BACKGROUND Lymphotoxin-α (LTα), located in the Major Histocompatibility Complex (MHC) class III region on chromosome 6, encodes a cytotoxic protein that mediates a variety of antiviral responses among other biological functions. Furthermore, several genotypes at this gene have been implicated in the onset of a number of complex diseases, including myocardial infarction, autoimmunity, and various types of cancer. However, little is known about levels of nucleotide variation and linkage disequilibrium (LD) in and near LTα, which could also influence phenotypic variance. To address this gap in knowledge, we examined sequence variation across ~ 10 kilobases (kbs), encompassing LTα and the upstream region, in 2039 individuals from the 1000 Genomes Project originating from 21 global populations. RESULTS Here, we observed striking patterns of diversity, including an excess of intermediate-frequency alleles, the maintenance of multiple common haplotypes and a deep coalescence time for variation (dating > 1.0 million years ago), in global populations. While these results are generally consistent with a model of balancing selection, we also uncovered a signature of positive selection in the form of long-range LD on chromosomes with derived alleles primarily in Eurasian populations. To reconcile these findings, which appear to support different models of selection, we argue that selective sweeps (particularly, soft sweeps) of multiple derived alleles in and/or near LTα occurred in non-Africans after their ancestors left Africa. Furthermore, these targets of selection were predicted to alter transcription factor binding site affinity and protein stability, suggesting they play a role in gene function. Additionally, our data also showed that a subset of these functional adaptive variants are present in archaic hominin genomes. CONCLUSIONS Overall, this study identified candidate functional alleles in a biologically-relevant genomic region, and offers new insights into the evolutionary origins of these loci in modern human populations.

中文翻译：

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对位于 6 号染色体 MHC III 类区域的 LTα 及其周围的古代多态性进行多重选择性扫描。


背景淋巴毒素-α (LTα) 位于 6 号染色体上的主要组织相容性复合体 (MHC) III 类区域，编码一种细胞毒性蛋白，可介导多种抗病毒反应以及其他生物学功能。此外，该基因的几种基因型与许多复杂疾病的发生有关，包括心肌梗塞、自身免疫和各种类型的癌症。然而，人们对 LTα 内及其附近的核苷酸变异和连锁不平衡 (LD) 水平知之甚少，这也可能影响表型变异。为了解决这一知识差距，我们检查了千碱基 (kbs) 范围内的序列变异，包括 LTα 和上游区域，来自 1000 个基因组计划的来自 21 个全球人群的 2039 个个体。结果在这里，我们观察到全球人群中惊人的多样性模式，包括中频等位基因过多、多种常见单倍型的维持以及变异的深层合并时间（可追溯到100万年前的>）。虽然这些结果总体上与平衡选择模型一致，但我们还发现了正选择的特征，其形式是主要在欧亚人群中具有衍生等位基因的染色体上的长​​程 LD。为了协调这些似乎支持不同选择模型的发现，我们认为，在非非洲人的祖先离开非洲后，LTα 内和/或附近的多个衍生等位基因的选择性清除（特别是软清除）发生在非非洲人身上。此外，这些选择目标预计会改变转录因子结合位点亲和力和蛋白质稳定性，表明它们在基因功能中发挥作用。 此外，我们的数据还表明，这些功能性适应性变体的一个子集存在于古人类基因组中。结论 总的来说，这项研究在生物学相关的基因组区域中确定了候选功能等位基因，并为现代人类群体中这些基因座的进化起源提供了新的见解。