Modern next-generation DNA sequencers support multiplex sequencing to improve throughput and decrease costs. This is done by pooling and sequencing samples together in parallel, which are later demultiplexed according to their unique indexes. When reads are assigned to the wrong index, called index cross-talk, information is leaked between samples. This creates a physical information side-channel, a well known class of vulnerabilities in information security, that may be used to modify

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... m results. Here we demonstrate the feasibility of such an attack through the use of a separately indexed library that causes a wild-type human exome to be misclassified as heterozygous at the sickle-cell locus. Simple methods can be used to minimize or detect attempts to modify genetic variants using this side-channel, such as filtering by read quality or finding outliers in read coverage. To further minimize this risk we recommend the use of new library preparation methods that reduce index cross-talk, like unique dual indexes, whenever samples are sequenced together in important applications. Biotechnology that interfaces molecular and digital information, like DNA sequencers, may have security risks typically associated with information systems, including the side-channel vulnerability described in this study. We encourage the community to consider the security of genomics-information pipelines before they reach mass adoption.