Clustering and conservation patterns of human microRNAs

MicroRNAs (miRNAs) are ∼22 nt-long non-coding RNA molecules, believed to play important roles in gene regulation. We present a comprehensive analysis of the conservation and clustering patterns of known miRNAs in human. We show that human miRNA gene clustering is significantly higher than expected at random. A total of 37% of the known human miRNA genes analyzed in this study appear in clusters of two or more with pairwise chromosomal distances of at most 3000 nt. Comparison of the miRNA sequences with their homologs in four other organisms reveals a typical conservation pattern, persistent throughout the clusters. Furthermore, we show enrichment in the typical conservation patterns and other miRNA-like properties in the vicinity of known miRNA genes, compared with random genomic regions. This may imply that additional, yet unknown, miRNAs reside in these regions, consistent with the current recognition that there are overlooked miRNAs. Indeed, by comparing our predictions with cloning results and with identified miRNA genes in other mammals, we corroborate the predictions of 18 additional human miRNA genes in the vicinity of the previously known ones. Our study raises the proportion of clustered human miRNAs that are <3000 nt apart to 42%. This suggests that the clustering of miRNA genes is higher than currently acknowledged, alluding to its evolutionary and functional implications

RepTar: a database of predicted cellular targets of host and viral miRNAs

Computational identification of putative microRNA (miRNA) targets is an important step towards elucidating miRNA functions. Several miRNA target-prediction algorithms have been developed followed by publicly available databases of these predictions. Here we present a new database offering miRNA target predictions of several binding types, identified by our recently developed modular algorithm RepTar. RepTar is based on identification of repetitive elements in 3′-UTRs and is independent of both evolutionary conservation and conventional binding patterns (i.e. Watson–Crick pairing of ‘seed’ regions). The modularity of RepTar enables the prediction of targets with conventional seed sites as well as rarer targets with non-conventional sites, such as sites with seed wobbles (G-U pairing in the seed region), 3′-compensatory sites and the newly discovered centered sites. Furthermore, RepTar’s independence of conservation enables the prediction of cellular targets of the less evolutionarily conserved viral miRNAs. Thus, the RepTar database contains genome-wide predictions of human and mouse miRNAs as well as predictions of cellular targets of human and mouse viral miRNAs. These predictions are presented in a user-friendly database, which allows browsing through the putative sites as well as conducting simple and advanced queries including data intersections of various types. The RepTar database is available at http://reptar.ekmd.huji.ac.il

Cytomegalovirus microRNAs Facilitate Persistent Virus Infection in Salivary Glands

Micro (mi)RNAs are small non-coding RNAs that regulate the expression of their targets' messenger RNAs through both translational inhibition and regulation of target RNA stability. Recently, a number of viruses, particularly of the herpesvirus family, have been shown to express their own miRNAs to control both viral and cellular transcripts. Although some targets of viral miRNAs are known, their function in a physiologically relevant infection remains to be elucidated. As such, no in vivo phenotype of a viral miRNA knock-out mutant has been described so far. Here, we report on the first functional phenotype of a miRNA knock-out virus in vivo. During subacute infection of a mutant mouse cytomegalovirus lacking two viral miRNAs, virus production is selectively reduced in salivary glands, an organ essential for virus persistence and horizontal transmission. This phenotype depends on several parameters including viral load and mouse genetic background, and is abolished by combined but not single depletion of natural killer (NK) and CD4+ T cells. Together, our results point towards a miRNA-based immunoevasion mechanism important for long-term virus persistence

Evaluation of European-based polygenic risk score for breast cancer in Ashkenazi Jewish women in Israel.

Peer reviewed: TrueFunder: Statistics NetherlandsFunder: Lower Saxonian Cancer SocietyFunder: Lise Boserup FundFunder: Heidelberger Zentrum für Personalisierte Onkologie Deutsches Krebsforschungszentrum In Der Helmholtz-Gemeinschaft; FundRef: http://dx.doi.org/10.13039/100018027Funder: Komen FoundationFunder: Claudia von Schilling Foundation for Breast Cancer ResearchFunder: Ligue Contre le Cancer; FundRef: http://dx.doi.org/10.13039/501100004099Funder: Sigrid Juselius FoundationFunder: Kuopion Yliopistollinen Sairaala; FundRef: http://dx.doi.org/10.13039/501100004092Funder: Sheffield Experimental Cancer Medicine CentreFunder: Stockholm läns landsting; FundRef: http://dx.doi.org/10.13039/501100011727Funder: Department of Health and Human Services (USA)Funder: Stichting Tegen Kanker; FundRef: http://dx.doi.org/10.13039/501100005026Funder: David F. and Margaret T. Grohne Family Foundation; FundRef: http://dx.doi.org/10.13039/100009769Funder: Sundhed og Sygdom, Det Frie Forskningsråd; FundRef: http://dx.doi.org/10.13039/100008392Funder: Stavros Niarchos FoundationFunder: Institute of the Ruhr University BochumFunder: Institute of Cancer Research; FundRef: http://dx.doi.org/10.13039/501100000027Funder: Fondation du cancer du sein du Québec; FundRef: http://dx.doi.org/10.13039/100016328Funder: Institut National de la Santé et de la Recherche Médicale; FundRef: http://dx.doi.org/10.13039/501100001677Funder: Institute for Prevention and Occupational MedicineFunder: K.G. Jebsen Centre for Breast Cancer ResearchFunder: Research Centre for Genetic Engineering and BiotechnologyFunder: Robert and Kate Niehaus Clinical Cancer Genetics InitiativeFunder: Rudolf Bartling FoundationFunder: Karolinska Institutet; FundRef: http://dx.doi.org/10.13039/501100004047Funder: Robert Bosch Stiftung; FundRef: http://dx.doi.org/10.13039/501100001646Funder: Intramural Research Funds of the National Cancer Institute (USA)Funder: Intramural Research Program of the Division of Cancer Epidemiology and GeneticsFunder: Centre International de Recherche sur le Cancer; FundRef: http://dx.doi.org/10.13039/100008700Funder: Queensland Cancer FundFunder: Red Temática de Investigación Cooperativa en CáncerFunder: Intramural Research Program of the National Institutes of HealthFunder: National Health Service (UK)Funder: Ministerie van Volksgezondheid, Welzijn en Sport; FundRef: http://dx.doi.org/10.13039/501100002999Funder: Märit and Hans Rausings Initiative Against Breast CancerFunder: Associazione Italiana per la Ricerca sul Cancro; FundRef: http://dx.doi.org/10.13039/501100005010Funder: Fundación Científica Asociación Española Contra el Cáncer; FundRef: http://dx.doi.org/10.13039/501100002704Funder: Agence Nationale de la Recherche; FundRef: http://dx.doi.org/10.13039/501100001665Funder: Dutch Prevention Funds,Funder: Agence Nationale de Sécurité Sanitaire de l'Alimentation, de l'Environnement et du TravailFunder: American Cancer Society; FundRef: http://dx.doi.org/10.13039/100000048Funder: Dutch Zorg OnderzoekFunder: Alexander von Humboldt-Stiftung; FundRef: http://dx.doi.org/10.13039/100005156Funder: Ministerio de Economia y Competitividad (Spain)Funder: Against Breast Cancer; FundRef: http://dx.doi.org/10.13039/100013129Funder: Mutuelle Générale de l’Education NationaleFunder: Dietmar-Hopp Foundation,Funder: Division of Cancer Prevention, National Cancer Institute; FundRef: http://dx.doi.org/10.13039/100007316Funder: World Cancer Research Fund; FundRef: http://dx.doi.org/10.13039/501100000321Funder: Genome QuébecFunder: National Cancer Research NetworkFunder: Berta Kamprad Foundation FBKSFunder: Biomedical Research Centre at Guy’s and St ThomasFunder: Genome Canada; FundRef: http://dx.doi.org/10.13039/100008762Funder: Friends of Hannover Medical SchoolFunder: Breast Cancer Research Foundation; FundRef: http://dx.doi.org/10.13039/100001006Funder: Breast Cancer NowFunder: UK National Institute for Health Research Biomedical Research CentreFunder: University of Crete; FundRef: http://dx.doi.org/10.13039/501100004429Funder: National Breast Cancer Foundation (Finland)Funder: European Regional Development Fund; FundRef: http://dx.doi.org/10.13039/501100008530Funder: National Breast Cancer Foundation (Australia)Funder: Directorate-General XII, Science, Research, and Development; FundRef: http://dx.doi.org/10.13039/501100012517Funder: Baden Württemberg Ministry of Science, Research and ArtsFunder: VicHealth; FundRef: http://dx.doi.org/10.13039/501100001231Funder: Victorian Breast Cancer Research Consortium.Funder: Finnish Cancer FoundationFunder: Fomento de la Investigación Clínica IndependienteFunder: the Cancer Biology Research Center (CBRC), Djerassi Oncology CenterFunder: Tel Aviv University Center for AI and Data ScienceFunder: University of OuluFunder: National Breast Cancer Foundation (JS)Funder: Safra Center for BioinformaticsFunder: Fondation de France, Institut National du CancerFunder: University of Utah; FundRef: http://dx.doi.org/10.13039/100007747Funder: National Cancer Center Research and Development Fund (Japan)Funder: Oak Foundation; FundRef: http://dx.doi.org/10.13039/100001275Funder: New South Wales Cancer CouncilFunder: North Carolina University Cancer Research FundFunder: Kreftforeningen; FundRef: http://dx.doi.org/10.13039/100008730Funder: Northern California Breast Cancer Family RegistryFunder: Institut Gustave RoussyFunder: Huntsman Cancer Institute, University of Utah; FundRef: http://dx.doi.org/10.13039/100010638Funder: Ovarian Cancer Research Fund; FundRef: http://dx.doi.org/10.13039/100001282Funder: NIHR Oxford Biomedical Research Centre; FundRef: http://dx.doi.org/10.13039/501100013373Funder: Hellenic Health Foundation; FundRef: http://dx.doi.org/10.13039/501100018706Funder: Oulun Yliopistollinen Sairaala; FundRef: http://dx.doi.org/10.13039/501100018949Funder: Helmholtz SocietyFunder: Herlev and Gentofte HospitalFunder: PSRSIIRI-701Funder: Helsinki University Hospital Research FundFunder: Cancer Council Victoria; FundRef: http://dx.doi.org/10.13039/501100000951Funder: National Research Council (Italy)Funder: Cancer Council Tasmania; FundRef: http://dx.doi.org/10.13039/501100001169Funder: Cancer Council Western Australia; FundRef: http://dx.doi.org/10.13039/501100001170Funder: Hamburger Krebsgesellschaft; FundRef: http://dx.doi.org/10.13039/100018515Funder: Gustav V Jubilee foundationFunder: National Program of Cancer RegistriesFunder: Cancer Council South Australia; FundRef: http://dx.doi.org/10.13039/501100000950Funder: Cancer Council NSW; FundRef: http://dx.doi.org/10.13039/501100001102Funder: Guy's & St. Thomas' NHS Foundation TrustFunder: Cancer Institute NSW; FundRef: http://dx.doi.org/10.13039/501100001171Funder: Cancer Foundation of Western AustraliaFunder: Netherlands Cancer Registry (NKR),Funder: Cancer Fund of North SavoBACKGROUND: Polygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women. METHODS: We generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel. RESULTS: In the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28). CONCLUSIONS: Extant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women

Evaluation of European-based polygenic risk score for breast cancer in Ashkenazi Jewish women in Israel

International audienceTo date, most BC GWASs have been performed Background Polygenic risk score (PRS), calculated in individuals of European (EUR) ancestry, and based on genome-wide association studies (GWASs), the generalisation of EUR-based PRS to other can improve breast cancer (BC) risk assessment. populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women. Methods We generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel. Results In the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28). Conclusions Extant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women