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.

参与白细胞迁移的分子在炎症与免疫应答的发生发展过程中发挥核心作用。本研究针对选择素簇（selectin cluster）、SELPLG、ICAM1以及VCAM1开展了FST分析。群体遗传分化显著较高的峰值仅局限于SELP基因的两个区域以及SELPLG基因的一个区域。重测序数据显示，涵盖SELP基因第11至13号外显子的区域在非洲人群与欧洲人群（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进行系统发育分析，结果显示存在两个深度分化的演化支，二者的最近共同祖先时间约为350万年（MY），同时还存在一个次要演化支，其最近共同祖先时间（TMRCA，time to the most recent common ancestor）约为220万年。剪接实验结果显示，单倍型对SELP基因第14号外显子的剪接保留无特异性影响。上述数据与多等位基因平衡选择模型相符；单核苷酸多态性分析显示，Val640Leu变异体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被正向选择推至较高频率。SELPLG基因区域未观察到偏离中性进化的现象。对黑猩猩SELP基因的重测序分析显示，其单倍型系统发育树具有极深的基部分支，这提示可能存在长期的平衡选择，或是存在祖先群体结构。由此可见，SELP基因经历了复杂的选择进化历史，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。关联研究若能同时考虑SELP基因复杂的单倍型结构，并对该基因中潜在的调控变异开展分析，将能获得更优的研究结果。