, rapid haplotype discovery, and rapid fitness decay appear to be the major factors shaping the HLA haplotype frequency distribution in the human population.
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