High-resolution genomic profiling of chromosomal aberrations using Infinium whole-genome genotyping
High-resolution genomic profiling of chromosomal aberrations using Infinium whole-genome genotyping
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DOI：
10.1101/gr.5402306
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发表时间：
2006-09-01
期刊：
影响因子：
7
通讯作者：
Gunderson, Kevin L.
中科院分区：
文献类型：
--
作者：
Peiffer, Daniel A.;Le, Jennie M.;Gunderson, Kevin L.
Array-CGH 是检测染色体畸变的强大工具。将高密度 SNP 基因分型技术引入基因组分析（称为 SNP-CGH）代表了进一步的进步，因为同时测量信号强度变化和等位基因组成的变化使得可以检测拷贝数变化和拷贝中性杂合性丢失 (LOH) 事件。我们展示了 SNP-CGH 与两个 Infinium 全基因组基因分型 BeadChip 的实用性，可检测 109,000 和 317,000 个 SNP 位点，以低于 100 kb 的有效分辨率检测具有体质畸变的样品以及肿瘤样品中的染色体畸变。检测到的畸变包括纯合缺失、半合缺失、拷贝中性 LOH、重复和扩增。通过分析 X 染色体滴定模型系统来模拟检测常见畸变的统计能力，并通过滴定来自肿瘤细胞的 gDNA 与其配对的正常细胞系的 gDNA 来模拟灵敏度。通过使用基因组浏览器来促进分析，该浏览器绘制沿染色体的归一化强度和等位基因比率的对数比率。我们开发了两种 SNP-CGH 分析模式：单一样本模式和配对样本模式。单样本模式通过参考从相似的 120 个参考样本生成的典型基因型簇来计算对数强度比和等位基因比，而配对样本模式则使用来自同一个体的配对正常参考样本。最后，比较了两种分析模式在分析不同类型输入 gDNA 时的效用：低输入量、片段化 gDNA 和 Phi29 全基因组预扩增 DNA。
Array-CGH is a powerful tool for the detection of chromosomal aberrations. The introduction of high-density SNP genotyping technology to genomic profiling, termed SNP-CGH, represents a further advance, since simultaneous measurement of both signal intensity variations and changes in allelic composition makes it possible to detect both copy number changes and copy-neutral loss-of-heterozygosity ( LOH) events. We demonstrate the utility of SNP-CGH with two Infinium whole-genome genotyping BeadChips, assaying 109,000 and 317,000 SNP loci, to detect chromosomal aberrations in samples bearing constitutional aberrations as well tumor samples at sub-100 kb effective resolution. Detected aberrations include homozygous deletions, hemizygous deletions, copy-neutral LOH, duplications, and amplifications. The statistical ability to detect common aberrations was modeled by analysis of an X chromosome titration model system, and sensitivity was modeled by titration of gDNA from a tumor cell with that of its paired normal cell line. Analysis was facilitated by using a genome browser that plots log ratios of normalized intensities and allelic ratios along the chromosomes. We developed two modes of SNP-CGH analysis, a single sample and a paired sample mode. The single sample mode computes log intensity ratios and allelic ratios by referencing to canonical genotype clusters generated from similar to 120 reference samples, whereas the paired sample mode uses a paired normal reference sample from the same individual. Finally, the two analysis modes are compared and contrasted for their utility in analyzing different types of input gDNA: low input amounts, fragmented gDNA, and Phi29 whole-genome pre-amplified DNA.