What is a microsatellite: a computational and experimental definition based upon repeat mutational behavior at A/T and GT/AC repeats.
What is a microsatellite: a computational and experimental definition based upon repeat mutational behavior at A/T and GT/AC repeats.
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DOI：
10.1093/gbe/evq046
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发表时间：
2010
影响因子：
3.3
通讯作者：
Makova KD
中科院分区：
文献类型：
--
作者：
Kelkar YD;Strubczewski N;Hile SE;Chiaromonte F;Eckert KA;Makova KD
微卫星在真核生物基因组中大量存在，并且具有高比率的链滑动诱导的重复数改变。它们是流行的遗传标记，它们的突变与许多神经系统疾病有关。然而，构成微卫星所需的最小重复次数一直存在争议，并且缺乏考虑其突变行为的微卫星定义。为了定义一个微卫星，我们研究了一系列重复大小的滑移动力学，利用两种方法。在计算上，我们评估了长度多态性重复基因座在10个ENCODE地区重新测序的四个人群，假设多态性的发生反映了链滑移率。实验上，我们确定了体外DNA聚合酶介导的链滑移错误率作为重复数的函数。在这两种方法中，我们比较了在串联重复的背景滑移率的链滑移率。我们观察到两种不同的突变行为模式。在小的重复次数，滑脱率低，从背景测量无法区分。随着重复序列的延长，观察到突变性的显著转变，使得在大重复数下的滑移率显著高于背景速率。对于所研究的单核苷酸和二核苷酸微卫星，过渡长度对应于类似数量的核苷酸（约10）。因此，微卫星阈值不是由重复序列中存在/不存在链滑移决定的，而是由相对于背景的滑移率的突然改变决定的。这些发现对于理解微卫星诱变、全基因组微卫星分析的标准化以及预测单个微卫星位点的多态性水平具有重要意义。
Microsatellites are abundant in eukaryotic genomes and have high rates of strand slippage-induced repeat number alterations. They are popular genetic markers, and their mutations are associated with numerous neurological diseases. However, the minimal number of repeats required to constitute a microsatellite has been debated, and a definition of a microsatellite that considers its mutational behavior has been lacking. To define a microsatellite, we investigated slippage dynamics for a range of repeat sizes, utilizing two approaches. Computationally, we assessed length polymorphism at repeat loci in ten ENCODE regions resequenced in four human populations, assuming that the occurrence of polymorphism reflects strand slippage rates. Experimentally, we determined the in vitro DNA polymerase-mediated strand slippage error rates as a function of repeat number. In both approaches, we compared strand slippage rates at tandem repeats with the background slippage rates. We observed two distinct modes of mutational behavior. At small repeat numbers, slippage rates were low and indistinguishable from background measurements. A marked transition in mutability was observed as the repeat array lengthened, such that slippage rates at large repeat numbers were significantly higher than the background rates. For both mononucleotide and dinucleotide microsatellites studied, the transition length corresponded to a similar number of nucleotides (approximately 10). Thus, microsatellite threshold is determined not by the presence/absence of strand slippage at repeats but by an abrupt alteration in slippage rates relative to background. These findings have implications for understanding microsatellite mutagenesis, standardization of genome-wide microsatellite analyses, and predicting polymorphism levels of individual microsatellite loci.
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影响因子：
30.8
作者：
CHU, CS;TRAPNELL, BC;CRYSTAL, RG
通讯作者：
CRYSTAL, RG
影响因子：
5.8
作者：
Baldi, P;Baisnée, PF
通讯作者：
Baisnée, PF
影响因子：
2
作者：
DEWACHTER, R
通讯作者：
DEWACHTER, R
影响因子：
9.8
作者：
Brinkmann, B;Klintschar, M;Rolf, B
通讯作者：
Rolf, B
影响因子：
7
作者：
Chen, Ken;McLellan, Michael D.;Mardis, Elaine R.
通讯作者：
Mardis, Elaine R.