We define DNA sequence by a bottom-up approach, starting with a real sequence from an actual biological sample. By providing axioms for notions of string, substring and strand, we formally define a DNA sequence, and a DNA molecule as composed of two antiparallel strands. We note that a sequence is a kind of group in which each member stands a certain relation to every other. The spatial aspects of a DNA sequence are also described.

The human genome consists of more than 3 billion base pairs built from four different nucleotides that hold the genetic information for the entire organism. The genome is commonly divided into coding and noncoding DNA sequences, with coding DNA sequences defined as those that can be transcribed into mRNA and translated into proteins, or genes. The genetic code determines the impact of a nucleotide change in a gene on the protein sequence and function, and it is essential to understanding the (...) genetic basis of many congenital diseases. The Human Genome Project has accelerated our understanding about the genome function. We now know that our genome consists of 20,000–25,000 genes that occupy only.. (shrink)

Recent advances in DNA sequencing have revolutionized the field of genomics, making it possible for even single research groups to generate large amounts of sequence data very rapidly and at a substantially lower cost. These high‐throughput sequencing technologies make deep transcriptome sequencing and transcript quantification, whole genome sequencing and resequencing available to many more researchers and projects. However, while the cost and time have been greatly reduced, the error profiles and limitations of the new platforms differ (...) significantly from those of previous sequencing technologies. The selection of an appropriate sequencing platform for particular types of experiments is an important consideration, and requires a detailed understanding of the technologies available; including sources of error, error rate, as well as the speed and cost of sequencing. We review the relevant concepts and compare the issues raised by the current high‐throughput DNA sequencing technologies. We analyze how future developments may overcome these limitations and what challenges remain. (shrink)

Whether, and to what degree, do patents granted on human genes cast a shadow of uncertainty over genomics and its applications? Will owners of patents on individual genes or clusters of genes sue those performing whole-genome analyses on human samples for patent infringement? These are related questions that have haunted molecular diagnostics companies and services, coloring scientific, clinical, and business decisions. Can the profusion of whole-genome analysis methods proceed without fear of patent infringement liability?Whole-genome sequencing is proceeding apace. Academic (...) centers have been performing whole-genome and -exome sequencing in research for at least five years, and academic clinical laboratories with national reach have been doing sequencing for clinical applications for almost as long. Companies have also been offering WGS and WES as a clinical service for a few years now. So far as we know, no one has been sued for infringement of “gene patents” for performing WGS. (shrink)

Hypotrichous ciliates extensively process genomic DNA during their life cycle. Processing occurs after cell mating, beginning with multiple rounds of DNA replication to form polytene chromosomes. Thousands of transposonlike elements are then excised from the chromosomes and destroyed, and thousands of short, internal eliminated sequences (IESs) are excised from coding and noncoding parts of genes and destroyed. IES removal from a gene is accompanied by splicing of the remaining chromosomal DNA segments to form a transcriptionally competent gene. For some genes (...) these DNA segments are in a scrambled order and are ligated into a genetically correct order at the time of IES removal. Next the polytene chromosomes are cut up band‐by‐band and all genes are excised from the chromosomes as short, linear molecules averaging 2.2 kbp (in Oxytricha nova). Gene excision is accompanied by destruction of all nongenic DNA, which, together with the transposonlike elements and IESs, accounts for ∼95% of the total sequence complexity of the genome in O. nova. Telomeric sequences are added to the excised gene‐sized DNA molecules. Finally, the gene‐sized molecules are replicated several times to form the macronucleus of the organism. (shrink)

Since their introduction about ten years ago the rapid methods for sequencing DNA based either on selective chemical degradation1 or primed enzymatic synthesis2 have been subject to a number of modifications and improvements.3, 4 Two recently published papers describe further advances in these technologies: a method for obtaining information about DNA sequences directly from uncloned mammalian genomic DNA5 and a possible first step towards the automation of DNA sequencing6.

The American Journal of Bioethics, Volume 12, Issue 10, Page 24-26, October 2012.

In this paper, we propose two four-base related 2D curves of DNA primary sequences and their corresponding single-base related 2D curves. The constructions of these graphical curves are based on the assignments of individual base to four different sinusoidal functions; then by connecting all these points on these four sinusoidal functions, we can get the F-B curves; similarly, by connecting the points on each of the four sinusoidal functions, we get the single-base related 2D curves. The proposed 2D curves are (...) all strictly non degenerate. Then, a 8-component characteristic vector is constructed to compare similarity among DNA sequences from different species based on a normalized geometrical centers of the proposed curves. As examples, we examine similarity among the coding sequences of the first exon of beta-globin gene from eleven species, similarity of cDNA sequences of beta-globin gene from eight species, and similarity of the whole mitochondrial genomes of 18 eutherian mammals. The experimental results well demonstrate the effectiveness of the proposed method. (shrink)

Constructivist biosemiotics foundations imply the first-person basis of cognition. CBF are developed by the biology of cognition, relational biology, enactive approach, ecology of mind, second order cybernetics, genetic epistemology, gestalt, ecological perception and affordances, and active inference by minimization of free energy. CBF reject the idea of an objective independent reality to be represented by information processing in order to be the fittest. CBF assumes that perception is the behavioral configuration of an object and objects are tokens for eigen-behaviors. Cognition (...) takes place in the organism-environment structural coupling during the ontogeny and phylogeny of all biological unities including unicellular organisms. Therefore, if exogenous DNA particles are just tokens for the cell signalling eigen-behaviors, if there is no ‘information’ in the DNA sequence, how can we explain that the same virus or trans- sequence is associated with a similar phenotype? We call this ‘exogenomic problem’. With this basic example, but sufficiently generic to the whole biological world, we agree respectively with Autopoiesis, -system, and Gaia theory: i) ‘Information, code and meaning’ in the DNA sequence belong to the domain of the observer’s description. ii) Genetic ‘information’ is not a program or algorithmic software in DNA sequence. Rather it is a microphysical observable mode of eigen-behaviors in biological unities. iii) The transfer and acquisition of DNA particles is a biospheric phenomenon that maintains its homeorhesis, symbiotic and biosemiotic entailment. Based on the theoretical and experimental results of these theories, it is concluded that genetic ‘information’ is not a genomic sequence, nor any kind of information, but for the cell DNA must embody physical forcing. Genetic characters are the effects and not the cause of phenotype and DNA particles do not ‘use or manipulate’ cellular metabolism. Rather, any cellular configuration change that occurred before or during DNA perturbation is determined on the basis of the cellular standpoint. (shrink)

In the original publication of the article, the y axis labels present in Figs. 1a and 2a are incorrect. The correct Figs. 1a and 2a are provided here.

This article proposes a new bi-directional way of understanding the convergence of biology and computing. It argues for a reciprocal interaction in which biology and computing have shaped and are currently reshaping each other. In so doing, we qualify both the view of a natural marriage and of a digital shaping of biology, which are common in the literature written by scientists, STS, and communication scholars. The DNA database is at the center of this interaction. We argue that DNA databases (...) are spaces of convergence for computing and biology that change in form, meaning, and function from the 1960s to the 2000s. The first part of the article shows how, in the 1980s, DNA sequencing shifted from passively incorporating computers to be increasingly modeled in digital coding and decoding. Information retrieval algorithms, reciprocally, were altered according to the peculiarities of DNA in the first sequence-storage databases. The second part of the article investigates the impact of these reciprocal interactions and globalization on the organization of research centers, ways of conducting big science, and scientific values. Through convergence and new technologies such as data mining, biology and computing were transformed technologically, institutionally, and culturally into a new bio-data enterprise called genomics. (shrink)

This chapter is concerned with the Cambrian explosion. It considers only one particular kind of explanation for the Cambrian radiation: that major innovations in animal body plan were produced from relatively few genetic changes of large phenotypic effect. It investigates the developmental genetic hypothesis of the origin and maintenance of body plans. This chapter suggests that the genetic architecture underlying body plans was not set during the Cambrian and has been immutable since. It shows that the link between body plan (...) and phylum can become blurry when the minor phyla are considered. (shrink)

The three‐dimensional structure of DNA depends subtly on its sequence, and this property is used by the proteins that regulate gene expression to locate their target sequences. Despite the large body of experimental data that has been accumulated on the relationship between sequence and DNA structure, we still do not fully understand the molecular basis for these properties, nor can we predict a three‐dimensional structure from a given sequence. We have been using computer modelling to tackle these problems. Some of (...) our results and the implications for understanding the biological role of key sequences are discussed here. (shrink)

Fred Sanger, the inventor of the first protein, RNA and DNA sequencing methods, has traditionally been seen as a technical scientist, engaged in laboratory bench work and not interested at all in intellectual debates in biology. In his autobiography and commentaries by fellow researchers, he is portrayed as having a trajectory exclusively dependent on technological progress. The scarce historical scholarship on Sanger partially challenges these accounts by highlighting the importance of professional contacts, institutional and disciplinary moves in his career, (...) spanning from 1940 to 1983. This paper will complement such literature by focusing, for the first time, on the transition of Sanger’s sequencing strategies from degrading to copying the target molecule, which occurred in the late 1960s as he was shifting from protein and RNA to DNA sequencing, shortly after his move from the Department of Biochemistry to the Laboratory of Molecular Biology, both based in Cambridge (UK). Through a reinterpretation of Sanger’s papers and retrospective accounts and a pioneering investigation of his laboratory notebooks, I will claim that sequencing shifted from the working procedures of organic chemistry to those of the emergent molecular biology. I will also argue that sequencing deserves a history in its own right as a practice and not as a technique subordinated to the development of molecular biology or genomics. My proposed history of sequencing leads to a reappraisal of current STS debates on bioinformatics, biotechnology and biomedicine. (shrink)

The fine‐structure analyses of the nopaline synthase (nos) promoter which is active constitutively in a wide range of plant tissues reveal that a portion of the upstream essential region for maximal transcription is a potential Z‐DNA‐forming element. Z‐DNA sequences are found in almost all plant‐promoter regions, suggesting that these structural elements may play important roles in plant gene expression.

Paradoxically, DNA sequence polymorphisms in cancer risk loci rarely correlate with the expression of cancer genes. Therefore, the molecular mechanism underlying an individual's susceptibility to cancer has remained largely unknown. However, recent evaluations of the correlations between DNA methylation and gene expression levels across healthy and cancerous genomes have revealed enrichment of disease‐related DNA methylation variations within disease‐associated risk loci. Moreover, it appears that transcriptional enhancers embedded in cancer risk loci often contain DNA methylation sites that closely define the expression (...) of prominent cancer genes, despite the lack of significant correlations between gene expression levels and the surrounding disease‐associated polymorphic sequences. We suggest that DNA methylation variations may obscure the effect of co‐residing risk sequence alleles. Analysis of enhancer methylation data may help to reveal the regulatory circuits underlying predisposition to cancers and other common diseases.Editor's suggested further reading in BioEssays DNA methylation reprogramming in cancer: Does it act by re‐configuring the binding landscape of Polycomb repressive complexes? Abstract. (shrink)

Recent studies based on next‐generation DNA sequencing have revealed that the female inactive X chromosome is replicated in a rapid, unorganized manner, and undergoes increased rates of mutation. These observations link the organization of DNA replication timing to gene regulation on one hand, and to the generation of mutations on the other hand. More generally, the exceptional biology of the inactive X chromosome highlights general principles of genome replication. Cells may control replication timing by a combination of intrinsic replication (...) origin properties, local chromatin states and global levels of replication factors, leading to a functional separation between the activity of genes and their mutation. (shrink)

This report is grounded in several social concepts: First, the primary goal of genetic testing should be to promote the well-being of the child. Second, the recognition that children are part of a network of family relationships supports an approach to potential conflicts that is not adversarial but, rather, emphasizes a deliberative process that seeks to promote the child's well-being within this context. Third, as children grow through successive stages of cognitive and moral development, parents and professionals should be attentive (...) to the child's increasing interest and ability to participate in decisions about his or her own welfare. (shrink)

Analysis of the DNA sequence associated with the nuclear matrix has made it possible to identify several types of DNA matrix association. Permanent attachment sites are detected in both transcriptionally active and inactive nuclei. Furthermore, replication origins have been shown to be permanently attached to the nuclear matrix. In transcriptionally active nuclei, expressed genes are also associated with the nuclear matrix. Finally, a special group of attachment sites is described; these sites are believed to maintain the fixed positions of individual (...) chromosomes in interphase nuclei. (shrink)

Variations in levels of apolipoprotein E have been tied to the risk and progression of Alzheimer's disease . Our group has previously compared and contrasted the promoters of the mouse and human ApoE gene promoter sequences and found notable similarities and significant differences that suggest the importance of the APOE promoter's role in the human disease. We examine here three specific single-nucleotide polymorphisms within the human APOE promoter region, specifically at -491 , -427 , and at -219 upstream from the (...) +1 transcription start site. The -219 and -491 polymorphic variations have significant association with instance of AD, and -491AA has significant risk even when stratified for the APOEepsilon4 allele. We also show significant effects on reporter gene expression in neuronal cell cultures, and, notably, these effects are modified by species origin of the cells. The -491 and -219 polymorphisms may have an interactive effect in addition to any independent activity. DNA-protein interactions differ between each polymorphic state. We propose SP1 and GATA as candidates for regulatory control of the -491 and -219 polymorphic sites. This work's significance lies in drawing connection among APOE promoter polymorphisms' associations with AD to functional promoter activity differences and specific changes in DNA-protein interactions in cell culture-based assays. Taken together, these results suggest that APOE expression levels are a risk factor for AD irrespective of APOEepsilon4 allele status. (shrink)

Recent completion of the human genome sequence is a spectacular achievement of the 20th-century biology. This achievement has opened the door for future revolutions in biological and medical sciences. By learning about the gene sequences and the individual genetic differences, scientists hope to understand the molecular basis of the normal state and the diseased state of life on one hand, and individualize medicine on the other hand. However, the human genome sequencing project was not an isolated, spectacular undertaking. Rather, (...) it was a natural extension and the culmination of the advances in the science and techniques of molecular biology. The present article is an attempt to summarize these major landmarks in the history of DNA research, beginning from the identification of “nuclein.”. (shrink)

Despite 250 years of work in systematics, the majority of species remains to be identified. Rising extinction rates and the need for increased biological monitoring lend urgency to this task. DNA sequencing, with key sequences serving as a “barcode”, has therefore been proposed as a technology that might expedite species identification. In particular, the mitochondrial cytochrome c oxidase subunit 1 gene has been employed as a possible DNA marker for species and a number of studies in a variety of (...) taxa have accordingly been carried out to examine its efficacy. In general, these studies demonstrate that DNA barcoding resolves most species, although some taxa have proved intractable. In some studies, barcoding provided a means of highlighting potential cryptic, synonymous or extinct species as well as matching adults with immature specimens. Higher taxa, however, have not been resolved as accurately as species. Nonetheless, DNA barcoding appears to offer a means of identifying species and may become a standard tool. BioEssays 29: 188–197, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

DNA methylation can be considered a component of epigenetic memory with a critical role during embryo development, and which undergoes dramatic reprogramming after fertilization. Though it has been a focus of research for many years, the reprogramming mechanism is still not fully understood. Recent results suggest that absence of maintenance at DNA replication is a major factor, and that there is an unexpected role for TET3-mediated oxidation of 5mC to 5hmC in guarding against de novo methylation. Base-resolution and genome-wide profiling (...) methods are enabling more comprehensive assessments of the extent to which ART might impair DNA methylation reprogramming, and which sequence elements are most vulnerable. Indeed, as we also review here, studies showing the effect of culture media, ovarian stimulation or embryo transfer on the methylation pattern of embryos emphasize the need to face ART-associated defects and search for strategies to mitigate adverse effects on the health of ART-derived children. DNA methylation, critical for embryo development, suffers significant changes after fertilization, including demethylation, remethylation and TET3-mediated oxidation of 5 mC to 5 hmC. In addition to infertility and environmental insults, ART could impact DNA methylation and ART related consequences in the offspring have been reported. (shrink)

The small, relatively constant size and conservative evolution of chloroplast DNA (cpDNA) make it an ideal molecule for tracing the evolutionary history of plant species. At lower taxonomic levels, cpDNA variation is easily and conveniently assayed by comparing restriction patterns and maps, while at higher taxonomic levels, DNA sequencing and inversion analysis are the methods of choice for comparing chloroplast genomes. The study of cpDNA variation has already yielded important new insights into the origin and evolution of many agriculturally (...) important crop plants, and promises to significantly enhance our phylogenetic understanding of the major lines of descent among land plants and algae. (shrink)

Certain sequences of double‐helical DNA can be recognized and tightly bound by oligonucleotides. The effects of such triple‐helical structures on DNA binding proteins have been studied. Stabilities of DNA triple‐helices at or near physiological conditions are sufficient to inhibit DNA binding proteins directed to overlapping sites. Such proteins include restriction endonucleases, methylases, transcription factors, and RNA polymerases. These and Other results suggest that oligonucleotide‐directed triple‐helix formation could provide the basis for designing artificial gene repressors. The general question of whether biological (...) systems employ RNA molecules for recognition and regulation of double‐helical DNA is discussed. (shrink)

To analyse the biological role of 5‐methylation of cytosine residues in DNA requires precise and efficient methods for detecting individual 5‐methylcytosines (5‐MeCs) in genomic DNA. The methods developed over the past decade rely on either differential enzymatic or chemical cleavage of DNA, or more recently on differential sensitivity to chemical conversion of one base to another. The most commonly used methods for studying the methylation profile of DNA, including the bisulphite base‐conversion method, are reviewed.

DNA barcodes, like traditional sources of taxonomic information, are potentially powerful heuristics in the identification of described species but require mindful analytical interpretation. The role of DNA barcoding in generating hypotheses of new taxa in need of formal taxonomic treatment is discussed, and it is emphasized that the recursive process of character evaluation is both necessary and best served by understanding the empirical mechanics of the discovery process. These undertakings carry enormous ramifications not only for the translation of DNA sequence (...) data into taxonomic information but also for our comprehension of the magnitude of species diversity and its disappearance. This paper examines the potential strengths and pitfalls of integrating DNA sequence data, specifically in the form of DNA barcodes as they are currently generated and analyzed, with taxonomic practice. (shrink)

The existence of DNA methylation in insects has been a controversial subject over a long period of time. The recently completed genome sequence of the honeybee Apis mellifera has revealed the first insect with a full complement of DNA methyltransferases.1 A parallel study demonstrated that these enzymes are catalytically active and that Apis genes can be methylated in specific patterns.2 These findings establish bees as a model to analyze the function of DNA methylation systems in invertebrate organisms and might also (...) be important to understand evolutionary aspects of DNA methylation in higher eukaryotes. BioEssays 29: 208–211, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

This paper assesses the effect of DNA barcoding—the use of informative genetic markers to identify and discriminate between species—on taxonomy. Throughout, we interpret this in terms of _varipraxis_, a concept we introduce to make sense of the treatment of biological variation by scientists and other practitioners. From its inception, DNA barcoding was criticised for being reductive, in attempting to replace multiple forms of taxonomic evidence with just one: DNA sequence variation in one or a few indicative genes. We show, though, (...) how DNA barcoding has not narrowed or reduced taxonomy in the way it was projected to. We examine the development and implementation of DNA barcoding across three kingdoms of life: animals, plants, and protists. Through this, we demonstrate that for DNA barcoding to work, the range of acceptable intra-specific variation needs to be demarcated from variation deemed to be characteristic of inter-specific differences. Consequently, biological processes responsible for particular patterns of variation need to be investigated and understood. This encourages an integrative disposition towards understanding and explaining the evolutionary processes affecting the rate and nature of change at the nucleotide level. We detail how the impact of DNA barcoding has manifested differently across the three kingdoms we examine, assessing this in terms of the ontological commitments that are held and instantiated in practice. Based on this evaluation, we consider the problem of studying multi-kingdom communities, and assess the consequences of our analysis for understanding classification and taxonomy. (shrink)

Genomic function is dictated by a combination of DNA sequence and the molecular mechanisms controlling access to genetic information. Access to DNA can be determined by the interpretation of covalent modifications that influence the packaging of DNA into chromatin, including DNA methylation and histone modifications. These modifications are believed to be forms of “epigenetic codes” that exist in discernable combinations that reflect cellular phenotype. Although DNA methylation is known to play important roles in gene regulation and genomic function, its contribution (...) to the encoding of epigenetic information is just beginning to emerge. Here we discuss paradigms associated with the various components of DNA methylation/demethylation and recent advances in the understanding of its dynamic regulation in the genome, integrating these mechanisms into a framework to explain how DNA methylation could contribute to epigenetic codes. (shrink)

Technological innovations such as next generation sequencing and DNA hybridisation enrichment have resulted in multi‐fold increases in both the quantity of ancient DNA sequence data and the time depth for DNA retrieval. To date, over 30 ancient genomes have been sequenced, moving from 0.7× coverage (mammoth) in 2008 to more than 50× coverage (Neanderthal) in 2014. Studies of rapid evolutionary changes, such as the evolution and spread of pathogens and the genetic responses of hosts, or the genetics of domestication (...) and climatic adaptation, are developing swiftly and the importance of palaeogenomics for investigating evolutionary processes during the last million years is likely to increase considerably. However, these new datasets require new methods of data processing and analysis, as well as conceptual changes in interpreting the results. In this review we highlight important areas of future technical and conceptual progress and discuss research topics in the rapidly growing field of palaeogenomics. -/- . (shrink)

Decoding the human genome in the past decades has brought into focus a computationally intensive operation through DNA profiling. The typical search space for these kinds of problems is extremely large and requires specialized hardware and algorithms to perform the necessary sequence analysis. In this paper, we propose an innovative and scalable approach to exact multi-pattern matching of nucleotide sequences by harnessing the massively parallel computing power found in commodity graphical processing units. Our approach places careful consideration on preprocessing of (...) DNA datasets and runtime performance, while exploiting the full capabilities of the heterogeneous platform it runs on. Finally, we evaluate our models against real-world DNA sequences. (shrink)

After yeast cells commit to the cell cycle in a process called START, genes required for DNA synthesis are expressed in late G1. Periodicity is mediated by a hexameric sequence, known as a MCB element, present in all DNA synthesis gene promoters. A complex that specifically binds MCBs has been identified. One polypeptide in the MCB complex is Swi6, a transcription factor that together with Swi4 also binds G1 cyclin promoters and participates in a positive feedback loop at START. The (...) finding that Swi6 is directly involved in both START and DNA synthesis gene control suggest a model in which Swi6, activated through its participation in START, serves as the central transcription factor in coordinating late G1 gene expression. The mechanism may be conserved in all eukaryotic cells. (shrink)

Long DNA palindromes pose a threat to genome stability. This instability is primarily mediated by slippage on the lagging strand of the replication fork between short directly repeated sequences close to the ends of the palindrome. The role of the palindrome is likely to be the juxtaposition of the directly repeated sequences by intrastrand base‐pairing. This intra‐strand base‐pairing, if present on both strands, results in a cruciform structure. In bacteria, cruciform structures have proved difficult to detect in vivo, suggesting that (...) if they form, they are either not replicated or are destroyed. SbcCD, a recently discovered exonuclease of Escherichia coli, is responsible for preventing the replication of long palindromes. These observations lead to the proposal that cells may have evolved a post‐replicative mechanism for the elimination and/or repair of large DNA secondary structures. (shrink)

DNA arrays have become the preferred method for large-scale expression measurement. Such data are needed in view of the large amounts of sequence data available: expression levels in a number of different tissues or situations provide a first step toward functional characterisation of new entities revealed by DNA sequencing. Although the basic principle of measurement is in all cases based on hybridisation of a mixed probe derived from tissue RNA to large sets of DNA fragments representing many genes, a (...) number of different forms of implementation of this principle are at hand. They are briefly described and compared, emphasizing the important issue of sensitivity and sample requirements and the accessibility of the methods to academic scientists. When these factors are taken into account, it appears that, contrary to a largely prevalent impression, the “best” approach is not necessarily always provided by the widely advertised glass microarrays or oligonucleotide chips. BioEssays 21:781–790, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

While large portions of the mammalian genome are known to replicate sequentially in a distinct, tissue‐specific order, recent studies suggest that the inactive X chromosome is duplicated rapidly via random, synchronous DNA synthesis at numerous adjacent regions. The rapid duplication of the inactive X chromosome was observed in high‐resolution studies visualizing DNA replication patterns in the nucleus, and by allele‐specific DNA sequencing studies measuring the extent of DNA synthesis. These studies conclude that inactive X chromosomes complete replication earlier than (...) previously thought and suggest that the strict order of DNA replication detected in the majority of genomic regions is not preserved in non‐transcribed, “silent” chromatin. These observations alter current concepts about the regulation of DNA replication in non‐transcribed portions of the genome in general and in the inactive X‐chromosome in particular. (shrink)

DNA methylation is a quintessential epigenetic mechanism. Widely considered a stable regulator of gene silencing, it represents a form of “molecular braille,” chemically printed on DNA to regulate its structure and the expression of genetic information. However, there was a time when methyl groups simply existed in cells, mysteriously speckled across the cytosine building blocks of DNA. Why was the code of life chemically modified, apparently by “no accident of enzyme action” (Wyatt 1951 )? If all cells in a body (...) share the same genome sequence, how do they adopt unique functions and maintain stable developmental states? Do cells remember? In this historical perspective, I review epigenetic history and principles and the tools, key scientists, and concepts that brought us the synthesis and discovery of prokaryotic and eukaryotic methylated DNA. Drawing heavily on Gerard Wyatt’s observation of asymmetric levels of methylated DNA across species, as well as to a pair of visionary 1975 DNA methylation papers, 5-methylcytosine is connected to DNA methylating enzymes in bacteria, the maintenance of stable cellular states over development, and to the regulation of gene expression through protein-DNA binding. These works have not only shaped our views on heritability and gene regulation but also remind us that core epigenetic concepts emerged from the intrinsic requirement for epigenetic mechanisms to exist. Driven by observations across prokaryotic and eukaryotic worlds, epigenetic systems function to access and interpret genetic information across all forms of life. Collectively, these works offer many guiding principles for our epigenetic understanding for today, and for the next generation of epigenetic inquiry in a postgenomics world. (shrink)