Fickelscher Ina, Liehr Thomas, Watts Kathryn, Bryant Victoria, Barber John C K, Heidemann Simone, Siebert Reiner, Hertz Jens Michael, Tumer Zeynep, Simon Thomas N
Institut fur Humangenetik und Anthropologie, Friedrich-Schiller University, Jena, Germany.
Am J Hum Genet. 2007 Oct;81(4):847-56. doi: 10.1086/521226. Epub 2007 Aug 28.
Human chromosome 2 contains large blocks of segmental duplications (SDs), both within and between proximal 2p and proximal 2q, and these may contribute to the frequency of the common variant inversion inv(2)(p11.2q13). Despite their being cytogenetically homogeneous, we have identified four different breakpoint combinations by fluorescence in situ hybridization mapping of 40 cases of inv(2)(p11.2q13) of European origin. For the vast majority of inversions (35/40), the breakpoints fell within the same spanning BACs, which hybridized to both 2p11.2 and 2q13 on the normal and inverted homologues. Sequence analysis revealed that these BACs contain a significant proportion of intrachromosomal SDs with sequence homology to the reciprocal breakpoint region. In contrast, BACs spanning the rare breakpoint combinations contain fewer SDs and with sequence homology only to the same chromosome arm. Using haplotype analysis, we identified a number of related family subgroups with identical or very closely related haplotypes. However, the majority of cases were not related, demonstrating for the first time that the inv(2)(p11.2q13) is a truly recurrent rearrangement. Therefore, there are three explanations to account for the frequent observation of the inv(2)(p11.2q13): the majority have arisen independently in different ancestors, while a minority either have been transmitted from a common founder or have different breakpoints at the molecular cytogenetic level.
人类2号染色体包含大量节段性重复（SDs），存在于近端2p和近端2q内部以及它们之间，这些可能导致常见变异倒位inv(2)(p11.2q13)的出现频率。尽管它们在细胞遗传学上是同质的，但我们通过对40例欧洲起源的inv(2)(p11.2q13)进行荧光原位杂交定位，确定了四种不同的断点组合。对于绝大多数倒位（35/40），断点落在相同的连续BAC内，这些BAC在正常和倒位同源染色体上均与2p11.2和2q13杂交。序列分析表明，这些BAC包含大量与相互断点区域具有序列同源性的染色体内SDs。相比之下，跨越罕见断点组合的BAC包含较少的SDs，且仅与同一条染色体臂具有序列同源性。通过单倍型分析，我们确定了一些具有相同或非常密切相关单倍型的相关家族亚组。然而，大多数病例并无关联，这首次证明inv(2)(p11.2q13)是一种真正反复出现的重排。因此，对于inv(2)(p11.2q13)频繁出现的现象有三种解释：大多数是在不同祖先中独立出现的，而少数要么是由共同的奠基者遗传而来，要么在分子细胞遗传学水平上具有不同的断点。
