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首页> 外文期刊>PLoS Computational Biology >HLA class I haplotype diversity is consistent with selection for frequent existing haplotypes
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HLA class I haplotype diversity is consistent with selection for frequent existing haplotypes

机译：HLA类I单倍型多样性与频繁现有单倍型的选择一致

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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.
机译：主要的组织代表性综合体（MHC）含有人类中最多态性遗传系统，适应性免疫系统的人白细胞抗原（HLA）基因。通过平衡选择，如负频率依赖的选择或杂合子优势，认为HLA中的高位等级多样性。通过病原体免疫逃逸的选择性压力可以维持许多不同HLA等位基因的可观频率。由于高HLA多态性需要非常大的样品尺寸，因此尚未广泛评估对位于基因座或单倍型的组合，或单倍型的选择压力尚未得到广泛评估。我们旨在通过分析HLA A〜C〜B〜DRB1〜DQB1单倍型频率来评估HLA单倍型水平在HLA单倍型水平的影响。与等位基因相比，HLA单倍型多样性模式表明纯化选择，随着某些HLA等位基因组合在高连杆不平衡中发生。在罕见的单倍型中，常见的单倍型和阴性（DIJ'<0）中，LINKAGE DURECHIBIRIUM是阳性（DIJ'> 0）。将单倍型频率分布拟合到几种群体动态模型中，我们发现当掺入显着的正频依赖性选择（FDS）时获得了最佳拟合。最后，纯合子的eWens-Watterson试验在研究的23个美国群体中均为5-otonus单倍型的过量纯合子，平均为28.43。单倍型多样性与HLA类I单倍型（HLA-A，-B，-C）的纯化选择最常一致，并且未被推断为HLA II类单倍型（-DRB1和-DQB1）。我们在进化理论的背景下讨论了我们的实证结果，探索了在MHC单倍型嵌段中保持高连锁不平衡的潜在选择机制。

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