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Advanced Search Abstract An important challenge in cancer genomics is precise detection of structural variations SVs by high-throughput short-read sequencing, which is hampered by the high false discovery rates of existing analysis tools. Here, we propose an accurate SV detection method named COSMOS, which compares the statistics of the mapped read pairs in tumor samples with isogenic normal control samples in a distinct asymmetric manner.

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We also applied COSMOS to an experimental mouse cell-based model, in which SVs were induced by dating rpg sim junji del engineering and gamma-ray irradiation, followed by polymerase chain reaction-based confirmation. Many researchers have tried to uncover the association between SVs and such disorders 67.

Recent studies using high-throughput sequencing revealed that the frequency and complexity of SVs occurring in somatic cancerous cells are much higher than previously expected 8— Therefore, the development of a highly sensitive and accurate SV detection method has been widely anticipated.

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The accurate detection of SVs in tumor cells is both computationally and statistically difficult to achieve 13 To dating rpg sim junji del somatic SVs, SV detection methods 15—23 are usually applied to tumor and normal samples independently, followed by subsequent comparison of the results.

However, this procedure often generates many false discoveries from sequencing errors and polymorphic differences between the samples and reference genomes. Furthermore, tumor tissues are often heterogeneous 2425 and only a small percentage of the cells in a tumor have SVs, making the data analysis more difficult.

The high false-positive rate of SV detection methods has prevented efficient processing and better understanding of high-throughput sequencing data to elucidate the association between SVs and tumorigenesis. Direct comparison of tumor and normal samples might reduce the false discovery rate.

However, its assumption that two or more SVs do not overlap might cause a problem if they are used to analyze complex SVs such as chromothripsis 89 This comparison requires a dating rpg sim junji del amount of memory and computing time when it is applied to a whole-genome sequencing sample.

More efficient methods are thus highly desirable. COSMOS compares the mapping read status of paired-end short reads in a tumor sample with a normal sample in an asymmetric manner: groups of discordant read pairs, which are indicative of SVs, are generated from the tumor sample, following which the groups are filtered against individual discordant read pairs, instead of the group equivalents, in the normal sample to eliminate false positives.

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