HLA DNA sequence variation among human populations: molecular signatures of demographic and selective events.
HLA DNA sequence variation among human populations: molecular signatures of demographic and selective events.
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DOI：
10.1371/journal.pone.0014643
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发表时间：
2011-02-01
期刊：
影响因子：
3.7
通讯作者：
Sanchez-Mazas A
中科院分区：
文献类型：
--
作者：
Buhler S;Sanchez-Mazas A
HLA等位基因之间的分子差异在人主要组织相容性复合体（MHC）基因的肽结合编码区内变化多达57个核苷酸，但仍不清楚这种变化是由随机过程还是由与HLA分子之间的功能差异相关的选择性约束引起的。虽然HLA等位基因在群体遗传学研究中通常被视为等距的分子单位，但群体之间的DNA序列多样性对于解释所观察到的HLA多态性也至关重要。在这项研究中，我们使用了为不同HLA等位基因定义的2，062个DNA序列的大型数据集，分析了全球约200个人群的23，500个个体中7个HLA基因的核苷酸多样性。我们首先分析了这些人群的HLA分子结构和多样性与地理变异的关系，我们进一步研究了可能的偏离选择性中性通过田岛的测试和错配分布。所有的结果进行了比较，通过经典的方法应用于HLA等位基因频率。我们的研究表明，全球模式的HLA核苷酸多样性人群之间的地理位置显着相关，虽然在某些特定情况下的分子信息揭示了意想不到的遗传关系。在所有位点，除了HLA-DPB 1，人群中积累了很高比例的非常不同的等位基因，这表明杂合子的优势，表达分子远HLA分子（不对称超显性选择模型）。然而，这两个不同的选择强度和不平等的基因转换水平可以解释的异质性错配位点之间观察到的分布。此外，在HLA-DPB 1位点观察到的序列差异的独特模式表明，目前的中性，但旧的选择性压力对这个基因。我们的结论是，HLA DNA序列有利地补充HLA等位基因频率作为用于探索人类群体的遗传史的数据来源，并且它们的分析允许更彻底地调查人类MHC分子进化。
Molecular differences between HLA alleles vary up to 57 nucleotides within the peptide binding coding region of human Major Histocompatibility Complex (MHC) genes, but it is still unclear whether this variation results from a stochastic process or from selective constraints related to functional differences among HLA molecules. Although HLA alleles are generally treated as equidistant molecular units in population genetic studies, DNA sequence diversity among populations is also crucial to interpret the observed HLA polymorphism. In this study, we used a large dataset of 2,062 DNA sequences defined for the different HLA alleles to analyze nucleotide diversity of seven HLA genes in 23,500 individuals of about 200 populations spread worldwide. We first analyzed the HLA molecular structure and diversity of these populations in relation to geographic variation and we further investigated possible departures from selective neutrality through Tajima's tests and mismatch distributions. All results were compared to those obtained by classical approaches applied to HLA allele frequencies. Our study shows that the global patterns of HLA nucleotide diversity among populations are significantly correlated to geography, although in some specific cases the molecular information reveals unexpected genetic relationships. At all loci except HLA-DPB1, populations have accumulated a high proportion of very divergent alleles, suggesting an advantage of heterozygotes expressing molecularly distant HLA molecules (asymmetric overdominant selection model). However, both different intensities of selection and unequal levels of gene conversion may explain the heterogeneous mismatch distributions observed among the loci. Also, distinctive patterns of sequence divergence observed at the HLA-DPB1 locus suggest current neutrality but old selective pressures on this gene. We conclude that HLA DNA sequences advantageously complement HLA allele frequencies as a source of data used to explore the genetic history of human populations, and that their analysis allows a more thorough investigation of human MHC molecular evolution.
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