Suchergebnisse

In the past decade, the view on genomic structural variation (SV) has been changed completely. SVs, previously considered rare events, are now recognized as the largest source of interindividual genetic variation affecting more bases than single nucleotide polymorphisms, variable number of tandem repeats and other small genetic variants. They have also been shown to play a role in phenotypic variation and in disease. In this review, the authors will provide an introduction to SV; a short historical perspective on the research of this source of genomic variation; a description of the types of structural variants, and on how they may have arisen; and an overview on methods of detecting structural variants, focusing on the analysis of high-throughput sequencing data. ; E.D. is supported by a Marie Curie Intraeuropean Fellowship (IEF), R.R. is supported through the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 262055. We acknowledge support of the Spanish Ministry of Economy and Competitiveness, 'Centro de Excelencia Severo Ochoa 2013-2017', SEV-2012-0208, the 'Secretaria d'Universitats i Recerca del Departament d'Economia' (2009 SGR 1502) and the 'PN de I+D+I 2008-2011' and ISCIII (SAF2008-00357). The research leading to these results reflects only the author s views and the funding agencies are not liable for any use that may be made of the information contained in this paper.

In recent years, next-generation sequencing (NGS) has become a cornerstone of clinical genetics and diagnostics. Many clinical applications require high precision, especially if rare events such as somatic mutations in cancer or genetic variants causing rare diseases need to be identified. Although random sequencing errors can be modeled statistically and deep sequencing minimizes their impact, systematic errors remain a problem even at high depth of coverage. Understanding their source is crucial to increase precision of clinical NGS applications. In this work, we studied the relation between recurrent biases in allele balance (AB), systematic errors, and false positive variant calls across a large cohort of human samples analyzed by whole exome sequencing (WES). We have modeled the AB distribution for biallelic genotypes in 987 WES samples in order to identify positions recurrently deviating significantly from the expectation, a phenomenon we termed allele balance bias (ABB). Furthermore, we have developed a genotype callability score based on ABB for all positions of the human exome, which detects false positive variant calls that passed state-of-the-art filters. Finally, we demonstrate the use of ABB for detection of false associations proposed by rare variant association studies. Availability: https://github.com/Francesc-Muyas/ABB. ; Spanish Ministry of Economy and Competitiveness, Grant/Award Number: 'Centro de Excelencia Severo Ochoa 2017–2021'; CERCA Programme/Generalitat de Catalunya; The "la Caixa" Foundation; CRG Emergent Translational Research Award; European Union's H2020 Research and Innovation Programme, Grant/Award Number: 635290 (PanCanRisk); MINECO Severo Ochoa Fellowship, Grant/Award Number: SVP‐2013‐0680066; PERIS Program, Grant/Award Number: SLT002/16/00310.

Although the etiology of obsessive-compulsive disorder (OCD) is largely unknown, it is accepted that OCD is a complex disorder. There is a known bi-directional interaction between the gut microbiome and brain activity. Several authors have reported associations between changes in gut microbiota and neuropsychiatric disorders, including depression or autism. Furthermore, a pediatric-onset neuropsychiatric OCD-related syndrome occurs after streptococcal infection, which might indicate that exposure to certain microbes could be involved in OCD susceptibility. However, only one study has investigated the microbiome of OCD patients to date. We performed 16S ribosomal RNA gene-based metagenomic sequencing to analyze the stool and oropharyngeal microbiome composition of 32 OCD cases and 32 age and gender matched controls. We estimated different α- and β-diversity measures and performed LEfSe and Wilcoxon tests to assess differences in bacterial distribution. OCD stool samples showed a trend towards lower bacterial α-diversity, as well as an increase of the relative abundance of Rikenellaceae, particularly of the genus Alistipes, and lower relative abundance of Prevotellaceae, and two genera within the Lachnospiraceae: Agathobacer and Coprococcus. However, we did not observe a different Bacteroidetes to Firmicutes ratio between OCD cases and controls. Analysis of the oropharyngeal microbiome composition showed a lower Fusobacteria to Actinobacteria ratio in OCD cases. In conclusion, we observed an imbalance in the gut and oropharyngeal microbiomes of OCD cases, including, in stool, an increase of bacteria from the Rikenellaceae family, associated with gut inflammation, and a decrease of bacteria from the Coprococcus genus, associated with DOPAC synthesis. ; This project was supported by grants from the Spanish ministry of science and innovation (MICINN; SAF2013-49108-R); the Carlos III Health Institute (PI16/00950, PI18/00856, PI19/01184); FEDER funds ('A way to build Europe') and by the Agency of University and Research Funding Management of the Catalan Government (2014 SGR 1672 and 2017 SGR 738). We thank CERCA Programme / Generalitat de Catalunya for institutional support. LD was supported by a Severo Ochoa grant (SVP-2013-068066), MA was supported by the Secretariat for Universities and Research of the Ministry of Business and Knowledge of the Government of Catalonia Grant co-funded by the European Social Fund (ESF) "ESF, Investing in your future" (2017 FI_B 00327), DSC was supported by a grant from the MICINN (BES-2014-069814) and RR was supported by a fellowship from the Health Department of the Generalitat de Catalunya through the PERIS 2016-2020 program (SLT002/16/00310).

Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research. ; This study was conducted with the support of the Ontario Institute for Cancer Research to P.C.B. through funding provided by the Government of Ontario. This work was supported by the Discovery Frontiers: Advancing Big Data Science in Genomics Research program, which is jointly funded by the Natural Sciences and Engineering Research Council (NSERC) of Canada, the Canadian Institutes of Health Research (CIHR), Genome Canada and the Canada Foundation for Innovation (CFI). P.C.B. was supported by a Terry Fox Research Institute New Investigator Award and a CIHR New Investigator Award. This work was supported by an NSERC Discovery grant and by Canadian Institutes of Health Research, grant #SVB-145586, to P.C.B. This work was supported by the NIH/NCI under award number P30CA016042 and an operating grant from the National Cancer Institute Early Detection Research Network (1U01CA214194-01)