Discovery of widespread transcription initiation at microsatellites predictable by sequence-based deep neural network

Using the Cap Analysis of Gene Expression (CAGE) technology, the FANTOM5 consortium provided one of the most comprehensive maps of transcription start sites (TSSs) in several species. Strikingly, ~72% of them could not be assigned to a specific gene and initiate at unconventional regions, outside promoters or enhancers. Here, we probe these unassigned TSSs and show that, in all species studied, a significant fraction of CAGE peaks initiate at microsatellites, also called short tandem repeats (STRs). To confirm this transcription, we develop Cap Trap RNA-seq, a technology which combines cap trapping and long read MinION sequencing. We train sequence-based deep learning models able to predict CAGE signal at STRs with high accuracy. These models unveil the importance of STR surrounding sequences not only to distinguish STR classes, but also to predict the level of transcription initiation. Importantly, genetic variants linked to human diseases are preferentially found at STRs with high transcription initiation level, supporting the biological and clinical relevance of transcription initiation at STRs. Together, our results extend the repertoire of non-coding transcription associated with DNA tandem repeats and complexify STR polymorphism

MD/PhD Training in Canada: Results from a national trainee and program director review

Purpose: There has been limited examination of clinician scientist training in Canada, particularly regarding training integration and funding. This study assessed program structure, funding, tuition and mentorship structures available at Canadian MD/PhD programs. Methods: Clinician Investigator Trainee Association of Canada administered an anonymous survey to current trainees and program directors that captured program structure, trainee funding, tuition and mentorship opportunities and needs across institutions. Results: In June 2015, 101/228 (44%) trainees and 9/13 (69%) program directors completed the online survey. In all programs, students completed the PhD degree prior to clerkship training. Seven programs offered research training upon completion of pre-clerkship, four offered concurrent clinical and research training, and three offered alternative structures. Nine held seminars exposing students to clinical and research integration and two offered clinician scientist skills courses. Stipend funding and tuition varied, especially during clinical training years. Regarding mentorship, all programs held regular meetings, though eight programs do not have formal mentorship opportunities. Both trainees and program directors identified the need for further career planning and development support as a student priority. Conclusion: MD/PhD programs varied by program structure, funding, tuition and mentorship opportunities. Mechanisms to share and spread program innovations should be instated. Students may benefit from concurrent research and clinical training as well as courses specific to clinician scientist skill development. Decreasing debt burden may attract and retain trainees in this demanding path. To ensure mentorship programs align with trainee priorities, program directors should directly collaborate with students in their development and evaluation

Human somatic cell mutagenesis creates genetically tractable sarcomas

Creating spontaneous yet genetically tractable human tumors from normal cells presents a fundamental challenge. Here we combined retroviral and transposon insertional mutagenesis to enable cancer gene discovery starting with human primary cells. We used lentiviruses to seed gain- and loss-of-function gene disruption elements, which were further deployed by Sleeping Beauty transposons throughout the genome of human bone explant mesenchymal cells. De novo tumors generated rapidly in this context were high-grade myxofibrosarcomas. Tumor insertion sites were enriched in recurrent somatic copy-number aberration regions from multiple cancer types and could be used to pinpoint new driver genes that sustain somatic alterations in patients. We identified HDLBP, which encodes the RNA-binding protein vigilin, as a candidate tumor suppressor deleted at 2q37.3 in greater than one out of ten tumors across multiple tissues of origin. Hybrid viral-transposon systems may accelerate the functional annotation of cancer genomes by enabling insertional mutagenesis screens in higher eukaryotes that are not amenable to germline transgenesis