Ensembl 2017

Aken, Bronwen; Achuthan, Premanand; Akanni, Wasiu; Amode, M Ridwan; Bernsdorff, Friederike; Bhai, Jyothish; Billis, Konstantinos; Carvalho-Silva, Denise; Cummins, Carla; Clapham, Peter; Gil, Laurent; Girón, Carlos García; Gordon, Leo I.; Hourlier, Thibaut; Hunt, Sarah; Janacek, Sophie H; Juettemann, Thomas; Keenan, Stephen; Laird, Matthew R.; Lavidas, Ilias; Maurel, Thomas; McLaren, William; Moore, Benjamin; Murphy, Daniel N.; Nag, Rishi; Newman, Victoria L.; Nuhn, Michael; Ong, Chuang Kee; Parker, Anne; Patrício, Mateus; Riat, Harpreet Singh; Sheppard, Daniel; Sparrow, Helen; Taylor, Kieron; Thormann, Anja; Vullo, Alessandro; Walts, Brandon; Wilder, Steven P.; Zadissa, Amonida; Kostadima, Myrto; Martin, Fergal J.; Muffato, Matthieu; Perry, Emily; Ruffier, Magali; Staines, Daniel M.; Trevanion, Stephen J.; Cunningham, Fiona; Yates, Andy; Zerbino, Daniel R.; Flicek, Paul

doi:10.1093/nar/gkw1104

Cited by 546 publications

(565 citation statements)

References 52 publications

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“…Intronic miRNAs were identified based on positional overlap with protein-coding genes in Ensembl version 88 (Aken et al 2017). Coordinates of 72,862 DHS sites in mouse liver, including 3378 sites that were identified as sex-biased with "standard stringency" settings, were provided by Ling et al (2010) and converted to the mm10 genome release with the liftOver from the UCSC Genome Browser (Tyner et al 2017).…”

Section: Association Of Mirnas With Upstream Regulatory Elementsmentioning

confidence: 99%

“…For clarity, we reversed the sign of their reported expression fold changes to be consistent with the main text. Data were compared between chicken and zebra finch based on 1-to-1 orthologs from Ensembl release 88 (Aken et al 2017) that were Z-linked in both species. All statistical analyses were performed in R version 3.2.2 (R Core Team 2015).…”

Section: Analysis Of Mir-2954-3p Targets In Chicken and Zebra Finchmentioning

confidence: 99%

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Sex-biased microRNA expression in mammals and birds reveals underlying regulatory mechanisms and a role in dosage compensation

et al. 2017

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Sexual dimorphism depends on sex-biased gene expression, but the contributions of microRNAs (miRNAs) have not been globally assessed. We therefore produced an extensive small RNA sequencing data set to analyze male and female miRNA expression profiles in mouse, opossum, and chicken. Our analyses uncovered numerous cases of somatic sex-biased miRNA expression, with the largest proportion found in the mouse heart and liver. Sex-biased expression is explained by miRNA-specific regulation, including sex-biased chromatin accessibility at promoters, rather than piggybacking of intronic miRNAs on sex-biased protein-coding genes. In mouse, but not opossum and chicken, sex bias is coordinated across tissues such that autosomal testis-biased miRNAs tend to be somatically male-biased, whereas autosomal ovary-biased miRNAs are female-biased, possibly due to broad hormonal control. In chicken, which has a Z/W sex chromosome system, expression output of genes on the Z Chromosome is expected to be male-biased, since there is no global dosage compensation mechanism that restores expression in ZW females after almost all genes on the W Chromosome decayed. Nevertheless, we found that the dominant liver miRNA, miR-122-5p, is Z-linked but expressed in an unbiased manner, due to the unusual retention of a W-linked copy. Another Z-linked miRNA, the male-biased miR-2954-3p, shows conserved preference for dosage-sensitive genes on the Z Chromosome, based on computational and experimental data from chicken and zebra finch, and acts to equalize male-to-female expression ratios of its targets. Unexpectedly, our findings thus establish miRNA regulation as a novel gene-specific dosage compensation mechanism.

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Section: Association Of Mirnas With Upstream Regulatory Elementsmentioning

confidence: 99%

Section: Analysis Of Mir-2954-3p Targets In Chicken and Zebra Finchmentioning

confidence: 99%

Sex-biased microRNA expression in mammals and birds reveals underlying regulatory mechanisms and a role in dosage compensation

et al. 2017

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“…1). The ACA trimer was the most commonly mutated site outside of a CG context, and this matches the most common site of non-CG methylation 13 . The mutation rate for a given region was linked to 5mC abundance.…”

mentioning

confidence: 72%

“…Transcriptional strand and expression level: Transcriptional strand bias analysis was performed by determining the template and non-template strands per gene as reported in Ensembl v75 13 . Overlapping gene bodies on the same strand were merged while overlapping regions defined by genes located on opposite strands were excluded.…”

Section: Assessment Of Mbd4 Status and Proportion Of Cg>tg Mutationsmentioning

confidence: 99%

Germline loss of MBD4 predisposes to leukaemia due to a mutagenic cascade driven by 5mC

Chew

Flensburg

et al. 2017

Preprint

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2Cytosine methylation is essential for normal mammalian development, yet also provides a major mutagenic stimulus. Methylcytosine (5mC) is prone to spontaneous deamination, which introduces cytosine to thymine transition mutations (C>T) upon replication 1 . Cells endure hundreds of 5mC deamination events each day and an intricate repair network is engaged to restrict this damage. Central to this network are the DNA glycosylases MBD4 2 and TDG 3,4 , which recognise T:G mispairing and initiate base excision repair (BER). Here we describe a novel cancer predisposition syndrome resulting from germline biallelic inactivation of MBD4 that leads to the development of acute myeloid leukaemia (AML). These leukaemias have an extremely high burden of C>T mutations, specifically in the context of methylated CG dinucleotides (CG>TG). This dependence on 5mC as a source of mutations may explain the remarkable observation that MBD4-deficient AMLs share a common set of driver mutations, including biallelic mutations in DNMT3A and hotspot mutations in IDH1/IDH2. By assessing serial samples taken over the course of treatment, we highlight a critical interaction with somatic mutations in DNMT3A that accelerates leukaemogenesis and accounts for the conserved path to AML. MBD4-deficiency was also detected, rarely, in sporadic cancers, which display the same mutational signature. Collectively these cancers provide a model of 5mC-dependent hypermutation and reveal factors that shape its mutagenic influence.We identified three patients with AML, including two siblings, that were distinctive because of their early age of onset (all <35 years old) and an extremely high mutational burden (~33-fold above what is typical for AML) (Fig. 1a, Clinical Synopsis). Virtually all of the somatic mutations identified were C>T in the context of a CG dinucleotide (>95% of SNVs) (Fig. 1b, Extended Data Fig. 1). This differs markedly from the distribution of C>T mutations in AML generally and is more refined than the mutational signature ascribed to ageing, which includes a strong contribution from 5mC deamination 5 . All three cases carried rare germline loss-offunction variants in the gene encoding the DNA glycosylase MBD4 2 (Fig. 1c, Extended Data Table 1). Case EMC-AML-1 carried a homozygous MBD4 in-frame deletion of Histidine 567 (His567) in the glycosylase domain. An in vitro glycosylase assay confirmed that loss of His567 results in a catalytically inactive MBD4 protein (Fig. 1c). The siblings (WEHI-AML-1, WEHI-AML-2) were compound heterozygotes with a frameshift in exon 3 and a variant that disrupts the splice acceptor of exon 7 (Fig. 1c, Extended Data Table 1). Analysis of the MBD4 mRNA allowed for phasing of the variants to distinct alleles and confirmed aberrant splicing that excludes exon 7 and disrupts the glycosylase domain (Extended Data Fig. 2). MBD4 has not previously been associated with haematological malignancy, but somatic mutations have been detected in sporadic colon cancers with mismatch repair (MMR) deficiency 6,7 . Two patients...

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“…Public Track hubs are available at the UCSC genome browser (Tyner et al 2016) at (genome.ucsc.edu/cgi-bin/hgHubConnect?) and the Ensembl genome browser (Hubbard et al 2007;Aken et al 2016) via a track hub registry search . CC-BY-ND 4.0 International license peer-reviewed) is the author/funder.…”

Section: Data Accessmentioning

confidence: 99%

UniProt Genomic Mapping for Deciphering Functional Effects of Missense Variants

McGarvey

Nightingale

Luo

et al. 2017

Preprint

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The integration of protein function knowledge in the UniProt Knowledgebase (UniProtKB) with genomic data provides unique opportunities for biomedical research by helping scientists to rapidly comprehend complex processes in biology. UniProtKB provides expert curation of functionally characterized variants reported in the literature, many of them associated with disease.Understanding the association of genetic variation with its functional consequences in proteins is essential for the interpretation of large-scale genomics data. UniProtKB protein sequences and sequence feature annotations such as active sites, modified sites, binding domains and amino acid variation have been mapped to the current build of the human genome (GRCh38). We have also created public track hubs for the Ensembl and UCSC browsers. We examine some specific biological examples in disease-related genes and proteins, illustrating the utility of combining protein and genome annotations for the functional interpretation of variants. We also present a larger comparison of UniProtKB variant and feature curation data that collocates with clinically observed SNP data from ClinVar, illustrating how protein and gene disease annotations currently compare and discuss some additional uses that might follow with combined annotation. The combination of gene and protein annotation can assist medical geneticists with the functional interpretation of variation. The genomic track hubs are downloadable from the UniProt FTP site (http://www.uniprot.org/downloads) and directly discoverable as public track hubs at the USCS and Ensembl genome browsers.

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Ensembl 2017

Cited by 546 publications

References 52 publications

Sex-biased microRNA expression in mammals and birds reveals underlying regulatory mechanisms and a role in dosage compensation

Sex-biased microRNA expression in mammals and birds reveals underlying regulatory mechanisms and a role in dosage compensation

Germline loss of MBD4 predisposes to leukaemia due to a mutagenic cascade driven by 5mC

UniProt Genomic Mapping for Deciphering Functional Effects of Missense Variants

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