A ~ 1 Mb inversion polymorphism exists within the 17q21.31 locus of the human genome as direct (H1) and inverted (H2) haplotype clades. This inversion region demonstrates high linkage disequilibrium, but the frequency of each haplotype differs across ancestries. While the H1 haplotype exists in all populations and shows a normal pattern of genetic variability and recombination, the H2 haplotype is enriched in European ancestry populations, is less frequent in African ancestry populations, and nearly absent in East Asian ancestry populations. H1 is a known risk factor for several neurodegenerative diseases, and has been associated with many other traits, suggesting its importance in cellular phenotypes of the brain and entire body. Conversely, H2 is protective for these diseases, but is associated with predisposition to recurrent microdeletion syndromes and neurodevelopmental disorders such as autism. Many single nucleotide variants and copy number variants define H1/H2 haplotypes and sub-haplotypes, but identifying the causal variant(s) for specific diseases and phenotypes is complex due to the extended linkage equilibrium. In this review, we assess the current knowledge of this inversion region regarding genomic structure, gene expression, cellular phenotypes, and disease association. We discuss recent discoveries and challenges, evaluate gaps in knowledge, and highlight the importance of understanding the effect of the 17q21.31 haplotypes to promote advances in precision medicine and drug discovery for several diseases.

中文翻译：

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揭示含有 MAPT 的 H1 和 H2 单倍型在神经退行性疾病中的复杂作用


人类基因组的 17q21.31 位点内存在约 1 Mb 的倒位多态性，作为直接 (H1) 和倒位 (H2) 单倍型进化枝。该倒位区域表现出高度连锁不平衡，但每个单倍型的频率因祖先而异。虽然 H1 单倍型存在于所有人群中，并显示出正常的遗传变异和重组模式，但 H2 单倍型在欧洲血统人群中丰富，在非洲血统人群中较少见，在东亚血统人群中几乎不存在。 H1 是多种神经退行性疾病的已知危险因素，并且与许多其他特征相关，表明它在大脑和整个身体的细胞表型中的重要性。相反，H2 对这些疾病具有保护作用，但与复发性微缺失综合征和自闭症等神经发育障碍的易感性有关。许多单核苷酸变异和拷贝数变异定义了 H1/H2 单倍型和亚单倍型，但由于连锁平衡的扩展，识别特定疾病和表型的因果变异非常复杂。在这篇综述中，我们评估了目前对该反转区域有关基因组结构、基因表达、细胞表型和疾病关联的了解。我们讨论了最近的发现和挑战，评估了知识差距，并强调了了解 17q21.31 单倍型的作用对于促进多种疾病的精准医学和药物发现进展的重要性。