Estimation and assessment of raw copy numbers at the single locus level
Estimation and assessment of raw copy numbers at the single locus level
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DOI：
10.1093/bioinformatics/btn016
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发表时间：
2008-03-01
期刊：
影响因子：
5.8
通讯作者：
Speed, T. P.
中科院分区：
文献类型：
--
作者：
Bengtsson, H.;Irizarry, R.;Speed, T. P.
动机：尽管已知拷贝数畸变有助于人类DNA的多样性并导致各种疾病，但许多畸变及其表型仍有待探索。单核苷酸多态性（SNP）阵列的最新发展为研究人员提供了比几年前更高数量级分辨率的基因型和染色体畸变识别工具。在基于阵列的拷贝数（CN）分析的基本问题是获得CN估计在一个单位点的分辨率具有高的准确性和精度，使下游分割方法更有可能success.Results：我们提出了一种预处理方法估计原始CN从Affyssoft SNP阵列。它的核心利用了类似于高密度寡核苷酸表达阵列的多芯片探针级模型。我们通过增加对序列特异性等位基因不平衡的调整来扩展该模型，例如等位基因A和等位基因B探针之间的交叉杂交。我们专注于总CN估计，这使我们能够进一步约束探针级模型，以增加CN估计的信噪比。通过控制PCR效应获得进一步的改进。模型的每一部分都是鲁棒拟合的。通过在单基因座分辨率（27 kb）至200 kb分辨率下对单独的氯化萘粗品区分X染色体（ChrX）上的一个和两个拷贝的能力进行定量评估。评估是用公开的HapMap数据完成的。
Motivation: Although copy-number aberrations are known to contribute to the diversity of the human DNA and cause various diseases, many aberrations and their phenotypes are still to be explored. The recent development of single-nucleotide polymorphism (SNP) arrays provides researchers with tools for calling genotypes and identifying chromosomal aberrations at an order-of-magnitude greater resolution than possible a few years ago. The fundamental problem in array-based copy-number (CN) analysis is to obtain CN estimates at a single-locus resolution with high accuracy and precision such that downstream segmentation methods are more likely to succeed.Results: We propose a preprocessing method for estimating raw CNs from Affymetrix SNP arrays. Its core utilizes a multichip probe-level model analogous to that for high-density oligonucleotide expression arrays. We extend this model by adding an adjustment for sequence-specific allelic imbalances such as cross-hybridization between allele A and allele B probes. We focus on total CN estimates, which allows us to further constrain the probe-level model to increase the signal-to-noise ratio of CN estimates. Further improvement is obtained by controlling for PCR effects. Each part of the model is fitted robustly. The performance is assessed by quantifying how well raw CNs alone differentiate between one and two copies on Chromosome X (ChrX) at a single-locus resolution (27kb) up to a 200kb resolution. The evaluation is done with publicly available HapMap data.