Divergent Allele Advantage at Human MHC Genes: Signatures of Past and Ongoing Selection.
Divergent Allele Advantage at Human MHC Genes: Signatures of Past and Ongoing Selection.
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DOI：
10.1093/molbev/msy116
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发表时间：
2018-09-01
影响因子：
10.7
通讯作者：
Lenz TL
中科院分区：
文献类型：
--
作者：
Pierini F;Lenz TL
主要组织相容性复合体（MHC）的高度多态性基因在适应性免疫中起关键作用。发散性等位基因优势是一种平衡选择机制，可能是其特殊多态性的原因之一。它假设具有更多不同等位基因的MHC基因型允许更广泛的抗原呈递到免疫效应细胞，从而提高免疫能力。然而，在不同的MHC基因中，成对序列差异与相应的结合肽库之间的直接关系尚未得到系统的研究。在这里，我们研究了五个关键的经典人类MHC基因（人类白细胞抗原；HLA-A, -B, -C， -DRB1和-DQB1）的这种关系，使用等位基因特异性计算结合预测来自广泛的人类病原体的118,097肽。对于所有五种人类MHC基因，杂合基因型的两个等位基因之间的遗传距离与这两个等位基因结合的肽总数呈正相关。根据MHC I类分子的主要抗原递呈途径，HLA-B和HLA-C等位基因与来源于细胞内病原体的肽具有特别强的相关性。有趣的是，这种偏向与细胞内和细胞外病原体之间不同的蛋白质组成相吻合，可能表明MHC I分子适应于呈现特异性的细胞内肽。最后，我们观察到等位基因的平均散度与其种群频率之间存在显著的正相关。总之，我们的研究结果支持发散性等位基因优势作为一种有意义的定量机制，通过病原体介导的选择导致MHC多样性的进化。
The highly polymorphic genes of the major histocompatibility complex (MHC) play a key role in adaptive immunity. Divergent allele advantage, a mechanism of balancing selection, is proposed to contribute to their exceptional polymorphism. It assumes that MHC genotypes with more divergent alleles allow for broader antigen-presentation to immune effector cells, by that increasing immunocompetence. However, the direct correlation between pairwise sequence divergence and the corresponding repertoire of bound peptides has not been studied systematically across different MHC genes. Here, we investigated this relationship for five key classical human MHC genes (human leukocyte antigen; HLA-A, -B, -C, -DRB1, and -DQB1), using allele-specific computational binding prediction to 118,097 peptides derived from a broad range of human pathogens. For all five human MHC genes, the genetic distance between two alleles of a heterozygous genotype was positively correlated with the total number of peptides bound by these two alleles. In accordance with the major antigen-presentation pathway of MHC class I molecules, HLA-B and HLA-C alleles showed particularly strong correlations for peptides derived from intracellular pathogens. Intriguingly, this bias coincides with distinct protein compositions between intra- and extracellular pathogens, possibly suggesting adaptation of MHC I molecules to present specifically intracellular peptides. Eventually, we observed significant positive correlations between an allele’s average divergence and its population frequency. Overall, our results support the divergent allele advantage as a meaningful quantitative mechanism through which pathogen-mediated selection leads to the evolution of MHC diversity.
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影响因子：
3.2
作者：
Buhler S;Nunes JM;Sanchez-Mazas A
通讯作者：
Sanchez-Mazas A
影响因子：
56.9
作者：
Carrington, M;Nelson, GW;O'Brien, SJ
通讯作者：
O'Brien, SJ
DOI：
10.1073/pnas.86.3.958
发表时间：
1989-02-01
影响因子：
11.1
作者：
HUGHES, AL;NEI, M
通讯作者：
NEI, M
影响因子：
4.1
作者：
BAUSE, E
通讯作者：
BAUSE, E
影响因子：
14.9
作者：
González-Galarza FF;Takeshita LY;Santos EJ;Kempson F;Maia MH;da Silva AL;Teles e Silva AL;Ghattaoraya GS;Alfirevic A;Jones AR;Middleton D
通讯作者：
Middleton D