Despite their deleterious effects, small insertions and deletions (InDels) have received far less attention than substitutions. Here we generated isogenic CRISPR-edited human cellular models of postreplicative repair dysfunction (PRRd), including individual and combined gene edits of DNA mismatch repair (MMR) and replicative polymerases (Pol ε and Pol δ). Unique, diverse InDel mutational footprints were revealed. However, the prevailing InDel classification framework was unable to discriminate these InDel signatures from background mutagenesis and from each other. To address this, we developed an alternative InDel classification system that considers flanking sequences and informative motifs (for example, longer homopolymers), enabling unambiguous InDel classification into 89 subtypes. Through focused characterization of seven tumor types from the 100,000 Genomes Project, we uncovered 37 InDel signatures; 27 were new. In addition to unveiling previously hidden biological insights, we also developed PRRDetect-a highly specific classifier of PRRd status in tumors, with potential implications for immunotherapies.
Climate change manifestation in the ocean, through warming, oxygen loss, increasing acidification, and changing particulate organic carbon flux (one metric of altered food supply), is projected to affect most deep-ocean ecosystems concomitantly with increasing direct human disturbance. Climate drivers will alter deep-sea biodiversity and associated ecosystem services, and may interact with disturbance from resource extraction activities or even climate geoengineering. We suggest that to ensure the effective management of increasing use of the deep ocean (e.g., for bottom fishing, oil and gas extraction, and deep-seabed mining), environmental management and developing regulations must consider climate change. Strategic planning, impact assessment and monitoring, spatial management, application of the precautionary approach, and full-cost accounting of extraction activities should embrace climate consciousness. Coupled climate and biological modeling approaches applied in the water and on the seafloor can help accomplish this goal. For example, Earth-System Model projections of climate-change parameters at the seafloor reveal heterogeneity in projected climate hazard and time of emergence (beyond natural variability) in regions targeted for deep-seabed mining. Models that combine climate-induced changes in ocean circulation with particle tracking predict altered transport of early life stages (larvae) under climate change. Habitat suitability models can help assess the consequences of altered larval dispersal, predict climate refugia, and identify vulnerable regions for multiple species under climate change. Engaging the deep observing community can support the necessary data provisioning to mainstream climate into the development of environmental management plans. To illustrate this approach, we focus on deep-seabed mining and the International Seabed Authority, whose mandates include regulation of all mineral-related activities in international waters and protecting the marine environment from the harmful effects of mining. However, achieving deep-ocean sustainability under the UN Sustainable Development Goals will require integration of climate consideration across all policy sectors.