Supplementary Material for: Recurrent Inversion Events at 17q21.31 Microdeletion Locus Are Linked to the <i>MAPT</i> H2 Haplotype
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The chromosomal band 17q21.31, containing the microtubule-associated protein tau <i>(MAPT)</i> gene, is a hotspot for chromosomal rearrangements. It is known to contain a common inversion polymorphism of approximately 900 kb in populations with European ancestry. The inverted configuration is linked to a distinct <i>MAPT</i> haplotype, H2, which is relatively common in Europeans but nearly absent in Asian and African populations. Recent studies have demonstrated that the H2 haplotype is ancestral in hominoids, and under positive selection in Europeans. This haplotype is also linked to events leading to the 17q21.31 microdeletion syndrome, one of the most common causes of ‘idiopathic’ mental retardation in people of European descent. We performed direct analysis of the chromosome structure by fluorescence in situ hybridization and observed heterozygosity of the inversion status for the H2 chromosomes, but not for the H1 haplotype. Inversion heterozygosity was also observed in a mother homozygous for the H2 haplotype, who transmitted the chromosome with the deletion to a proband with 17q21.31 microdeletion syndrome. Our results highlight an allele-specific sensitivity to chromosome rearrangements and suggest that it is the heterozygosity of inversion status that predisposes to the 17q21.31 microdeletion syndrome.
包含微管相关蛋白tau（microtubule-associated protein tau, MAPT）基因的17q21.31染色体带是染色体重排的热点区域。已知在欧洲血统人群中，该区域存在一段长度约900kb的常见倒位多态性（inversion polymorphism）。该倒位构型与独特的MAPT单倍型（haplotype）H2相关联：H2单倍型在欧洲人群中较为常见，但在亚洲与非洲人群中几乎不存在。近期研究证实，H2单倍型是人猿总科（hominoids）的祖先单倍型，并在欧洲人群中受到正选择作用。该单倍型还与引发17q21.31微缺失综合征的事件相关，而17q21.31微缺失综合征是欧洲血统人群"特发性"智力障碍最常见的致病原因之一。我们通过荧光原位杂交（fluorescence in situ hybridization, FISH）对染色体结构开展直接分析，观察到H2染色体存在倒位状态的杂合性（heterozygosity），但H1单倍型未出现该特征。我们还在一名H2单倍型纯合的母亲体内观察到倒位杂合性，该母亲将携带缺失的染色体传递给了一名患有17q21.31微缺失综合征的先证者（proband）。本研究结果凸显了染色体重排的等位基因特异性敏感性，并表明倒位状态的杂合性是17q21.31微缺失综合征的易感诱因。
