LINE- and Alu-containing genomic instability hotspot at 16q24.1 associated with recurrent and nonrecurrent CNV deletions causative for ACDMPV.
LINE- and Alu-containing genomic instability hotspot at 16q24.1 associated with recurrent and nonrecurrent CNV deletions causative for ACDMPV.
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DOI：
10.1002/humu.23608
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发表时间：
2018-12
期刊：
影响因子：
3.9
通讯作者：
Stankiewicz P
中科院分区：
文献类型：
--
作者：
Szafranski P;Kośmider E;Liu Q;Karolak JA;Currie L;Parkash S;Kahler SG;Roeder E;Littlejohn RO;DeNapoli TS;Shardonofsky FR;Henderson C;Powers G;Poisson V;Bérubé D;Oligny L;Michaud JL;Janssens S;De Coen K;Van Dorpe J;Dheedene A;Harting MT;Weaver MD;Khan AM;Tatevian N;Wambach J;Gibbs KA;Popek E;Gambin A;Stankiewicz P
转座元件通过插入新基因座或通过介导同源、微同源或同源驱动的 DNA 重组或修复来修饰人类基因组，从而导致基因组结构变异。肺泡毛细血管发育不良伴肺静脉错位 (ACDMPV) 是一种罕见的致命性新生儿发育性肺疾病，由 FOXF1 或其远端组织特异性增强子的点突变或拷贝数变异 (CNV) 缺失引起。 45 个 ACDMPV 致病性 CNV 缺失（其中连接点已被测序）中，85% 的两个断点中至少有一个位于逆转录转座子中，其中一半以上是 Alu 元件。我们描述了 16q24.1 处一个新的约 35 kb 大的基因组不稳定热点，涉及两个进化上年轻的 LINE-1(L1) 元件，L1PA2 和 L1PA3，侧翼的 AluY，两个 AluSx、AluSx1 和 AluJr 元件。 L1 在这个位置的出现与泛人大猩猩分支的分支相一致，并且先于 AluSx、AluSx1 和 AluJr 的插入。我们的数据表明，除了介导复发性 CNV 之外，L1 和 Alu 逆转录转座子还可以使人类基因组倾向于形成不同大小的 CNV，这与临床和进化相关。尽管如此，该位点的表观遗传或其他基因组特征也可能导致其不稳定性增加。
Transposable elements modify human genome by inserting into new loci or by mediating homology-, microhomology-, or homeology-driven DNA recombination or repair, resulting in genomic structural variation. Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a rare, lethal, neonatal developmental lung disorder caused by point mutations or copy-number variant (CNV) deletions of FOXF1 or its distant tissue-specific enhancer. Eighty five per cent of 45 ACDMPV-causative CNV deletions, of which junctions have been sequenced, had at least one of their two breakpoints located in a retrotransposon, with more than half of them being Alu elements. We describe a novel ~35 kb-large genomic instability hotspot at 16q24.1, involving two evolutionarily young LINE-1(L1) elements, L1PA2 and L1PA3, flanking AluY, two AluSx, AluSx1, and AluJr elements. The occurrence of L1s at this location coincided with the branching out of the Homo-Pan-Gorilla clade, and was preceded by the insertion of AluSx, AluSx1, and AluJr. Our data show that, in addition to mediating recurrent CNVs, L1 and Alu retrotransposons can predispose the human genome to formation of variably sized CNVs, both of clinical and evolutionary relevance. Nonetheless, epigenetic or other genomic features of this locus might also contribute to its increased instability.
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DOI：
10.1146/annurev-genom-082509-141802
发表时间：
2011
影响因子：
8.7
作者：
Beck CR;Garcia-Perez JL;Badge RM;Moran JV
通讯作者：
Moran JV
影响因子：
4.5
作者：
de Koning AP;Gu W;Castoe TA;Batzer MA;Pollock DD
通讯作者：
Pollock DD
影响因子：
4.9
作者：
Hancks DC;Kazazian HH Jr
通讯作者：
Kazazian HH Jr
影响因子：
3.5
作者：
Gu, Shen;Yuan, Bo;Lupski, James R.
通讯作者：
Lupski, James R.
影响因子：
12.3
作者：
Billings, Timothy;Parvanov, Emil D.;Petkov, Petko M.
通讯作者：
Petkov, Petko M.