Resolving individuals contributing trace amounts of DNA to highly complex mixtures using high-density SNP genotyping microarrays.
Resolving individuals contributing trace amounts of DNA to highly complex mixtures using high-density SNP genotyping microarrays.
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DOI：
10.1371/journal.pgen.1000167
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发表时间：
2008-08-29
期刊：
影响因子：
4.5
通讯作者：
Craig DW
中科院分区：
文献类型：
--
作者：
Homer N;Szelinger S;Redman M;Duggan D;Tembe W;Muehling J;Pearson JV;Stephan DA;Nelson SF;Craig DW
我们使用高密度单核苷酸多态性（SNP）基因分型微阵列，以证明准确和稳健地确定个体是否在一个复杂的基因组DNA混合物的能力。我们首先开发了一个理论框架，用于检测一个人的存在下的混合物，然后显示，通过模拟，与我们的方法相关联的限制，并最终证明实验识别特定个体的基因组DNA的存在下的一系列高度复杂的基因组混合物，包括混合物中的个人贡献小于0.1%的总基因组DNA。这些发现改变了SNP在法医混合物中识别单个痕量贡献者的感知效用，并建议未来的研究工作评估由于样品污染而导致的先前次优DNA来源的可行性。这些发现还表明，跨队列的综合统计数据，如等位基因频率或基因型计数，不会掩盖全基因组关联研究中的身份。这些研究结果的影响进行了讨论。在这份报告中，我们描述了一个框架，准确和强大的解决个人是否在一个复杂的基因组DNA混合物使用高密度单核苷酸多态性（SNP）基因分型微阵列。我们开发了一个理论框架，用于检测混合物中个体的存在，通过模拟显示其限制，并最终通过实验证明在一系列高度复杂的基因组混合物中个体基因组DNA的存在的识别。我们的方法证明了在复杂的混合物中直接识别来自单个贡献者的痕量（<1%）DNA。我们展示了如何探针强度分析的高密度SNP数据可以使用，即使是实验噪声的微阵列。我们讨论了这些发现在两个领域的影响：法医学和全基因组关联（GWA）遗传研究。在法医学中，确定一个人是否向复杂的混合物中贡献了微量的基因组DNA是一个巨大的挑战。在GWA研究中，有相当大的推动力使实验数据公开，以便数据可以与其他研究相结合。我们的研究结果表明，这种方法并不完全隐藏身份，因为它是直接评估的概率，一个人或亲戚参加了GWA研究。
We use high-density single nucleotide polymorphism (SNP) genotyping microarrays to demonstrate the ability to accurately and robustly determine whether individuals are in a complex genomic DNA mixture. We first develop a theoretical framework for detecting an individual's presence within a mixture, then show, through simulations, the limits associated with our method, and finally demonstrate experimentally the identification of the presence of genomic DNA of specific individuals within a series of highly complex genomic mixtures, including mixtures where an individual contributes less than 0.1% of the total genomic DNA. These findings shift the perceived utility of SNPs for identifying individual trace contributors within a forensics mixture, and suggest future research efforts into assessing the viability of previously sub-optimal DNA sources due to sample contamination. These findings also suggest that composite statistics across cohorts, such as allele frequency or genotype counts, do not mask identity within genome-wide association studies. The implications of these findings are discussed. In this report we describe a framework for accurately and robustly resolving whether individuals are in a complex genomic DNA mixture using high-density single nucleotide polymorphism (SNP) genotyping microarrays. We develop a theoretical framework for detecting an individual's presence within a mixture, show its limits through simulation, and finally demonstrate experimentally the identification of the presence of genomic DNA of individuals within a series of highly complex genomic mixtures. Our approaches demonstrate straightforward identification of trace amounts (<1%) of DNA from an individual contributor within a complex mixture. We show how probe-intensity analysis of high-density SNP data can be used, even given the experimental noise of a microarray. We discuss the implications of these findings in two fields: forensics and genome-wide association (GWA) genetic studies. Within forensics, resolving whether an individual is contributing trace amounts of genomic DNA to a complex mixture is a tremendous challenge. Within GWA studies, there is a considerable push to make experimental data publicly available so that the data can be combined with other studies. Our findings show that such an approach does not completely conceal identity, since it is straightforward to assess the probability that a person or relative participated in a GWA study.
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