Loss-of-function uORF mutations in human malignancies

Ribosome profiling revealed widespread translational activity at upstream open reading frames (uORFs) and validated uORF-mediated translational control as a commonly repressive mechanism of gene expression. Translational activation of proto-oncogenes through loss-of-uORF mutations has been demonstrated, yet a systematic search for cancer-associated genetic alterations in uORFs is lacking. Here, we applied a PCR-based, multiplex identifier-tagged deep sequencing approach to screen 404 uORF translation initiation sites of 83 human tyrosine kinases and 49 other proto-oncogenes in 308 human malignancies. We identified loss-of-function uORF mutations in EPHB1 in two samples derived from breast and colon cancer, and in MAP2K6 in a sample of colon adenocarcinoma. Both mutations were associated with enhanced translation, suggesting that loss-of-uORF-mediated translational induction of the downstream main protein coding sequence may have contributed to carcinogenesis. Computational analysis of whole exome sequencing datasets of 464 colon adenocarcinomas subsequently revealed another 53 non-recurrent somatic mutations functionally deleting 22 uORF initiation and 31 uORF termination codons, respectively. These data provide evidence for somatic mutations affecting uORF initiation and termination codons in human cancer. The insufficient coverage of uORF regions in current whole exome sequencing datasets demands for future genome-wide analyses to ultimately define the contribution of uORF-mediated translational deregulation in oncogenesis

The lower bathyal and abyssal seafloor fauna of eastern Australia

Background Our knowledge of the benthic fauna at lower bathyal to abyssal (LBA, > 2000 m) depths off Eastern Australia was very limited with only a few samples having been collected from these habitats over the last 150 years. In May–June 2017, the IN2017_V03 expedition of the RV Investigator sampled LBA benthic communities along the lower slope and abyss of Australia’s eastern margin from off mid-Tasmania (42°S) to the Coral Sea (23°S), with particular emphasis on describing and analysing patterns of biodiversity that occur within a newly declared network of offshore marine parks. Methods The study design was to deploy a 4 m (metal) beam trawl and Brenke sled to collect samples on soft sediment substrata at the target seafloor depths of 2500 and 4000 m at every 1.5 degrees of latitude along the western boundary of the Tasman Sea from 42° to 23°S, traversing seven Australian Marine Parks. Results The biological sampling included 35 beam trawls, 28 Brenke sleds, 8 box cores, 20 surface meso-zooplankton tows, and 7 Deep Towed Camera transects. In total, 25,710 specimens were identified to 1084 taxonomic entities, including 847 species-level, 144 genus-level and 69 family-level and 24 higher-level taxa. Of the species-level taxa, only 457 were assigned species-level taxonomic names, which implies that up to 58% of the collected fauna is undescribed. In addition, the ranges of numerous species have been extended to include the western Tasman Sea. Conclusions The lower bathyal and abyssal fauna of soft sediment seafloors off eastern Australia has been systematically surveyed for the first time. The resultant collections will provide the foundation for much future ecological, biogeographical, phylogenetic and taxonomic research