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1.  Fate by RNA methylation: m6A steers stem cell pluripotency 
Genome Biology  2015;16(1):43.
The N6-methyladenosine (m6A) modification of mRNA has a crucial function in regulating pluripotency in murine stem cells: it facilitates resolution of naïve pluripotency towards differentiation.
PMCID: PMC4336730
2.  It’s only human 
Genome Biology  2014;15(2):104.
PMCID: PMC4056517  PMID: 24517726
3.  Erratum to: The draft genome of a socially polymorphic halictid bee, Lasioglossum albipes 
Genome Biology  2015;16(1):34.
During the type-setting of the final version of the article [1] some of the additional files were swapped, and several were completely replaced. The correct files are republished in this Erratum.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-014-0574-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4326530
4.  Rapid reprogramming of epigenetic and transcriptional profiles in mammalian culture systems 
Genome Biology  2015;16(1):11.
The DNA methylation profiles of mammalian cell lines differ from those of the primary tissues from which they were derived, exhibiting increasing divergence from the in vivo methylation profile with extended time in culture. Few studies have directly examined the initial epigenetic and transcriptional consequences of adaptation of primary mammalian cells to culture, and the potential mechanisms through which this epigenetic dysregulation occurs is unknown.
We demonstrate that adaptation of mouse embryonic fibroblasts to cell culture results in a rapid reprogramming of epigenetic and transcriptional states. We observed global 5-hydroxymethylcytosine (5hmC) erasure within three days of culture initiation. Loss of genic 5hmC was independent of global 5-methylcytosine (5mC) levels and could be partially rescued by addition of vitamin C. Significantly, 5hmC loss was not linked to concomitant changes in transcription. Discrete promoter-specific gains of 5mC were also observed within seven days of culture initiation. Against this background of global 5hmC loss we identified a handful of developmentally important genes that maintained their 5hmC profile in culture, including the imprinted loci Gnas and H19. Similar outcomes were identified in the adaption of CD4+ T cells to culture.
We report a dramatic and novel consequence of adaptation of mammalian cells to culture in which global loss of 5hmC occurs, suggesting rapid concomitant loss of methylcytosine dioxygenase activity. The observed epigenetic and transcriptional re-programming occurs much earlier than previously assumed, and has significant implications for the use of cell lines as faithful mimics of in vivo epigenetic and physiological processes.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-014-0576-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4334405  PMID: 25648825
5.  Assembling allopolyploid genomes: no longer formidable 
Genome Biology  2015;16(1):27.
A combined approach of whole genome shotgun sequencing and ultra-high density linkage mapping using skim sequencing of a segregating population is effective for assembling allopolyploid genomes.
See related Research,
PMCID: PMC4312463
6.  Analysis of long non-coding RNAs highlights tissue-specific expression patterns and epigenetic profiles in normal and psoriatic skin 
Genome Biology  2015;16(1):24.
Although analysis pipelines have been developed to use RNA-seq to identify long non-coding RNAs (lncRNAs), inference of their biological and pathological relevance remains a challenge. As a result, most transcriptome studies of autoimmune disease have only assessed protein-coding transcripts.
We used RNA-seq data from 99 lesional psoriatic, 27 uninvolved psoriatic, and 90 normal skin biopsies, and applied computational approaches to identify and characterize expressed lncRNAs. We detect 2,942 previously annotated and 1,080 novel lncRNAs which are expected to be skin specific. Notably, over 40% of the novel lncRNAs are differentially expressed and the proportions of differentially expressed transcripts among protein-coding mRNAs and previously-annotated lncRNAs are lower in psoriasis lesions versus uninvolved or normal skin. We find that many lncRNAs, in particular those that are differentially expressed, are co-expressed with genes involved in immune related functions, and that novel lncRNAs are enriched for localization in the epidermal differentiation complex. We also identify distinct tissue-specific expression patterns and epigenetic profiles for novel lncRNAs, some of which are shown to be regulated by cytokine treatment in cultured human keratinocytes.
Together, our results implicate many lncRNAs in the immunopathogenesis of psoriasis, and our results provide a resource for lncRNA studies in other autoimmune diseases.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-014-0570-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4311508
7.  Comprehensive miRNA sequence analysis reveals survival differences in diffuse large B-cell lymphoma patients 
Genome Biology  2015;16(1):18.
Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease, with 30% to 40% of patients failing to be cured with available primary therapy. microRNAs (miRNAs) are RNA molecules that attenuate expression of their mRNA targets. To characterize the DLBCL miRNome, we sequenced miRNAs from 92 DLBCL and 15 benign centroblast fresh frozen samples and from 140 DLBCL formalin-fixed, paraffin-embedded tissue samples for validation.
We identify known and candidate novel miRNAs, 25 of which are associated with survival independently of cell-of-origin and International Prognostic Index scores, which are established indicators of outcome. Of these 25 miRNAs, six miRNAs are significantly associated with survival in our validation cohort. Abundant expression of miR-28-5p, miR-214-5p, miR-339-3p, and miR-5586-5p is associated with superior outcome, while abundant expression of miR-324-5p and NOVELM00203M is associated with inferior outcome. Comparison of DLBCL miRNA-seq expression profiles with those from other cancer types identifies miRNAs that were more abundant in B-cell contexts. Unsupervised clustering of miRNAs identifies two clusters of patients that have distinct differences in their outcomes. Our integrative miRNA and mRNA expression analyses reveal that miRNAs increased in abundance in DLBCL appear to regulate the expression of genes involved in metabolism, cell cycle, and protein modification. Additionally, these miRNAs, including one candidate novel miRNA, miR-10393-3p, appear to target chromatin modification genes that are frequent targets of somatic mutation in non-Hodgkin lymphomas.
Our comprehensive sequence analysis of the DLBCL miRNome identifies candidate novel miRNAs and miRNAs associated with survival, reinforces results from previous mutational analyses, and reveals regulatory networks of significance for lymphomagenesis.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-014-0568-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4308918
8.  Avianbase: a community resource for bird genomics 
Genome Biology  2015;16(1):21.
Giving access to sequence and annotation data for genome assemblies is important because, while facilitating research, it places both assembly and annotation quality under scrutiny, resulting in improvements to both. Therefore we announce Avianbase, a resource for bird genomics, which provides access to data released by the Avian Phylogenomics Consortium.
PMCID: PMC4310197
9.  Identification of evolutionarily meaningful information within the mammalian RNA editing landscape 
Genome Biology  2014;15(1):103.
A large comparative genomic sequence study has determined the extent of conservation between RNA editing sites within the mammalian evolutionary tree.
See related research by Pinto et al.,
PMCID: PMC4053966  PMID: 24468094
10.  Of RNA-binding proteins and their targets: interaction determines expression 
Genome Biology  2014;15(1):102.
Combining the prediction of interactions between mRNAs and RNA-binding proteins with experimental expression profiles uncovers novel regulatory paradigms concerning proliferation and differentiation processes.
See related research,
PMCID: PMC4053697  PMID: 24468021
11.  To be or not to be a piRNA: genomic origin and processing of piRNAs 
Genome Biology  2014;15(1):204.
Piwi-interacting RNAs (piRNAs) originate from genomic regions dubbed piRNA clusters. How cluster transcripts are selected for processing into piRNAs is not understood. We discuss evidence for the involvement of chromatin structure and maternally inherited piRNAs in determining their fate.
PMCID: PMC4053809  PMID: 24467990
12.  Smaug destroys a huge treasure 
Genome Biology  2014;15(1):101.
Smaug, a protein repressing translation and inducing mRNA decay, directly controls an unexpectedly large number of maternal mRNAs driving early Drosophila development.
See related research,
PMCID: PMC4054708  PMID: 24468051
13.  Methods for comprehensive experimental identification of RNA-protein interactions 
Genome Biology  2014;15(1):203.
The importance of RNA-protein interactions in controlling mRNA regulation and non-coding RNA function is increasingly appreciated. A variety of methods exist to comprehensively define RNA-protein interactions. We describe these methods and the considerations required for designing and interpreting these experiments.
PMCID: PMC4054858  PMID: 24467948
14.  Seq and CLIP through the miRNA world 
Genome Biology  2014;15(1):202.
High-throughput sequencing of RNAs crosslinked to Argonaute proteins reveals not only a multitude of atypical miRNA binding sites but also of miRNA targets with atypical functions, and can be used to infer quantitative models of miRNA-target interaction strength.
PMCID: PMC4053862  PMID: 24460822
15.  Extending reference assembly models 
Genome Biology  2015;16(1):13.
The human genome reference assembly is crucial for aligning and analyzing sequence data, and for genome annotation, among other roles. However, the models and analysis assumptions that underlie the current assembly need revising to fully represent human sequence diversity. Improved analysis tools and updated data reporting formats are also required.
PMCID: PMC4305238  PMID: 25651527
16.  The draft genome of Primula veris yields insights into the molecular basis of heterostyly 
Genome Biology  2015;16(1):12.
The flowering plant Primula veris is a common spring blooming perennial that is widely cultivated throughout Europe. This species is an established model system in the study of the genetics, evolution, and ecology of heterostylous floral polymorphisms. Despite the long history of research focused on this and related species, the continued development of this system has been restricted due the absence of genomic and transcriptomic resources.
We present here a de novo draft genome assembly of P. veris covering 301.8 Mb, or approximately 63% of the estimated 479.22 Mb genome, with an N50 contig size of 9.5 Kb, an N50 scaffold size of 164 Kb, and containing an estimated 19,507 genes. The results of a RADseq bulk segregant analysis allow for the confident identification of four genome scaffolds that are linked to the P. veris S-locus. RNAseq data from both P. veris and the closely related species P. vulgaris allow for the characterization of 113 candidate heterostyly genes that show significant floral morph-specific differential expression. One candidate gene of particular interest is a duplicated GLOBOSA homolog that may be unique to Primula (PveGLO2), and is completely silenced in L-morph flowers.
The P. veris genome represents the first genome assembled from a heterostylous species, and thus provides an immensely important resource for future studies focused on the evolution and genetic dissection of heterostyly. As the first genome assembled from the Primulaceae, the P. veris genome will also facilitate the expanded application of phylogenomic methods in this diverse family and the eudicots as a whole.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-014-0567-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4305239  PMID: 25651398
17.  Exon identity crisis: disease-causing mutations that disrupt the splicing code 
Genome Biology  2014;15(1):201.
Cis-acting RNA elements control the accurate expression of human multi-exon protein coding genes. Single nucleotide variants altering the fidelity of this regulatory code and, consequently, pre-mRNA splicing are expected to contribute to the etiology of numerous human diseases.
PMCID: PMC4053859  PMID: 24456648
18.  An analysis of DNA methylation in human adipose tissue reveals differential modification of obesity genes before and after gastric bypass and weight loss 
Genome Biology  2015;16(1):8.
Environmental factors can influence obesity by epigenetic mechanisms. Adipose tissue plays a key role in obesity-related metabolic dysfunction, and gastric bypass provides a model to investigate obesity and weight loss in humans.
Here, we investigate DNA methylation in adipose tissue from obese women before and after gastric bypass and significant weight loss. In total, 485,577 CpG sites were profiled in matched, before and after weight loss, subcutaneous and omental adipose tissue. A paired analysis revealed significant differential methylation in omental and subcutaneous adipose tissue. A greater proportion of CpGs are hypermethylated before weight loss and increased methylation is observed in the 3′ untranslated region and gene bodies relative to promoter regions. Differential methylation is found within genes associated with obesity, epigenetic regulation and development, such as CETP, FOXP2, HDAC4, DNMT3B, KCNQ1 and HOX clusters. We identify robust correlations between changes in methylation and clinical trait, including associations between fasting glucose and HDAC4, SLC37A3 and DENND1C in subcutaneous adipose. Genes investigated with differential promoter methylation all show significantly different levels of mRNA before and after gastric bypass.
This is the first study reporting global DNA methylation profiling of adipose tissue before and after gastric bypass and associated weight loss. It provides a strong basis for future work and offers additional evidence for the role of DNA methylation of adipose tissue in obesity.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-014-0569-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4301800  PMID: 25651499
19.  Churchill: an ultra-fast, deterministic, highly scalable and balanced parallelization strategy for the discovery of human genetic variation in clinical and population-scale genomics 
Genome Biology  2015;16(1):6.
While advances in genome sequencing technology make population-scale genomics a possibility, current approaches for analysis of these data rely upon parallelization strategies that have limited scalability, complex implementation and lack reproducibility. Churchill, a balanced regional parallelization strategy, overcomes these challenges, fully automating the multiple steps required to go from raw sequencing reads to variant discovery. Through implementation of novel deterministic parallelization techniques, Churchill allows computationally efficient analysis of a high-depth whole genome sample in less than two hours. The method is highly scalable, enabling full analysis of the 1000 Genomes raw sequence dataset in a week using cloud resources.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-014-0577-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4333267  PMID: 25600152
20.  Next-generation plant science: putting big data to work 
Genome Biology  2014;15(1):301.
A Report on the Plant Genomes & Biotechnology: From Genes to Networks meeting, held at the Cold Spring Harbor Laboratories, USA, December 4–7, 2013.
PMCID: PMC4053971  PMID: 24423368
21.  ALLMAPS: robust scaffold ordering based on multiple maps 
Genome Biology  2015;16(1):3.
The ordering and orientation of genomic scaffolds to reconstruct chromosomes is an essential step during de novo genome assembly. Because this process utilizes various mapping techniques that each provides an independent line of evidence, a combination of multiple maps can improve the accuracy of the resulting chromosomal assemblies. We present ALLMAPS, a method capable of computing a scaffold ordering that maximizes colinearity across a collection of maps. ALLMAPS is robust against common mapping errors, and generates sequences that are maximally concordant with the input maps. ALLMAPS is a useful tool in building high-quality genome assemblies. ALLMAPS is available at:
PMCID: PMC4305236  PMID: 25583564
22.  CIRI: an efficient and unbiased algorithm for de novo circular RNA identification 
Genome Biology  2015;16(1):4.
Recent studies reveal that circular RNAs (circRNAs) are a novel class of abundant, stable and ubiquitous noncoding RNA molecules in animals. Comprehensive detection of circRNAs from high-throughput transcriptome data is an initial and crucial step to study their biogenesis and function. Here, we present a novel chiastic clipping signal-based algorithm, CIRI, to unbiasedly and accurately detect circRNAs from transcriptome data by employing multiple filtration strategies. By applying CIRI to ENCODE RNA-seq data, we for the first time identify and experimentally validate the prevalence of intronic/intergenic circRNAs as well as fragments specific to them in the human transcriptome.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-014-0571-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4316645  PMID: 25583365
23.  De novo assembly of bacterial transcriptomes from RNA-seq data 
Genome Biology  2015;16(1):1.
Transcriptome assays are increasingly being performed by high-throughput RNA sequencing (RNA-seq). For organisms whose genomes have not been sequenced and annotated, transcriptomes must be assembled de novo from the RNA-seq data. Here, we present novel algorithms, specific to bacterial gene structures and transcriptomes, for analysis of bacterial RNA-seq data and de novo transcriptome assembly. The algorithms are implemented in an open source software system called Rockhopper 2. We find that Rockhopper 2 outperforms other de novo transcriptome assemblers and offers accurate and efficient analysis of bacterial RNA-seq data. Rockhopper 2 is available at
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-014-0572-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4316799  PMID: 25583448
24.  Modulation of microRNA editing, expression and processing by ADAR2 deaminase in glioblastoma 
Genome Biology  2015;16(1):5.
ADAR enzymes convert adenosines to inosines within double-stranded RNAs, including microRNA (miRNA) precursors, with important consequences on miRNA retargeting and expression. ADAR2 activity is impaired in glioblastoma and its rescue has anti-tumoral effects. However, how ADAR2 activity may impact the miRNome and the progression of glioblastoma is not known.
By integrating deep-sequencing and array approaches with bioinformatics analyses and molecular studies, we show that ADAR2 is essential to edit a small number of mature miRNAs and to significantly modulate the expression of about 90 miRNAs in glioblastoma cells. Specifically, the rescue of ADAR2 activity in cancer cells recovers the edited miRNA population lost in glioblastoma cell lines and tissues, and rebalances expression of onco-miRNAs and tumor suppressor miRNAs to the levels observed in normal human brain. We report that the major effect of ADAR2 is to reduce the expression of a large number of miRNAs, most of which act as onco-miRNAs. ADAR2 can edit miR-222/221 and miR-21 precursors and decrease the expression of the corresponding mature onco-miRNAs in vivo and in vitro, with important effects on cell proliferation and migration.
Our findings disclose an additional layer of complexity in miRNome regulation and provide information to better understand the impact of ADAR2 editing enzyme in glioblastoma. We propose that ADAR2 is a key factor for maintaining edited-miRNA population and balancing the expression of several essential miRNAs involved in cancer.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-014-0575-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4326501  PMID: 25582055
25.  Identification of novel fusion genes in lung cancer using breakpoint assembly of transcriptome sequencing data 
Genome Biology  2015;16(1):7.
Genomic translocation events frequently underlie cancer development through generation of gene fusions with oncogenic properties. Identification of such fusion transcripts by transcriptome sequencing might help to discover new potential therapeutic targets. We developed TRUP (Tumor-specimen suited RNA-seq Unified Pipeline) (, a computational approach that combines split-read and read-pair analysis with de novo assembly for the identification of chimeric transcripts in cancer specimens. We apply TRUP to RNA-seq data of different tumor types, and find it to be more sensitive than alternative tools in detecting chimeric transcripts, such as secondary rearrangements in EML4-ALK-positive lung tumors, or recurrent inactivating rearrangements affecting RASSF8.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-014-0558-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4300615  PMID: 25650807

Results 1-25 (3555)