On the immortality of television sets: "function" in the human genome according to the evolution-free gospel of ENCODE.
TL;DR: The ENCODE results were predicted by one of its authors to necessitate the rewriting of textbooks and it is detailed the many logical and methodological transgressions involved in assigning functionality to almost every nucleotide in the human genome.
Abstract: A recent slew of ENCyclopedia Of DNA Elements (ENCODE) Consortium publications, specifically the article signed by all Consortium members, put forward the idea that more than 80% of the human genome is functional. This claim flies in the face of current estimates according to which the fraction of the genome that is evolutionarily conserved through purifying selection is less than 10%. Thus, according to the ENCODE Consortium, a biological function can be maintained indefinitely without selection, which implies that at least 80 − 10 = 70% of the genome is perfectly invulnerable to deleterious mutations, either because no mutation can ever occur in these “functional” regions or because no mutation in these regions can ever be deleterious. This absurd conclusion was reached through various means, chiefly by employing the seldom used “causal role” definition of biological function and then applying it inconsistently to different biochemical properties, by committing a logical fallacy known as “affirming the consequent,” by failing to appreciate the crucial difference between “junk DNA” and “garbage DNA,” by using analytical methods that yield biased errors and inflate estimates of functionality, by favoring statistical sensitivity over specificity, and by emphasizing statistical significance rather than the magnitude of the effect. Here, we detail the many logical and methodological transgressions involved in assigning functionality to almost every nucleotide in the human genome. The ENCODE results were predicted by one of its authors to necessitate the rewriting of textbooks. We agree, many textbooks dealing with marketing, mass-media hype, and public relations may well have to be rewritten.
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Journal Article•
TL;DR: The comparison of related genomes has emerged as a powerful lens for genome interpretation as mentioned in this paper, which reveals a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons.
Abstract: The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ∼4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ∼60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease.
926 citations
Massachusetts Institute of Technology1, California Institute of Technology2, Stanford University3, Harvard University4, Broad Institute5, Duke University6, University of Massachusetts Medical School7, National Institutes of Health8, University of Southern California9, Yale University10, Florida State University11, Cold Spring Harbor Laboratory12, Wellcome Trust Sanger Institute13, University of California, Santa Cruz14, Princeton University15, University of California, San Diego16, University of Washington17, University of Chicago18, Pennsylvania State University19
TL;DR: The strengths and limitations of biochemical, evolutionary, and genetic approaches for defining functional DNA segments, potential sources for the observed differences in estimated genomic coverage, and the biological implications of these discrepancies are reviewed.
Abstract: With the completion of the human genome sequence, attention turned to identifying and annotating its functional DNA elements. As a complement to genetic and comparative genomics approaches, the Encyclopedia of DNA Elements Project was launched to contribute maps of RNA transcripts, transcriptional regulator binding sites, and chromatin states in many cell types. The resulting genome-wide data reveal sites of biochemical activity with high positional resolution and cell type specificity that facilitate studies of gene regulation and interpretation of noncoding variants associated with human disease. However, the biochemically active regions cover a much larger fraction of the genome than do evolutionarily conserved regions, raising the question of whether nonconserved but biochemically active regions are truly functional. Here, we review the strengths and limitations of biochemical, evolutionary, and genetic approaches for defining functional DNA segments, potential sources for the observed differences in estimated genomic coverage, and the biological implications of these discrepancies. We also analyze the relationship between signal intensity, genomic coverage, and evolutionary conservation. Our results reinforce the principle that each approach provides complementary information and that we need to use combinations of all three to elucidate genome function in human biology and disease.
691 citations
McGill University1, Johns Hopkins University School of Medicine2, Massachusetts Institute of Technology3, University of Rochester4, Cold Spring Harbor Laboratory5, University of Cambridge6, Max Delbrück Center for Molecular Medicine7, National Institutes of Health8, University of British Columbia9, Cornell University10
TL;DR: The fundamental properties of TEs and their complex interactions with their cellular environment are introduced, which are crucial to understanding their impact and manifold consequences for organismal biology.
Abstract: Transposable elements (TEs) are major components of eukaryotic genomes. However, the extent of their impact on genome evolution, function, and disease remain a matter of intense interrogation. The rise of genomics and large-scale functional assays has shed new light on the multi-faceted activities of TEs and implies that they should no longer be marginalized. Here, we introduce the fundamental properties of TEs and their complex interactions with their cellular environment, which are crucial to understanding their impact and manifold consequences for organismal biology. While we draw examples primarily from mammalian systems, the core concepts outlined here are relevant to a broad range of organisms.
691 citations
TL;DR: High-throughput sequencing technologies are revolutionizing the life sciences, and the past 12 months have seen a burst of genome sequences from non-model organisms, in each case representing a fundamental source of data of significant importance to biological research.
Abstract: High-throughput sequencing technologies are revolutionizing the life sciences. The past 12 months have seen a burst of genome sequences from non-model organisms, in each case representing a fundamental source of data of significant importance to biological research. This has bearing on several aspects of evolutionary biology, and we are now beginning to see patterns emerging from these studies. These include significant heterogeneity in the rate of recombination that affects adaptive evolution and base composition, the role of population size in adaptive evolution, and the importance of expansion of gene families in lineage-specific adaptation. Moreover, resequencing of population samples (population genomics) has enabled the identification of the genetic basis of critical phenotypes and cast light on the landscape of genomic divergence during speciation.
607 citations
TL;DR: The cellular demands of nucleotide biosynthesis, their metabolic pathways and mechanisms of regulation during the cell cycle are reviewed and how this may lead to potential new approaches to drug development in diseases such as cancer is discussed.
Abstract: Nucleotides are required for a wide variety of biological processes and are constantly synthesized de novo in all cells. When cells proliferate, increased nucleotide synthesis is necessary for DNA replication and for RNA production to support protein synthesis at different stages of the cell cycle, during which these events are regulated at multiple levels. Therefore the synthesis of the precursor nucleotides is also strongly regulated at multiple levels. Nucleotide synthesis is an energy intensive process that uses multiple metabolic pathways across different cell compartments and several sources of carbon and nitrogen. The processes are regulated at the transcription level by a set of master transcription factors but also at the enzyme level by allosteric regulation and feedback inhibition. Here we review the cellular demands of nucleotide biosynthesis, their metabolic pathways and mechanisms of regulation during the cell cycle. The use of stable isotope tracers for delineating the biosynthetic routes of the multiple intersecting pathways and how these are quantitatively controlled under different conditions is also highlighted. Moreover, the importance of nucleotide synthesis for cell viability is discussed and how this may lead to potential new approaches to drug development in diseases such as cancer.
595 citations
Cites background from "On the immortality of television se..."
...ADSS Adenylosuccinate synthetase 1q44 11 (3) USF1 Pax-5 NRSF form 1 USF2...
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...11 2,3,5 (3) SRY, HOXA9, HOXA9B, Meis-1,...
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...3-q32 13 (3) c-Fos USF1 AP-1 NRF-2 USF-1 c-Jun...
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...Enzyme names: (1) carbamoyl phosphate synthase II (CPSII); (2) aspartate transcarbamoylase (ATCase); (3) carbamoyl aspartate dehydratase = dihydroorotase [CAD encodes enzymes 1 + 2 + 3]; (4) dihydroorotate dehydrogenase; (5) orotate phosphoribosyltransferase; (6) orotidine-5-phosphate decarboxylase (OMP decarboxylase)....
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...Transaminase8 (3) (cytoplasmic) 10q24....
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References
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TL;DR: The results of an international collaboration to produce and make freely available a draft sequence of the human genome are reported and an initial analysis is presented, describing some of the insights that can be gleaned from the sequence.
Abstract: The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution. Here we report the results of an international collaboration to produce and make freely available a draft sequence of the human genome. We also present an initial analysis of the data, describing some of the insights that can be gleaned from the sequence.
22,269 citations
TL;DR: The Encyclopedia of DNA Elements project provides new insights into the organization and regulation of the authors' genes and genome, and is an expansive resource of functional annotations for biomedical research.
Abstract: The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall, the project provides new insights into the organization and regulation of our genes and genome, and is an expansive resource of functional annotations for biomedical research.
13,548 citations
TL;DR: Two small lin-4 transcripts of approximately 22 and 61 nt were identified in C. elegans and found to contain sequences complementary to a repeated sequence element in the 3' untranslated region (UTR) of lin-14 mRNA, suggesting that lin- 4 regulates lin- 14 translation via an antisense RNA-RNA interaction.
11,932 citations
Journal Article•
TL;DR: The Encyclopedia of DNA Elements project provides new insights into the organization and regulation of the authors' genes and genome, and is an expansive resource of functional annotations for biomedical research.
Abstract: The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall, the project provides new insights into the organization and regulation of our genes and genome, and is an expansive resource of functional annotations for biomedical research.
8,106 citations
"On the immortality of television se..." refers background in this paper
...Curiously, Ward and Kellis, who estimated that only approximately 9% of the genome is under selection (Smith et al. 2004), themselves embody this incongruity, as they are coauthors of the principal publication of the ENCODE Consortium (ENCODE Project Consortium 2012)....
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...%) are intrachromosomal, that the distance between interacting sites ranges between 105 and 107 nucleotides, and that the majority of interactions cannot be explained by a commonality of function (ENCODE Project Consortium 2012)....
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...The ENCODE Project Consortium assigns function to 80.4% of the genome (ENCODE Project Consortium 2012)....
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...The latest batch of ENCODE Consortium publications, specifically the article signed by all Consortium members (ENCODE Project Consortium 2012), has much more ambitious interpretative aims (and a much better orchestrated public relations campaign)....
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...The 2012 ENCODE estimate (ENCODE Project Consortium 2012) of 80.4% represents a significant increase over the 2007 value....
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