2025年2月12日出版的《自然》杂志发表了丹麦科学家的一项最新研究成果。来自丹麦哥本哈根大学的Anders Albrechtsen研究组的论文发现了格陵兰岛的遗传结构是由人口、结构和选择形成的。

研究人员表示，格陵兰因纽特人和其他土著居民参与基因研究的人数不足，导致保健机会不平等。

为了解决这个问题，课题组人员对5996名具有广泛表型的格陵兰人的测序或估算基因组进行了分析。小组量化了它们历史上的种群瓶颈，以及它如何塑造了它们的遗传结构，使它们拥有更少、但更常见的可变位点。因此，与欧洲相比，该课题组研究人员发现格陵兰岛与代谢性状的高影响全基因组关联是欧洲的两倍。课题组人员推断，高影响力的变异是在人口从美洲原住民分裂出来之后出现的，它们是北极特有的，并表明其中一些变异不仅是遗传漂变的结果，也是自然选择的结果。

课题组人员还发现，来自欧洲的代谢特征多基因评分在格陵兰人身上的准确性只有欧洲人的一半，加上北极特定的变异，整体准确性提高到与欧洲人相同的水平。同样，公共遗传数据库中缺乏代表性使得格陵兰因纽特人的遗传临床筛查更加困难，但格陵兰数据的纳入通过将非遗传性候选变异的数量减少六倍来补救这一问题。

最后，研究人员确定了明显的遗传精细结构，该结构解释了格陵兰单基因疾病患病率的差异，并与最近的流动性变化一起，导致某些隐性疾病风险的预测未来降低。这些结果说明了包括格陵兰人的数据如何能够大大减少基于基因组的医疗保健的不平等。

附：英文原文

Title: Genetic architecture in Greenland is shaped by demography, structure and selection

Author: Stger, Frederik Filip, Andersen, Mette K., Li, Zilong, Hjerresen, Jasmin Pernille, He, Shixu, Santander, Cindy G., Jensen, Rasmus Tanderup, Rex, Karsten Fleischer, Thuesen, Anne Cathrine Baun, Hanghj, Kristian, Seiding, Inge Hst, Jrsboe, Emil, Stinson, Sara Elizabeth, Rasmussen, Malthe Sebro, Balboa, Renzo F., Larsen, Christina Viskum Lytken, Bjerregaard, Peter, Schubert, Mikkel, Meisner, Jonas, Linneberg, Allan, Grarup, Niels, Zeggini, Eleftheria, Nielsen, Rasmus, Jrgensen, Marit E., Hansen, Torben, Moltke, Ida, Albrechtsen, Anders

Issue&Volume: 2025-02-12

Abstract: Greenlandic Inuit and other indigenous populations are underrepresented in genetic research1,2, leading to inequity in healthcare opportunities. To address this, we performed analyses of sequenced or imputed genomes of 5,996 Greenlanders with extensive phenotypes. We quantified their historical population bottleneck and how it has shaped their genetic architecture to have fewer, but more common, variable sites. Consequently, we find twice as many high-impact genome-wide associations to metabolic traits in Greenland compared with Europe. We infer that the high-impact variants arose after the population split from Native Americans and thus are Arctic-specific, and show that some of them are common due to not only genetic drift but also selection. We also find that European-derived polygenic scores for metabolic traits are only half as accurate in Greenlanders as in Europeans, and that adding Arctic-specific variants improves the overall accuracy to the same level as in Europeans. Similarly, lack of representation in public genetic databases makes genetic clinical screening harder in Greenlandic Inuit, but inclusion of Greenlandic data remedies this by reducing the number of non-causal candidate variants by sixfold. Finally, we identify pronounced genetic fine structure that explains differences in prevalence of monogenic diseases in Greenland and, together with recent changes in mobility, leads to a predicted future reduction in risk for certain recessive diseases. These results illustrate how including data from Greenlanders can greatly reduce inequity in genomic-based healthcare.

DOI: 10.1038/s41586-024-08516-4

Source: https://www.nature.com/articles/s41586-024-08516-4