Studies of somatic mutation have so far focused on cancer or other severe diseases, with little attention to the basic biology of this important class of variation. As a consequence, the somatic variation catalog to be produced by the SMaHT network fills an essential need. To build this catalog, novel methods and approaches are required since current methods cannot comprehensively assess somatic structural variation (SV) nor transposon activation at scale, or with adequate resolution. We will develop novel computational methods based on long-read sequencing and will make the methods broadly available across the SMaHT network. The approaches will leverage new algorithmic and machine learning approaches, be scalable and provide a reduced error rate, at lower cost. There will be a special focus on the identification of the movement of transposons across the genome. For this we will implement better annotation and characterization of insertions and translocations that are evidence for transposition. In addition, we will identify methylation signals from long-read sequencing data. Correlation of methylation changes and somatic & mosaic mutations will reveal how these genomic alterations shape the methylation patterns in critical regions and likely impact genes. To foster the collaboration with other groups we will closely work together with SMaHT sequencing and analysis centers. Multiple activities such as the formation of a NIST & SMaHT somatic variation benchmarks, as well as annual Hackathons, will engage investigators from around the world. The group’s history of successful methods development will ensure that the SMaHT network will receive useful and comprehensive new tools to extend the knowledge of somatic and mosaic SVs and transposition.

This proposal will leverage high coverage long and short-read sequencing data to develop novel computational methods to improve the characterization of somatic and mosaic structural variation (SV) and transposition events together with their epigenetic consequences across three tissues and 34 individuals. The methods will be developed in coordination with the SMaHT network, and tools and results will be shared with all sequencing centers, in coordination with the DAC, enabling seamless incorporation of the software and our results into the network. The results will include a catalog of SV, transposition and methylation, in somatic tissues, that will enable new insights into the consequences of these variants, across the human population.