165 results found
Wragg JW, Roos L, Vucenovic D, et al., 2020, Embryonic tissue differentiation is characterized by transitions in cell cycle dynamic-associated core promoter regulation, NUCLEIC ACIDS RESEARCH, Vol: 48, Pages: 8374-8392, ISSN: 0305-1048
Yu C, Cvetesic N, Gupta K, et al., 2020, TBPL2/TFIIA complex overhauls oocyte transcriptome during oocyte growth
<jats:p>The first steps of oocyte development from primordial follicle are characterised by a growth phase, when unique RNA and protein reserves are created to achieve oocyte competence. During this growth, oocytes do not divide and the general transcription factor TATA binding protein (TBP) is replaced by its paralogue, TBPL2 (also called TBP2 or TRF3), which is essential for RNA polymerase II transcription (Pol II) <jats:sup>1,2</jats:sup>. However, the composition and function of transcription machinery and the regulatory mechanisms mediating Pol II transcription during this developmental stage remain unknown. In somatic cells, the general transcription factor TFIID, which contains TBP and 13 TBP-associated factors, is the first to bind gene promoters to nucleate Pol II transcription initiation<jats:sup>3</jats:sup>. Here, we show that in oocytes TBPL2 does not assemble into a canonical TFIID complex, while it stably associates with TFIIA via distinct TFIIA interactions when compared to TBP. Our transcript analyses in wild type and <jats:italic>Tbpl2</jats:italic><jats:sup><jats:italic>-/-</jats:italic></jats:sup> oocytes demonstrates that TBPL2 mediates transcription of oocyte-expressed genes, including mRNA destabilisation factors genes, as well as specific endogenous retroviral elements (ERVs). Transcription start site (TSS) mapping from wild-type and <jats:italic>Tbpl2</jats:italic><jats:sup><jats:italic>-/-</jats:italic></jats:sup> growing oocytes demonstrates that TBPL2 has a strong preference for TATA-like motif in gene core promoters driving specific sharp TSS selection. This is in marked contrast with TBP/TFIID-driven TATA-less gene promoters in preceding stages that have broad TSS architecture. We anticipate that our findings describing oocyte-specific transcription regulation will help to understand the mechanisms associated with primary ovarian insuff
Lewis SH, Ross L, Bain SA, et al., 2020, ------Widespread conservation and lineage-specific diversification of genome-wide DNA methylation patterns across arthropods, PLOS GENETICS, Vol: 16, ISSN: 1553-7404
Lenhard B, Sternberg MJE, 2020, Computational Resources for Molecular Biology: Special Issue 2020, JOURNAL OF MOLECULAR BIOLOGY, Vol: 432, Pages: 3361-3363, ISSN: 0022-2836
Nepal C, Taranta A, Hadzhiev Y, et al., 2020, Ancestrally Duplicated Conserved Noncoding Element Suggests Dual Regulatory Roles of HOTAIR in cis and trans, ISCIENCE, Vol: 23
Bonetti A, Agostini F, Suzuki AM, et al., 2020, RADICL-seq identifies general and cell type-specific principles of genome-wide RNA-chromatin interactions, NATURE COMMUNICATIONS, Vol: 11, ISSN: 2041-1723
Lewis S, Ross L, Bain SA, et al., 2020, Widespread conservation and lineage-specific diversification of genome-wide DNA methylation patterns across arthropods, Publisher: Cold Spring Harbor Laboratory
<jats:title>Abstract</jats:title><jats:p>Cytosine methylation is an ancient epigenetic modification yet its function and extent within genomes is highly variable across eukaryotes. In mammals, methylation controls transposable elements and regulates the promoters of genes. In insects, DNA methylation is generally restricted to a small subset of transcribed genes, with both intergenic regions and transposable elements (TEs) depleted of methylation. The evolutionary origin and the function of these methylation patterns are poorly understood. Here we characterise the evolution of DNA methylation across the arthropod phylum. While the common ancestor of the arthropods had low levels of TE methylation and did not methylate promoters, both of these functions have evolved independently in centipedes and mealybugs. In contrast, methylation of the exons of a subset of transcribed genes is ancestral and widely conserved across the phylum, but has been lost in specific lineages. Remarkably the same set of genes are likely to be methylated in all species that retained exon-enriched methylation. We show that these genes have characteristic patterns of expression correlating to broad transcription initiation sites and well-positioned nucleosomes, providing new insights into potential mechanisms driving methylation patterns over hundreds of millions of years.</jats:p><jats:sec><jats:title>Author Summary</jats:title><jats:p>Animals develop from a single cell to form a complex organism with many specialised cells. Almost all of the fantastic variety of cells must have the same sequence of DNA, and yet they have distinct identities that are preserved even when they divide. This remarkable process is achieved by turning different sets of genes on or off in different types of cell using molecular mechanisms known as “epigenetic gene regulation”.</jats:p><jats:p>Surprisingly, though all animals need epigenetic gene
Nepal C, Hadzhiev Y, Balwierz P, et al., 2020, Dual-initiation promoters with intertwined canonical and TCT/TOP transcription start sites diversify transcript processing, Nature Communications, Vol: 11, ISSN: 2041-1723
Variations in transcription start site (TSS) selection reflect diversity of preinitiation complexes and can impact on post-transcriptional RNA fates. Most metazoan polymerase II-transcribed genes carry canonical initiation with pyrimidine/purine (YR) dinucleotide, while translation machinery-associated genes carry polypyrimidine initiator (5'-TOP or TCT). By addressing the developmental regulation of TSS selection in zebrafish we uncovered a class of dual-initiation promoters in thousands of genes, including snoRNA host genes. 5'-TOP/TCT initiation is intertwined with canonical initiation and used divergently in hundreds of dual-initiation promoters during maternal to zygotic transition. Dual-initiation in snoRNA host genes selectively generates host and snoRNA with often different spatio-temporal expression. Dual-initiation promoters are pervasive in human and fruit fly, reflecting evolutionary conservation. We propose that dual-initiation on shared promoters represents a composite promoter architecture, which can function both coordinately and divergently to diversify RNAs.
Fornes O, Castro-Mondragon JA, Khan A, et al., 2020, JASPAR 2020: update of the open-access database of transcription factor binding profiles, NUCLEIC ACIDS RESEARCH, Vol: 48, Pages: D87-D92, ISSN: 0305-1048
Baresic A, Nash AJ, Dahoun T, et al., 2020, Understanding the genetics of neuropsychiatric disorders: the potential role of genomic regulatory blocks, MOLECULAR PSYCHIATRY, Vol: 25, Pages: 6-18, ISSN: 1359-4184
Tan G, Polychronopoulos D, Lenhard B, 2019, CNEr: A toolkit for exploring extreme noncoding conservation, PLOS COMPUTATIONAL BIOLOGY, Vol: 15, ISSN: 1553-734X
Nash AJ, Lenhard B, 2019, A novel measure of non-coding genome conservation identifies genomic regulatory blocks within primates, BIOINFORMATICS, Vol: 35, Pages: 2354-2361, ISSN: 1367-4803
Cvetesic N, Pahita E, Lenhard B, 2019, Transcription Start Site Mapping Using Super-low Input Carrier-CAGE, JOVE-JOURNAL OF VISUALIZED EXPERIMENTS, ISSN: 1940-087X
Lenhard B, Sternberg MJE, 2019, Computation resources for molecular biology: Special issue 2019, Journal of Molecular Biology, Vol: 431, Pages: 2395-2397, ISSN: 0022-2836
Ferreirós-Vidal I, Carroll T, Zhang T, et al., 2019, Feedforward regulation of Myc coordinates lineage-specific with housekeeping gene expression during B cell progenitor cell differentiation, PLoS Biology, Vol: 17, ISSN: 1544-9173
The differentiation of self-renewingprogenitor cells requires not only the regulation of lineage-and developmental stage-specific genes, but also the coordinated adaptation of housekeeping functionsfrom a metabolically active, proliferative state towards quiescence. How metabolic and cell cycle states are coordinated with the regulation of cell type-specific genes is an important question, as dissociation between differentiation, cell cycle, and metabolic states is a hallmark of cancer. Here we use a model system to systematically identify key transcriptional regulators of Ikaros-dependent B cell progenitor differentiation. We find that the coordinated regulation of housekeeping functions and tissue-specific gene expressionrequires afeedforward circuit whereby Ikarosdownregulates the expression of Myc. Our findings show how coordination between differentiation and housekeeping statescan be achieved by interconnected regulators. Similar principles likely coordinate differentiation and housekeeping functions during progenitor cell differentiation in other cell lineages.
Tan G, Polychronopoulos D, Lenhard B, 2019, CNEr: a toolkit for exploring extreme noncoding conservation, Publisher: Cold Spring Harbor Laboratory
<jats:title>Abstract</jats:title><jats:p>Conserved Noncoding Elements (CNEs) are elements exhibiting extreme noncoding conservation in Metazoan genomes. They cluster around developmental genes and act as long-range enhancers, yet nothing that we know about their function explains the observed conservation levels. Clusters of CNEs coincide with topologically associating domains (TADs), indicating ancient origins and stability of TAD locations. This has suggested further hypotheses about the still elusive origin of CNEs, and has provided a comparative genomics-based method of estimating the position of TADs around developmentally regulated genes in genomes where chromatin conformation capture data is missing. To enable researchers in gene regulation and chromatin biology to start deciphering this phenomenon, we developed<jats:italic>CNEr</jats:italic>, a R/Bioconductor toolkit for large-scale identification of CNEs and for studying their genomic properties. We apply<jats:italic>CNEr</jats:italic>to two novel genome comparisons - fruit fly vs tsetse fly, and two sea urchin genomes - and report novel insights gained from their analysis. We also show how to reveal interesting characteristics of CNEs by coupling CNEr with existing Bioconductor packages.<jats:italic>CNEr</jats:italic>is available at Bioconductor (<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://bioconductor.org/packages/CNEr/">https://bioconductor.org/packages/CNEr/</jats:ext-link>) and maintained at github (<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://github.com/ge11232002/CNEr">https://github.com/ge11232002/CNEr</jats:ext-link>).</jats:p>
Borlin CS, Cvetesic N, Holland P, et al., 2019, Saccharomyces cerevisiae displays a stable transcription start site landscape in multiple conditions, FEMS YEAST RESEARCH, Vol: 19, ISSN: 1567-1356
CRISPR/Cas9 is a powerful genome-editing tool, but spurious off-target edits present a barrier to therapeutic applications. To understand how CRISPR/Cas9 discriminates between on-targets and off-targets, we have developed a single-molecule assay combining optical tweezers with fluorescence to monitor binding to λ-DNA. At low forces, the Streptococcus pyogenes Cas9 complex binds and cleaves DNA specifically. At higher forces, numerous off-target binding events appear repeatedly at the same off-target sites in a guide-RNA-sequence-dependent manner, driven by the mechanical distortion of the DNA. Using single-molecule Förster resonance energy transfer (smFRET) and cleavage assays, we show that DNA bubbles induce off-target binding and cleavage at these sites, even with ten mismatches, as well as at previously identified in vivo off-targets. We propose that duplex DNA destabilization during cellular processes (for example, transcription, replication, etc.) can expose these cryptic off-target sites to Cas9 activity, highlighting the need for improved off-target prediction algorithms.
Newton M, Taylor B, Driessen R, et al., 2018, DNA stretching induces Cas9 off-target binding and cleavage, Nature Structural and Molecular Biology, ISSN: 1545-9985
CRISPR/Cas9 is a powerful genome editing tool, but spurious off-target edits present a barrier towards therapeutic applications. To understand how CRISPR/Cas9 discrimi-nates between on- and off-targets, we have developed a single-molecule assay com-bining optical tweezers with fluorescence to monitor binding to λ-DNA. At low forces, the Streptococcus pyogenes Cas9 complex binds and cleaves DNA specifically. At higher forces, numerous off-target binding events appear repeatedly at the same off-target sites in a guide-RNA-sequence dependent manner, driven by the mechanical distortion of the DNA. Using single-molecule FRET and cleavage assays, we show that DNA bubbles induce off-target binding and cleavage at these sites, even with 10 mis-matches, as well as at previously identified in vivo off-targets. We propose that duplex DNA destabilization during cellular processes (e.g., transcription, replication, etc) can expose these cryptic off-target sites to Cas9 activity, highlighting the need for improved off-target prediction algorithms.
Marletaz F, Firbas PN, Maeso I, et al., 2018, Amphioxus functional genomics and the origins of vertebrate gene regulation, Nature, Vol: 564, Pages: 64-70, ISSN: 0028-0836
Vertebrates have greatly elaborated the basic chordate body plan and evolved highly distinctive genomes that have been sculpted by two whole-genome duplications. Here we sequence the genome of the Mediterranean amphioxus (Branchiostoma lanceolatum) and characterize DNA methylation, chromatin accessibility, histone modifications and transcriptomes across multiple developmental stages and adult tissues to investigate the evolution of the regulation of the chordate genome. Comparisons with vertebrates identify an intermediate stage in the evolution of differentially methylated enhancers, and a high conservation of gene expression and its cis-regulatory logic between amphioxus and vertebrates that occurs maximally at an earlier mid-embryonic phylotypic period. We analyse regulatory evolution after whole-genome duplications, and find that—in vertebrates—over 80% of broadly expressed gene families with multiple paralogues derived from whole-genome duplications have members that restricted their ancestral expression, and underwent specialization rather than subfunctionalization. Counter-intuitively, paralogues that restricted their expression increased the complexity of their regulatory landscapes. These data pave the way for a better understanding of the regulatory principles that underlie key vertebrate innovations.
Cvetesic N, Leitch HG, Borkowska M, et al., 2018, SLIC-CAGE: high-resolution transcription start site mapping using nanogram-levels of total RNA, Genome Research, Vol: 28, Pages: 1943-1956, ISSN: 1088-9051
Cap analysis of gene expression (CAGE) is a methodology for genome-wide quantitative mapping of mRNA 5′ ends to precisely capture transcription start sites at a single nucleotide resolution. In combination with high-throughput sequencing, CAGE has revolutionized our understanding of rules of transcription initiation, led to discovery of new core promoter sequence features and discovered transcription initiation at enhancers genome-wide. The biggest limitation of CAGE is that even the most recently improved version (nAnT-iCAGE) still requires large amounts of total cellular RNA (5 micrograms), preventing its application to scarce biological samples such as those from early embryonic development or rare cell types. Here, we present SLIC-CAGE, a Super-Low Input Carrier-CAGE approach to capture 5′ ends of RNA polymerase II transcripts from as little as 5-10 ng of total RNA. The dramatic increase in sensitivity is achieved by specially designed, selectively degradable carrier RNA. We demonstrate the ability of SLIC-CAGE to generate data for genome-wide promoterome with 1000-fold less material than required by existing CAGE methods by generating a complex, high quality library from mouse embryonic day (E) 11.5 primordial germ cells.
Merkenschlager M, Cuartero S, Weiss F, et al., 2018, Control of inducible gene expression links cohesin to hematopoietic progenitor self-renewal and differentiation, Nature Immunology, Vol: 19, Pages: 932-941, ISSN: 1529-2908
Cohesin is important for 3D genome organization. Nevertheless, even the complete removal of cohesin has surprisingly little impact on steady-state gene transcription and enhancer activity. Here we show that cohesin is required for the core transcriptional response of primary macrophages to microbial signals, and for inducible enhancer activity that underpins inflammatory gene expression. Consistent with a role for inflammatory signals in promoting myeloid differentiation of hematopoietic stem and progenitor cells (HPSCs), cohesin mutations in HSPCs led to reduced inflammatory gene expression and increased resistance to differentiation-inducing inflammatory stimuli. These findings uncover an unexpected dependence of inducible gene expression on cohesin, link cohesin with myeloid differentiation, and may help explain the prevalence of cohesin mutations in human acute myeloid leukemia.
Börlin CS, Cvetesic N, Holland P, et al., 2018, Saccharomyces cerevisiae displays a stable transcription start site landscape in multiple conditions, Publisher: Cold Spring Harbor Laboratory
<jats:title>ABSTRACT</jats:title><jats:p>One of the fundamental processes that determine cellular fate is regulation of gene transcription. Understanding these regulatory processes is therefore essential for understanding cellular responses to changes in environmental conditions. At the core promoter, the regulatory region containing the transcription start site (TSS), all inputs regulating transcription are integrated. Here, we used Cap Analysis of Gene Expression (CAGE) to analyze the pattern of transcription start sites at four different environmental conditions (limited in ethanol, limited in nitrogen, limited in glucose and limited in glucose under anaerobic conditions) using the Saccharomyces cerevisiae strain CEN.PK113-7D. With this experimental setup we were able to show that the TSS landscape in yeast is stable at different metabolic states of the cell. We also show that the shape index, a characteristic feature of each TSS describing the spatial distribution of transcription initiation events, has a surprisingly strong negative correlation with the measured expression levels. Our analysis supplies a set of high quality TSS annotations useful for metabolic engineering and synthetic biology approaches in the industrially relevant laboratory strain CEN.PK113-7D, and provides novel insights into yeast TSS dynamics and gene regulation.</jats:p>
Lessel D, Gehbauer C, Bramswig NC, et al., 2018, BCL11B mutations in patients affected by a neurodevelopmental disorder with reduced type 2 innate lymphoid cells, BRAIN, Vol: 141, Pages: 2299-2311, ISSN: 0006-8950
Li C, Lenhard B, Luscombe NM, 2018, Integrated analysis sheds light on evolutionary trajectories of young transcription start sites in the human genome, Genome Research, Vol: 28, Pages: 676-688, ISSN: 1088-9051
Understanding the molecular mechanisms and evolution of the gene regulatory system remains a major challenge in biology. Transcription start sites (TSSs) are especially interesting because they are central to initiating gene expression. Previous studies revealed widespread transcription initiation and fast turnover of TSSs in mammalian genomes. Yet, how new TSSs originate and how they evolve over time remain poorly understood. To address these questions, we analyzed ∼200,000 human TSSs by integrating evolutionary (inter- and intra-species) and functional genomic data, particularly focusing on evolutionarily young TSSs that emerged in the primate lineage. TSSs were grouped according to their evolutionary age using sequence alignment information as a proxy. Comparisons of young and old TSSs revealed that (1) new TSSs emerge through a combination of intrinsic factors, like the sequence properties of transposable elements and tandem repeats, and extrinsic factors such as their proximity to existing regulatory modules; (2) new TSSs undergo rapid evolution that reduces the inherent instability of repeat sequences associated with a high propensity of TSS emergence; and (3) once established, the transcriptional competence of surviving TSSs is gradually enhanced, with evolutionary changes subject to temporal (fewer regulatory changes in younger TSSs) and spatial constraints (fewer regulatory changes in more isolated TSSs). These findings advance our understanding of how regulatory innovations arise in the genome throughout evolution and highlight the genomic robustness and evolvability in these processes.
Hill PWS, Leitch HG, Requena CE, et al., 2018, Epigenetic reprogramming enables the transition from primordial germ cell to gonocyte, Nature, Vol: 555, Pages: 392-396, ISSN: 0028-0836
Gametes are highly specialized cells that can give rise to the next generation through their ability to generate a totipotent zygote. In mice, germ cells are first specified in the developing embryo around embryonic day (E) 6.25 as primordial germ cells (PGCs)1. Following subsequent migration into the developing gonad, PGCs undergo a wave of extensive epigenetic reprogramming around E10.5–E11.52,3,4,5,6,7,8,9,10,11, including genome-wide loss of 5-methylcytosine2,3,4,5,7,8,9,10,11. The underlying molecular mechanisms of this process have remained unclear, leading to our inability to recapitulate this step of germline development in vitro12,13,14. Here we show, using an integrative approach, that this complex reprogramming process involves coordinated interplay among promoter sequence characteristics, DNA (de)methylation, the polycomb (PRC1) complex and both DNA demethylation-dependent and -independent functions of TET1 to enable the activation of a critical set of germline reprogramming-responsive genes involved in gamete generation and meiosis. Our results also reveal an unexpected role for TET1 in maintaining but not driving DNA demethylation in gonadal PGCs. Collectively, our work uncovers a fundamental biological role for gonadal germline reprogramming and identifies the epigenetic principles of the PGC-to-gonocyte transition that will help to guide attempts to recapitulate complete gametogenesis in vitro.
Danks GB, Navratilova P, Lenhard B, et al., 2018, Distinct core promoter codes drive transcription initiation at key developmental transitions in a marine chordate, BMC Genomics, Vol: 19, ISSN: 1471-2164
BACKGROUND: Development is largely driven by transitions between transcriptional programs. The initiation of transcription at appropriate sites in the genome is a key component of this and yet few rules governing selection are known. Here, we used cap analysis of gene expression (CAGE) to generate bp-resolution maps of transcription start sites (TSSs) across the genome of Oikopleura dioica, a member of the closest living relatives to vertebrates. RESULTS: Our TSS maps revealed promoter features in common with vertebrates, as well as striking differences, and uncovered key roles for core promoter elements in the regulation of development. During spermatogenesis there is a genome-wide shift in mode of transcription initiation characterized by a novel core promoter element. This element was associated with > 70% of male-specific transcription, including the use of cryptic internal promoters within operons. In many cases this led to the exclusion of trans-splice sites, revealing a novel mechanism for regulating which mRNAs receive the spliced leader. Binding of the cell cycle regulator, E2F1, is enriched at the TSS of maternal genes in endocycling nurse nuclei. In addition, maternal promoters lack the TATA-like element found in zebrafish and have broad, rather than sharp, architectures with ordered nucleosomes. Promoters of ribosomal protein genes lack the highly conserved TCT initiator. We also report an association between DNA methylation on transcribed gene bodies and the TATA-box. CONCLUSIONS: Our results reveal that distinct functional promoter classes and overlapping promoter codes are present in protochordates like in vertebrates, but show extraordinary lineage-specific innovations. Furthermore, we uncover a genome-wide, developmental stage-specific shift in the mode of TSS selection. Our results provide a rich resource for the study of promoter structure and evolution in Metazoa.
Khan A, Fornes O, Stigliani A, et al., 2018, Erratum: JASPAR 2018: update of the open-access database of transcription factor binding profiles and its web framework, Nucleic Acids Research, Vol: 46, Pages: D1284-D1284, ISSN: 0305-1048
Khan A, Fornes O, Stigliani A, et al., 2017, JASPAR 2018: update of the open-access database of transcription factor binding profiles and its web framework., Nucleic Acids Research, Vol: 46, Pages: D260-D266, ISSN: 0305-1048
JASPAR (http://jaspar.genereg.net) is an open-access database of curated, non-redundant transcription factor (TF)-binding profiles stored as position frequency matrices (PFMs) and TF flexible models (TFFMs) for TFs across multiple species in six taxonomic groups. In the 2018 release of JASPAR, the CORE collection has been expanded with 322 new PFMs (60 for vertebrates and 262 for plants) and 33 PFMs were updated (24 for vertebrates, 8 for plants and 1 for insects). These new profiles represent a 30% expansion compared to the 2016 release. In addition, we have introduced 316 TFFMs (95 for vertebrates, 218 for plants and 3 for insects). This release incorporates clusters of similar PFMs in each taxon and each TF class per taxon. The JASPAR 2018 CORE vertebrate collection of PFMs was used to predict TF-binding sites in the human genome. The predictions are made available to the scientific community through a UCSC Genome Browser track data hub. Finally, this update comes with a new web framework with an interactive and responsive user-interface, along with new features. All the underlying data can be retrieved programmatically using a RESTful API and through the JASPAR 2018 R/Bioconductor package.
Polychronopoulos D, King JWD, Nash AJ, et al., 2017, Conserved non-coding elements: developmental gene regulation meets genome organization., Nucleic Acids Research, Vol: 45, Pages: 12611-12624, ISSN: 0305-1048
Comparative genomics has revealed a class of non-protein-coding genomic sequences that display an extraordinary degree of conservation between two or more organisms, regularly exceeding that found within protein-coding exons. These elements, collectively referred to as conserved non-coding elements (CNEs), are non-randomly distributed across chromosomes and tend to cluster in the vicinity of genes with regulatory roles in multicellular development and differentiation. CNEs are organized into functional ensembles called genomic regulatory blocks-dense clusters of elements that collectively coordinate the expression of shared target genes, and whose span in many cases coincides with topologically associated domains. CNEs display sequence properties that set them apart from other sequences under constraint, and have recently been proposed as useful markers for the reconstruction of the evolutionary history of organisms. Disruption of several of these elements is known to contribute to diseases linked with development, and cancer. The emergence, evolutionary dynamics and functions of CNEs still remain poorly understood, and new approaches are required to enable comprehensive CNE identification and characterization. Here, we review current knowledge and identify challenges that need to be tackled to resolve the impasse in understanding extreme non-coding conservation.
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