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HLA class I haplotype diversity is consistent with selection for frequent existing haplotypes

Alter, Idan ; Gragert, Loren ; Fingerson, Stephanie ; Maiers, Martin ; Louzoun, Yoram Weissing, Franz J.

PLoS computational biology, 2017-08, Vol.13 (8), p.e1005693-e1005693 [Periódico revisado por pares]

United States: Public Library of Science

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Título:
HLA class I haplotype diversity is consistent with selection for frequent existing haplotypes
Autor: Alter, Idan ; Gragert, Loren ; Fingerson, Stephanie ; Maiers, Martin ; Louzoun, Yoram
Weissing, Franz J.
Assuntos: Adaptive systems ; Alleles ; Antigens ; Biodiversity ; Biological diversity ; Biology and Life Sciences ; Computational Biology ; Drb1 protein ; Empirical analysis ; Frequency dependence ; Frequency distribution ; Gene polymorphism ; Genetic aspects ; Genetic diversity ; Genetic Variation - genetics ; Genetics ; Genomes ; Genomics ; Haplotypes ; Haplotypes - genetics ; Heterozygote advantage ; Heterozygotes ; Histocompatibility antigen HLA ; Histocompatibility antigens ; Histocompatibility Antigens Class I - genetics ; HLA antigens ; HLA histocompatibility antigens ; Homozygosity ; Humans ; Immune system ; Immunology ; Linkage Disequilibrium ; Major histocompatibility complex ; Medicine and Health Sciences ; Models, Genetic ; Observations ; Polymorphism ; Population ; Population studies ; Selection, Genetic - genetics ; Software ; T cell receptors
É parte de: PLoS computational biology, 2017-08, Vol.13 (8), p.e1005693-e1005693
Notas: new_version
ObjectType-Article-1
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The authors have declared that no competing interests exist.
Descrição: 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.
Editor: United States: Public Library of Science
Idioma: Inglês

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HLA class I haplotype diversity is consistent with selection for frequent existing haplotypes

Alter, Idan ; Gragert, Loren ; Fingerson, Stephanie ; Maiers, Martin ; Louzoun, Yoram Weissing, Franz J.

United States: Public Library of Science

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