Weighted pooling--practical and cost-effective techniques for pooled high-throughput sequencing.
Weighted pooling--practical and cost-effective techniques for pooled high-throughput sequencing.
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DOI：
10.1093/bioinformatics/bts208
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发表时间：
2012-06-15
期刊：
影响因子：
--
通讯作者：
Rosset S
中科院分区：
文献类型：
--
作者：
Golan D;Erlich Y;Rosset S
动机：尽管测序成本迅速下降，但对大量个体进行测序仍然非常昂贵。最近，提出了几种复杂的合并设计，其可以在具有显著较小数量的池的大群组中识别稀有等位基因的携带者，从而显著降低这种大规模测序项目的成本。这些方法使用组合合并设计，其中每个个体存在或不存在于池中。然后，可以推断池中的载波数量，并通过组合跨池的信息，重建载波的身份。结果如下：我们表明，可以获得进一步的效率和成本降低，通过使用“加权”的设计，其中不同的个人捐赠不同量的DNA池。直觉上，在这种情况下，池中突变体读段的数量不仅指示携带者的数量，而且指示它们的身份。我们描述和研究一个强大的例子，这样的加权设计，使用非重叠池。我们证明，这种方法不仅更容易实现和分析，但也有竞争力的准确性与组合设计时，确定罕见的变异，是上级常见的变异测序。然后，我们讨论如何加权可以纳入现有的组合设计，以提高其准确性，并证明使用模拟所产生的改善。最后，我们认为加权设计有足够的能力来促进常见等位基因的检测，因此它们可以用作全外显子组测序项目的基石。联系方式：saharon@post.tau.ac.il
Motivation: Despite the rapid decline in sequencing costs, sequencing large cohorts of individuals is still prohibitively expensive. Recently, several sophisticated pooling designs were suggested that can identify carriers of rare alleles in large cohorts with a significantly smaller number of pools, thus dramatically reducing the cost of such large-scale sequencing projects. These approaches use combinatorial pooling designs where each individual is either present or absent from a pool. One can then infer the number of carriers in a pool, and by combining information across pools, reconstruct the identity of the carriers. Results: We show that one can gain further efficiency and cost reduction by using ‘weighted’ designs, in which different individuals donate different amounts of DNA to the pools. Intuitively, in this situation, the number of mutant reads in a pool does not only indicate the number of carriers, but also their identity. We describe and study a powerful example of such weighted designs, using non-overlapping pools. We demonstrate that this approach is not only easier to implement and analyze but is also competitive in terms of accuracy with combinatorial designs when identifying rare variants, and is superior when sequencing common variants. We then discuss how weighting can be incorporated into existing combinatorial designs to increase their accuracy and demonstrate the resulting improvement using simulations. Finally, we argue that weighted designs have enough power to facilitate detection of common alleles, so they can be used as a cornerstone of whole-exome sequencing projects. Contact: saharon@post.tau.ac.il
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