High participation rate among 25 721 patients with broad age range in a hospital-based research project involving whole-genome sequencing – the Lausanne Institutional Biobank.
Swiss Med Wkly. 2017;147:w14528
Authors: Bochud M, Currat C, Chapatte L, Roth C, Mooser V
AIMS: We aimed to evaluate the interest of adult inpatients and selected outpatients in engaging in a large, real-life, hospital-based, genomic medicine research project and in receiving clinically actionable incidental findings.
METHODS: Within the framework of the cross-sectional Institutional Biobank of Lausanne, Switzerland, a total of 25721 patients of the CHUV University Hospital were systematically invited to grant researchers access to their biomedical data and to donate blood for future analyses, including whole-genome sequencing. Multivariable logistic regression analysis was used to identify personal factors, including age, gender, religion, ethnicity, citizenship, education level and mode of admission, associated with willingness to participate in this genomic research project and with interest in receiving clinically actionable incidental findings.
RESULTS: The overall participation rate was 79% (20343/25721). Participation rate declined progressively with age, averaging 83%, 75%, 67% and 62% in patients aged <64 years (n = 13108), ≥64 years (n = 12613), ≥80 years (n = 4557) and ≥90 years (n = 1050), respectively. Factors associated with participation substantially differed between age strata. Patients less likely to participate included women (odds ratio 0.86, [95% confidence interval 0.79-0.95] and 0.78 [0.71-0.85] before and after age 64, respectively), non-Swiss (0.81 [0.74-0.90] and 0.58 [0.52-0.65]) and those admitted through the emergency ward (0.88 [0.79-0.98] and 0.66 [0.60-0.73]). Religion and marital status were associated with participation among patients aged <64 years. A total of 19 018 (93%) participants were willing to be re-contacted for incidental findings. A high education level was associated with higher participation rate, but not with higher willingness to receive incidental findings within the population who had agreed to participate.
CONCLUSION: A large proportion of adult patients, even among the elderly, are willing to actively participate and receive incidental findings in this systematic hospital-based precision and genomic medicine research program with broad consent.
PMID: 29063527 [PubMed – indexed for MEDLINE]
PLATO software provides analytic framework for investigating complexity beyond genome-wide association studies.
Nat Commun. 2017 10 27;8(1):1167
Authors: Hall MA, Wallace J, Lucas A, Kim D, Basile AO, Verma SS, McCarty CA, Brilliant MH, Peissig PL, Kitchner TE, Verma A, Pendergrass SA, Dudek SM, Moore JH, Ritchie MD
Genome-wide, imputed, sequence, and structural data are now available for exceedingly large sample sizes. The needs for data management, handling population structure and related samples, and performing associations have largely been met. However, the infrastructure to support analyses involving complexity beyond genome-wide association studies is not standardized or centralized. We provide the PLatform for the Analysis, Translation, and Organization of large-scale data (PLATO), a software tool equipped to handle multi-omic data for hundreds of thousands of samples to explore complexity using genetic interactions, environment-wide association studies and gene-environment interactions, phenome-wide association studies, as well as copy number and rare variant analyses. Using the data from the Marshfield Personalized Medicine Research Project, a site in the electronic Medical Records and Genomics Network, we apply each feature of PLATO to type 2 diabetes and demonstrate how PLATO can be used to uncover the complex etiology of common traits.
PMID: 29079728 [PubMed – indexed for MEDLINE]
Polη O-GlcNAcylation governs genome integrity during translesion DNA synthesis.
Nat Commun. 2017 12 05;8(1):1941
Authors: Ma X, Liu H, Li J, Wang Y, Ding YH, Shen H, Yang Y, Sun C, Huang M, Tu Y, Liu Y, Zhao Y, Dong MQ, Xu P, Tang TS, Guo C
DNA polymerase η (Polη) facilitates translesion DNA synthesis (TLS) across ultraviolet (UV) irradiation- and cisplatin-induced DNA lesions implicated in skin carcinogenesis and chemoresistant phenotype formation, respectively. However, whether post-translational modifications of Polη are involved in these processes remains largely unknown. Here, we reported that human Polη undergoes O-GlcNAcylation at threonine 457 by O-GlcNAc transferase upon DNA damage. Abrogation of this modification results in a reduced level of CRL4CDT2-dependent Polη polyubiquitination at lysine 462, a delayed p97-dependent removal of Polη from replication forks, and significantly enhanced UV-induced mutagenesis even though Polη focus formation and its efficacy to bypass across cyclobutane pyrimidine dimers after UV irradiation are not affected. Furthermore, the O-GlcNAc-deficient T457A mutation impairs TLS to bypass across cisplatin-induced lesions, causing increased cellular sensitivity to cisplatin. Our findings demonstrate a novel role of Polη O-GlcNAcylation in TLS regulation and genome stability maintenance and establish a new rationale to improve chemotherapeutic treatment.
PMID: 29208956 [PubMed – indexed for MEDLINE]
Advances in Engineering the Fly Genome with the CRISPR-Cas System.
Genetics. 2018 01;208(1):1-18
Authors: Bier E, Harrison MM, O’Connor-Giles KM, Wildonger J
Drosophila has long been a premier model for the development and application of cutting-edge genetic approaches. The CRISPR-Cas system now adds the ability to manipulate the genome with ease and precision, providing a rich toolbox to interrogate relationships between genotype and phenotype, to delineate and visualize how the genome is organized, to illuminate and manipulate RNA, and to pioneer new gene drive technologies. Myriad transformative approaches have already originated from the CRISPR-Cas system, which will likely continue to spark the creation of tools with diverse applications. Here, we provide an overview of how CRISPR-Cas gene editing has revolutionized genetic analysis in Drosophila and highlight key areas for future advances.
PMID: 29301946 [PubMed – indexed for MEDLINE]