Data from: An evolutionary history of the selectin gene cluster in humans

Molecules involved in leukocyte trafficking have a central role in the development of inflammatory and immune responses. We performed FST analysis of the selectin cluster, as well as of SELPLG, ICAM1 and VCAM1. Peaks of significantly high population genetic differentiation were restricted to two regions in SELP and one in SELPLG. Resequencing data indicated that the region covering SELP exons 11–13 displays high nucleotide diversity in Africans and Europeans (CEU), and a high level of within-species diversity compared with inter-specific divergence. Analysis of inferred haplotypes revealed a complex phylogeny with two deeply separated clades that coalesce at ~3.5 million years (MY) plus a minor clade with a TMRCA (time to the most recent common ancestor) of ~2.2 MY. A splicing assay indicated no haplotype-specific effect on SELP exon 14 inclusion. These data are consistent with a model of multiallelic balancing selection; single-nucleotide polymorphism analysis indicated that the Val640Leu variant represents a likely selection target. In populations of Asian ancestry a distinct haplotype, possibly carrying regulatory variants, has been driven to high frequency by positive selection. No deviation from neutrality was observed for the SELPLG region. Resequencing of SELP in chimpanzees revealed a haplotype phylogeny with extremely deep basal branches, suggesting either long-standing balancing selection or ancestral population structure. Thus, SELP has experienced a complex selective history, possibly as a result of local adaptation. Variants in the gene have been associated with autoimmune and cardiovascular diseases. Association studies would benefit from both taking the complex SELP haplotype structure into account and from analysis of possible regulatory variants in the gene.参与白细胞迁移（leukocyte trafficking）的分子在炎症与免疫应答的发生过程中发挥核心作用。我们针对选择素簇（selectin cluster）、P选择素配体（SELPLG）、细胞间黏附分子1（ICAM1）以及血管细胞黏附分子1（VCAM1）开展了FST分析（Fixation Index, FST）。群体遗传分化显著升高的峰值仅局限于P选择素基因（SELP）的两个区域以及P选择素配体（SELPLG）的一个区域。重测序数据显示，覆盖P选择素基因（SELP）第11至13号外显子的区域在非洲人群与欧洲血统人群（CEU）中呈现出较高的核苷酸多样性，且相较于种间分化，该区域的种内多样性水平更高。对推断得到的单倍型的分析显示，其系统发育结构较为复杂：存在两个分化极深的进化枝，二者的溯祖时间约为350万年（million years, MY），另有一个次要进化枝的最近共同祖先时间（time to the most recent common ancestor, TMRCA）约为220万年。剪接实验结果表明，单倍型对P选择素基因（SELP）第14号外显子的保留并无特异性影响。上述数据与多等位基因平衡选择模型相符；单核苷酸多态性（single-nucleotide polymorphism, SNP）分析显示，Val640Leu变异可能是选择作用的靶标。在亚洲血统人群中，一种可能携带调控变异的独特单倍型已通过正向选择被推向了高频率。P选择素配体（SELPLG）区域未观察到偏离中性进化的现象。对黑猩猩体内P选择素基因（SELP）的重测序结果显示，其单倍型系统发育树拥有极深的基部分支，这提示该区域可能存在长期的平衡选择，或是保留了祖先种群结构。由此可见，P选择素基因（SELP）经历了复杂的选择历史，这可能是局部适应的结果。该基因的变异与自身免疫性疾病及心血管疾病存在关联。在开展关联研究时，若同时考虑P选择素基因（SELP）复杂的单倍型结构，并对该基因中可能存在的调控变异进行分析，将有助于提升研究质量。