Genomic variation within alpha satellite DNA influences centromere location on human chromosomes with metastable epialleles.
Genomic variation within alpha satellite DNA influences centromere location on human chromosomes with metastable epialleles.
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DOI：
10.1101/gr.206706.116
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发表时间：
2016-10
期刊：
影响因子：
7
通讯作者：
Sullivan BA
中科院分区：
文献类型：
--
作者：
Aldrup-MacDonald ME;Kuo ME;Sullivan LL;Chew K;Sullivan BA
阿尔法卫星是一种串联组织的重复DNA，占基因组的5%，存在于所有人类着丝粒中。确定数量的171-bp单体被组织成染色体特异性高阶重复序列（HOR），重复数千次。至少有一半的人类染色体在其着丝粒区域内具有两个或更多个不同的HOR α随体阵列。我们先前表明，智人17号染色体（HSA 17）的两个α卫星阵列，D17 Z1和D17 Z1-B，表现为着丝粒表观等位基因，即，由含有着丝粒组蛋白变体CENPA的染色质和其他着丝粒蛋白的募集定义的着丝粒，可以在D17 Z1或D17 Z1-B形成。人类群体中的一些个体是功能性杂合子，因为D17 Z1在一个同源物上是活性着丝粒，而D17 Z1-B在另一个同源物上是活性着丝粒。在这项研究中，我们的目的是了解着丝粒的位置是如何确定HSA 17的分子基础。具体而言，我们专注于D17 Z1基因组变异作为表观等位基因形成的驱动因素。我们发现主要由HOR大小和序列变体组成的D17 Z1阵列在功能上不太胜任。他们要么招募了减少量的着丝粒特异性组蛋白变体CENPA，HSA 17在有丝分裂中不稳定，要么着丝粒在D17 Z1-B组装，HSA 17稳定。我们的研究表明，人类着丝粒区域的高度重复的非编码DNA内的基因组变异对基因组稳定性和基本的染色体功能具有显著的影响。
Alpha satellite is a tandemly organized type of repetitive DNA that comprises 5% of the genome and is found at all human centromeres. A defined number of 171-bp monomers are organized into chromosome-specific higher-order repeats (HORs) that are reiterated thousands of times. At least half of all human chromosomes have two or more distinct HOR alpha satellite arrays within their centromere regions. We previously showed that the two alpha satellite arrays of Homo sapiens Chromosome 17 (HSA17), D17Z1 and D17Z1-B, behave as centromeric epialleles, that is, the centromere, defined by chromatin containing the centromeric histone variant CENPA and recruitment of other centromere proteins, can form at either D17Z1 or D17Z1-B. Some individuals in the human population are functional heterozygotes in that D17Z1 is the active centromere on one homolog and D17Z1-B is active on the other. In this study, we aimed to understand the molecular basis for how centromere location is determined on HSA17. Specifically, we focused on D17Z1 genomic variation as a driver of epiallele formation. We found that D17Z1 arrays that are predominantly composed of HOR size and sequence variants were functionally less competent. They either recruited decreased amounts of the centromere-specific histone variant CENPA and the HSA17 was mitotically unstable, or alternatively, the centromere was assembled at D17Z1-B and the HSA17 was stable. Our study demonstrates that genomic variation within highly repetitive, noncoding DNA of human centromere regions has a pronounced impact on genome stability and basic chromosomal function.
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影响因子：
7
作者：
Miga KH;Newton Y;Jain M;Altemose N;Willard HF;Kent WJ
通讯作者：
Kent WJ
影响因子：
64.5
作者：
Okada, Teruaki;Ohzeki, Jun-Ichirou;Masumoto, Hiroshi
通讯作者：
Masumoto, Hiroshi
影响因子：
4.4
作者：
MAHTANI, MM;WILLARD, HF
通讯作者：
WILLARD, HF
影响因子：
1.6
作者：
EARNSHAW, WC;RATRIE, H;STETTEN, G
通讯作者：
STETTEN, G
影响因子：
1.6
作者：
ALEXANDROV, IA;MITKEVICH, SP;YUROV, YB
通讯作者：
YUROV, YB