PDF(Pubmed)
Abstract：
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.
摘要：
人类基因组的17q21.31基因座中存在一个〜1Mb反转多态性，作为直接（H1）和反向（H2）单倍型进化枝。这个反转区显示出高度的连锁不平衡，但是每个单倍型的频率在不同祖先之间是不同的。虽然H1单倍型存在于所有种群中，并显示出正常的遗传变异和重组模式，H2单倍型在欧洲血统人群中丰富，在非洲祖先人群中频率较低，在东亚祖先人群中几乎不存在。H1是几种神经退行性疾病的已知危险因素，并与许多其他特征有关，表明其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。许多单核苷酸变体和拷贝数变体定义H1/H2单倍型和亚单倍型。但是，由于扩展的连锁平衡，确定特定疾病和表型的因果变异是复杂的。在这次审查中,我们评估了关于基因组结构的这个反转区的当前知识，基因表达，细胞表型，和疾病关联。我们讨论最近的发现和挑战，评估知识差距，并强调了了解17q21.31单倍型对促进精准医学和几种疾病药物发现进展的重要性。
