Unique molecular identifiers (UMIs) show outstanding performance in targeted high-throughput resequencing, being the most promising approach for the accurate identification of rare variants in complex DNA samples. This approach has application in multiple areas, including cancer diagnostics, thus demanding dedicated software and algorithms. Here we introduce MAGERI, a computational pipeline that efficiently handles all caveats of UMI-based analysis to obtain high-fidelity mutation profiles and call ultra-rare variants. Using an extensive set of benchmark datasets including gold-standard biological samples with known variant frequencies, cell-free DNA from tumor patient blood samples and publicly available UMI-encoded datasets we demonstrate that our method is both robust and efficient in calling rare variants. The versatility of our software is supported by accurate results obtained for both tumor DNA and viral RNA samples in datasets prepared using three different UMI-based protocols.

Pirogov Russian National Research Medical University Ostrovityanova 1 Moscow Russia Evrogen JSC Miklukho Maklaya 16 10 Moscow Russia

Shemyakin Ovchinnikov Institute of bioorganic chemistry RAS Miklukho Maklaya 16 10 Moscow Russia

Shemyakin Ovchinnikov Institute of bioorganic chemistry RAS Miklukho Maklaya 16 10 Moscow Russia Pirogov Russian National Research Medical University Ostrovityanova 1 Moscow Russia

Shemyakin Ovchinnikov Institute of bioorganic chemistry RAS Miklukho Maklaya 16 10 Moscow Russia Pirogov Russian National Research Medical University Ostrovityanova 1 Moscow Russia Central European Institute of Technology Masaryk University Brno Czech republic

Shemyakin Ovchinnikov Institute of bioorganic chemistry RAS Miklukho Maklaya 16 10 Moscow Russia Pirogov Russian National Research Medical University Ostrovityanova 1 Moscow Russia Central European Institute of Technology Masaryk University Brno Czech republic Skolkovo Institute of Science and Technology Nobel 3 Moscow Russia

Shemyakin Ovchinnikov Institute of bioorganic chemistry RAS Miklukho Maklaya 16 10 Moscow Russia Pirogov Russian National Research Medical University Ostrovityanova 1 Moscow Russia Evrogen JSC Miklukho Maklaya 16 10 Moscow Russia

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