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Analyzing the association of SCNA boundaries with replication timing

Nature Biotechnology volume 30, pages 1045–1046 (2012)Cite this article

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De and Michor respond

Our paper1 analyzed DNA replication timing patterns at the two boundaries of somatic copy-number alterations (SCNAs) in a large number of cancer samples and reported that, in general, these boundaries tend to be replicated at the same time during cell division. We found that the observed frequency of such events is significantly higher than the pattern expected by chance, based upon two independent statistical strategies: Fisher's test and a permutation analysis. Bilke and Ginden2 now highlight the fact that although individual replication timing domains are typically short, the human genome contains many higher-order replication timing structures, wherein long stretches of early- or late-replicating domains are interrupted only briefly by short regions with different replication timing. They argue that ignoring such structures would lead to an overestimation of the association between replication timing and SCNA boundaries, and therefore they prefer permutation analyses to Fisher's test. Nevertheless, when Bilke and Ginden2 repeat our analyses, they reproduce the published results and confirm the q value of <1 × 10−5 that we reported1. They caution, however, that the statistical significance of the permutation analysis could be driven by the large size of the data set and might decrease when unknown biases are taken into account (for example, permutation across chromosomes instead of within chromosomes).

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Figure 1: The distribution of observed/expected values obtained using a simple permutation approach for SCNAs grouped according to their size, with permutation performed within chromosomes.
Figure 2: Comparison of the enrichment using Fisher's test and permutation test for SCNAs of length > 5 Mb.
Figure 3: The distribution of observed/expected values obtained using a simple permutation approach for SCNAs grouped according to their size, with permutation performed across chromosomes.

References

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Authors and Affiliations

  1. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Subhajyoti De & Franziska Michor

  2. Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA

    Subhajyoti De & Franziska Michor

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  1. Subhajyoti De
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  2. Franziska Michor
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Correspondence to Franziska Michor.

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De, S., Michor, F. Analyzing the association of SCNA boundaries with replication timing. Nat Biotechnol 30, 1045–1046 (2012). https://doi.org/10.1038/nbt.2414

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