Distinct Mutational Behaviors Differentiate Short Tandem Repeats from Microsatellites in the Human Genome
Distinct Mutational Behaviors Differentiate Short Tandem Repeats from Microsatellites in the Human Genome
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DOI：
10.1093/gbe/evs116
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发表时间：
2013-01-01
影响因子：
3.3
通讯作者：
Makova, Kateryna D.
中科院分区：
文献类型：
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作者：
Ananda, Guruprasad;Walsh, Erin;Makova, Kateryna D.
串联重复序列（TR）的突变倾向随着重复序列数量的增加而增加，并且在超过临界边界时变得非常明显，将其转化为微卫星（MS）。然而，人们对不同类型的TR和基序的突变行为及其相关机制缺乏清晰的认识，也没有就短TR和长TR之间是否存在界限达成共识。这阻碍了我们对MSs突变特性的理解和它们作为遗传标记的有效利用。利用来自1000 Genomes Pilot-1 Project的179个个体的indel call，确定了4个主要TR类别的多态性发生率，并利用分段回归形式化了其与重复数的变化关系。我们观察到单核苷酸、二核苷酸、三核苷酸和四核苷酸分别在9、5、4和4次重复时从更快到更慢的指数增长转变为双相体制。我们使用体外诱变实验来评估链滑移错误对易变性的贡献。str和MSs的绝对多态性水平不同，但更重要的是它们的变异增长率不同。尽管链滑移是驱动单核苷酸多态性发生的主要因素，但由于链滑移，二核苷酸多态性的发生率高于预期，这表明可能有其他细胞因素驱动人类基因组中二核苷酸的易变性。利用数百个人类基因组，我们提出了第一个全面的，全基因组的TR突变行为分析，包括几个基序大小和组成。
A tandem repeat's (TR) propensity to mutate increases with repeat number, and can become very pronounced beyond a critical boundary, transforming it into a microsatellite (MS). However, a clear understanding of the mutational behavior of different TR classes and motifs and related mechanisms is lacking, as is a consensus on the existence of a boundary separating short TRs (STRs) from MSs. This hinders our understanding of MSs' mutational properties and their effective use as genetic markers. Using indel calls for 179 individuals from 1000 Genomes Pilot-1 Project, we determined polymorphism incidence for four major TR classes, and formalized its varying relationship with repeat number using segmented regression. We observed a biphasic regime with a transition from a faster to a slower exponential growth at 9, 5, 4, and 4 repeats for mono-, di-, tri-, and tetranucleotide TRs, respectively. We used an in vitro mutagenesis assay to evaluate the contribution of strand slippage errors to mutability. STRs and MSs differ in their absolute polymorphism levels, but more importantly in their rates of mutability growth. Although strand slippage is a major factor driving mononucleotide polymorphism incidence, dinucleotide polymorphism incidence is greater than that expected due to strand slippage alone, indicating that additional cellular factors might be driving dinucleotide mutability in the human genome. Leveraging on hundreds of human genomes, we present the first comprehensive, genome-wide analysis of TR mutational behavior, encompassing several motif sizes and compositions.