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A Sourcebook for the Worldwide Discovery of a Creative Organic Universe
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IV. Ecosmomics: An Independent Source Script of Generative, Self-Similar, Complex Network Systems

1. Paleogenomics, Archaeogenomics: Natural Ancestry

Kellis, Manolis, et al. Defining Functional DNA Elements in the Human Genome. Proceedings of the National Academy of Sciences. 111/6131, 2014. Some thirty researchers within an ENCODE Project and European Bioinformatics Institute aegis, including Ewan Birney and Marc Gerstein, post a 2014 update of humankind’s endeavor to fully sequence the generative code that brought creatures to appear and anthropo sapiens to these abilities. An expanded scope, re the Abstract, is now discussed that engages the “complementary nature of evolutionary, biochemical, and genetic evidence.”

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. (Abstract)

Krause, Johannes and Thomas Trappe. A Short History of Humanity: A New History of Old Europe. New York: Random House, 2021. As the book description cites, this work is all about novel archaeogenetic reconstructions of further and nearer European inhabitants, their migrations, settlements, and so on by which to fill in a more complete narrative.

Johannes Krause is the director of the Max Planck Institute for Evolutionary Anthropology and a brilliant pioneer in the field of archaeogenetics—archaeology augmented by DNA sequencing technology—which has allowed scientists to reconstruct human history reaching back hundreds of thousands of years before recorded time. In this account, Krause and journalist Thomas Trappe rewrite the peopling of Europe from the Neanderthals and Denisovans to the present. Krause and Trappe vividly introduce the prehistoric cultures of the ancient Europeans: the Aurignacians as artisans who carved flutes and animal forms from bird bones more than 40,000 years ago; the Varna, who buried their loved ones with gold long before the Pharaohs of Egypt; and the Gravettians, big-game hunters who were Europe’s most successful early settlers until they perished in the ice age.

Kundaje, Anshul, et al. Integrative Analysis of 111 Reference Human Epigenomes. Nature. 518/317, 2015. In a special issue on this Human Epigenome Project (www.epigenome.org,) seen as a follow up to the 2001 Human Genome and 2012 ENCODE achievements, a NIH Roadmap Epigenomics Consortium team of 100 co-authors describes a similar sequencing of this newly realized, epi-genetic function. We cite it’s Abstract, an NIH Roadmap introduction, and editorial excerpts from this issue which describe this radical expansion of genomic functions. More articles are available on the NIH site, and herein such as Cell-of-Origin Chromaton Organization Shapes the Mutational Landscape of Cancer. As this Cosmos Opus and Logos Opus proceeds, as collaborative humankind deciphers an ever-expanding “genetic” realm, this knowledge can be fed back to cure the beings it arose from.

The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease. (Abstract)

The NIH Roadmap Epigenomics Mapping Consortium was launched with the goal of producing a public resource of human epigenomic data to catalyze basic biology and disease-oriented research. The Consortium leverages experimental pipelines built around next-generation sequencing technologies to map DNA methylation, histone modifications, chromatin accessibility and small RNA transcripts in stem cells and primary ex vivo tissues selected to represent the normal counterparts of tissues and organ systems frequently involved in human disease. The Consortium expects to deliver a collection of normal epigenomes that will provide a framework or reference for comparison and integration within a broad array of future studies. (www.roadmapepigenomics.org)

Beyond the Genome: The Greek prefix epi- can signify upon, on, over, near, at, before, and after. Most of those could apply to its use in the term ‘epigenetics’ — particularly the last of them. It is some 14 years, almost to the day, that Nature published the draft sequence of the human genome. Now, in this issue, we publish results from a subsequent study on the non-genetic modifications to the genome — epigenetic modifications — that crucially determine which genes are expressed by which cell type, and when. Upon the genome, on the genome, over the genome — take your pick — epigenetics collectively describes changes in the regulation of gene expression that can be passed on to a cell’s progeny but are not due to changes to the nucleotide sequence of the gene. (518/273)

Librado, Pablo, et al. Ancient Genomic Changes Associated with Domestication of the Horse. Science. 356/442, 2017. An international team of 33 scientists from Denmark, France, Pakistan, Switzerland, Spain, Saudi Arabia, Germany, and Kazakhstan, coordinated by the Centre for GeoGenetics, Copenhagen, advance our human reconstruction of animal evolution, in this case of the important Equine family. After a century of bone fossils, this novel genomic skill is a major contribution to a more accurate filling in of life’s creaturely lineage.

The genomic changes underlying both early and late stages of horse domestication remain largely unknown. We examined the genomes of 14 early domestic horses from the Bronze and Iron Ages, dating to between ~4.1 and 2.3 thousand years before present. We find early domestication selection patterns supporting the neural crest hypothesis, which provides a unified developmental origin for common domestic traits. Within the past 2.3 thousand years, horses lost genetic diversity and archaic DNA tracts introgressed from a now-extinct lineage. We also reveal that Iron Age Scythian steppe nomads implemented breeding strategies involving no detectable inbreeding and selection for coat-color variation and robust forelimbs. (Abstract)

Linderholm, Anna. Ancient DNA: The Next Generation – Chapter and Verse. Journal of the Linnean Society. Online July, 2015. As a leading authority, a University of Oxford research archaeologist reviews some three decades of endeavors to recover and sequence evolutionary genomes from hominids to dinosaurs. Progress was slow until the 2000s when automated, high speed techniques came into widespread service. And we make note of more good use of a textual analogy, for we really do seem to be opening and reading a natural transcripture.

The genome(s) contains all the information an organism needs to exist, reproduce, and evolve. The human genome contains 3.2 billion bases, which can be hard to envisage. If we use the example of a book, and compare it to the human genome, it might be easier to understand the vastness of it all. The book contains 3.2 billion letters without spaces for the bases A,C, G, T divided into chapters (human chromosomes) which would make it around 70 million letters (bp) per chapter. Until the introduction of next-generation sequencing (NGS), we were often only able to read a few of the larger remaining sentences. However as technology has progressed, we are now much more easily able to read very short sentences, and combine these into complete chapters and sometimes the entire book. The progress made in the last decade is staggering; the field has gone from recovering hundreds of bp to hundreds of millions. (1)

Llamas, Bastien, et al. Human Evolution: A Tale from Ancient Genomes. Philosophical Transactions of the Royal Society B. Vol.372/Iss.1713, 2016. For this Evo-Devo in the Genomics Era issue, Llamas, University of Adelaide, with Eske Willerslev and Ludovic Orlando, Center for GeoGenetics, Natural History Museum of Denmark, provide an update survey of abilities and progress in retro-sequencing the genetic endowments of our hominid ancestors.

The field of human ancient DNA (aDNA) has moved from mitochondrial sequencing that suffered from contamination and provided limited biological insights, to become a fully genomic discipline that is changing our conception of human history. Recent successes include the sequencing of extinct hominins, and true population genomic studies of Bronze Age populations. Among the emerging areas of aDNA research, the analysis of past epigenomes is set to provide more new insights into human adaptation and disease susceptibility through time. Starting as a mere curiosity, ancient human genetics has become a major player in the understanding of our evolutionary history. (Abstract)

Maher, Brendan. The Human Encyclopedia. Nature. 489/46, 2012. An introduction to the revolutionary findings of the ENCODE Project, as reported by Gina Kolata above. Over the span noted by Mark Gerstein, second quote, from the 1950s to 2000 was a period of identifying discrete nucleotide molecules (the definition of a “gene” still in abeyance). In the 2000s and 2010s a new approach, driven by computational sequencing instruments, can discern these heretofore undetected, equally real, nonlinear network interactions between elements, that compose and inform a whole genome. See Declan Clarke 2012, above for more synopsis.

This issue of Nature is all about ENCODE, with many entries. Another description is “An Integrated Encyclopedia of DNA Elements in the Human Genome,” by The ENCODE Project Consortium, accompanied by a long global listing of laboratories and personnel. Among others are “Landscape of Transcription in Human Cells,” Sarah Djebali, et al (some 100 coauthors), “Non-Coding but Functional,” Ines Barroso, and “Architecture of the Human Regulatory Network Derived from ENCODE Data,” Mark Gerstein, et al, which concludes “This study provides the first detailed analysis of how human regulatory information is organized.” By its lights are revealed “clear design principles” which are “general features of transcription” braced by “connectivity and hierarchical organization.”

Many biologists suspected that the information responsible for the wondrous complexity of humans lay somewhere in the ‘deserts’ between the genes. ENCODE, which started in 2003, is a massive data-collection effort designed to populate this terrain. The aim is to catalogue the ‘functional’ DNA sequences that lurk there, learn when and in which cells they are active and trace their effects on how the genome is packaged, regulated and read. (Maher, 46) After all, says (Mark) Gerstein,, it took more that half a century to get from the realization that DNA is the hereditary material of life to the sequence of the human genome. “You could almost imagine that the scientific programme for the next century is really understanding that sequence.” (Maher, 48)

The Encyclopedia of DNA Elements (ENCODE) project aims to delineate all functional elements encoded in the human genome. Operationally, we define a functional element as a discrete genome segment that encodes a defined product (for example, protein or non-coding RNA) or displays a reproducible biochemical signature (for example, protein binding, or a specific chromatin structure). (57) Here we describe the production and initial analysis of 1,640 data sets designed to annotate functional elements in the entire human genome. Together, these efforts reveal important features about the organization and function of the human genome, summarized below. * The vast majority (80.4%) of the human genome participates in at least one biochemical RNA- and/or chromatin-associated event in at least one cell type. Much of the genome lies close to a regulatory event. (Consortium, 57)

Concordantly, we observed an increased overlap of genic regions. As the determination of genic regions is currently defined by the cumulative lengths of the isoforms and their genetic association to phenotypic characteristics, the likely continued reduction in the lengths of intergenic regions will steadily lead to the overlap of most genes previously assumed to be distinct genetic loci. This supports and is consistent with earlier observations of a highly interleaved transcribed genome12, but more importantly, prompts the reconsideration of the definition of a gene. As this is a consistent characteristic of annotated genomes, we would propose that the transcript be considered as the basic atomic unit of inheritance. Concomitantly, the term gene would then denote a higher-order concept intended to capture all those transcripts (eventually divorced from their genomic locations) that contribute to a given phenotypic trait. (Djebali, et al, 108)

A central goal in biology is to understand how a limited cohort of transcription factors is able to organize the large diversity of gene-expression patterns in different cell types and conditions. Over the past decade, system-wide analyses of transcription-factor-binding patterns have been performed in unicellular model organisms, such as Escherichia coli and yeast, and have revealed a great deal of information about the organization of regulatory information. These studies have provided insights into such features as network hubs1, connectivity correlations, hierarchical organization and network motifs. Moreover, more complex networks that integrate disparate forms of genomic and proteomic data, such as protein–protein interactions and phosphorylation, have related gene regulation to other biological processes. (Gerstein, et al, 91)

Malaspinas, Anna-Sapfo, et al. A Genomic History of Aboriginal Australia. Nature. Online September, 2016. Some 80 collaborators across Europe to the USA, Saudi Arabia, Malaysia, and Australia achieve a retrospective synthesis of genetic and linguistic techniques and findings to reconstruct with how early homo sapiens migratory waves came to people the continents. See also a commentary, Aborigines and Eurasians Rode One Migration Wave, in Science (search Culotta). All human beings came from Africa we now know (to wit, everyone has African heritage), this Aboriginal advent is an earliest passage, just as their stories aver.

The population history of Aboriginal Australians remains largely uncharacterized. Here we generate high-coverage genomes for 83 Aboriginal Australians (speakers of Pama–Nyungan languages) and 25 Papuans from the New Guinea Highlands. We find that Papuan and Aboriginal Australian ancestors diversified 25–40 thousand years ago (kya), suggesting pre-Holocene population structure in the ancient continent of Sahul (Australia, New Guinea and Tasmania). However, all of the studied Aboriginal Australians descend from a single founding population that differentiated ~10–32 kya. We infer a population expansion in northeast Australia during the Holocene epoch (past 10,000 years) associated with limited gene flow from this region to the rest of Australia, consistent with the spread of the Pama–Nyungan languages. We estimate that Aboriginal Australians and Papuans diverged from Eurasians 51–72 kya, following a single out-of-Africa dispersal, and subsequently admixed with archaic populations. (Abstract)

Marciniak, Stephanie and George Perry. Harnessing Ancient Genomes to Study the History of Human Adaptation. Nature Reviews Genetics. Online September, 2017. Penn State anthropologists describe novel retrospective sequencing abilities that can recreate how homo sapiens evolved and emerged to be able to altogether do this. See also Inferring Past Environments from Ancient Epigenomes by David Gokhman,et al in Molecular Biology and Evolution (34/10, 2017).

The past several years have witnessed an explosion of successful ancient human genome-sequencing projects, with genomic-scale ancient DNA data sets now available for more than 1,100 ancient human and archaic hominin (for example, Neandertal) individuals. Recent 'evolution in action' analyses have started using these data sets to identify and track the spatiotemporal trajectories of genetic variants associated with human adaptations to novel and changing environments, agricultural lifestyles, and introduced or co-evolving pathogens. Together with evidence of adaptive introgression of genetic variants from archaic hominins to humans and emerging ancient genome data sets for domesticated animals and plants, these studies provide novel insights into human evolution and the evolutionary consequences of human behaviour that go well beyond those that can be obtained from modern genomic data or the fossil and archaeological records alone. (Abstract)

Martinez-Pastor, Mar, et al. Transcriptional Regulation in Archaea: From Individual Genes to Global Regulatory Networks. Annual Review of Genetics. 51/143, 2917. We enter this chapter because Duke University computational biologists move beyond the sequencing of prior genetic codes to quantify even in this early domain the important, complementary presence of gene regulatory interconnections.

Archaea are major contributors to biogeochemical cycles, possess unique metabolic capabilities, and resist extreme stress. To regulate the expression of genes encoding these unique programs, archaeal cells use gene regulatory networks (GRNs) composed of transcription factor proteins and their target genes. Recent developments in genetics, genomics, and computational methods used with archaeal model organisms have enabled the mapping and prediction of global GRN structures. Here, we review recent progress made in this area from investigating the mechanisms of transcriptional regulation of individual genes to small-scale subnetworks and genome-wide global networks. At each level, archaeal GRNs consist of a hybrid of bacterial, eukaryotic, and uniquely archaeal mechanisms. (Abstract excerpt)

Archaea: Microorganisms which are similar to bacteria in size and simplicity of structure but radically different in molecular organization. They are now believed to constitute an ancient group which is intermediate between the bacteria and eukaryotes. They are also called archaebacteria.

Miraldo, Andreia, et al. An Anthropocene Map of Genetic Diversity. Science. 353/1532, 2017. A ten person international team based at the Centre for GeoGenetics, University of Copenhagen, apply novel abilities to sequence present and past creaturely genomes so to begin to assemble a global inventory. See also Emerging Patterns in Macrogenetics by Simon Blanchet, et al in Trends in Genetics (33/9, 2017).

The Anthropocene is witnessing a loss of biodiversity, with well-documented declines in the diversity of ecosystems and species. For intraspecific genetic diversity, however, we lack even basic knowledge on its global distribution. We georeferenced 92,801 mitochondrial sequences for >4500 species of terrestrial mammals and amphibians, and found that genetic diversity is 27% higher in the tropics than in nontropical regions. Overall, habitats that are more affected by humans hold less genetic diversity than wilder regions, although results for mammals are sensitive to choice of genetic locus. Our study associates geographic coordinates with publicly available genetic sequences at a massive scale, yielding an opportunity to investigate both the drivers of this component of biodiversity and the genetic consequences of the anthropogenic modification of nature. (Abstract)

Misof, Bernhard, et al. Phylogenomics Resolves the Timing and Pattern of Insect Evolution. Science. 346/763, 2014. As an example of the reach of novel abilities to decipher ancient genomes, an international team of 42 researchers from Germany, China, USA, Australia, Japan, Austria, Mexico, and Greece describe an extensive sequencing of insect species. These efforts result in a highly detailed “phylogenetic tree of past insect relationships” and of “ordinal and interordinal node age estimates.” To reflect, mind you, what kind of a creation or existence, billions of years on, via a sapient planetary species, proceeds to intentionally reconstruct all the prior genome endowments?

Insects are the most speciose group of animals, but the phylogenetic relationships of many major lineages remain unresolved. We inferred the phylogeny of insects from 1478 protein-coding genes. Phylogenomic analyses of nucleotide and amino acid sequences, with site-specific nucleotide or domain-specific amino acid substitution models, produced statistically robust and congruent results resolving previously controversial phylogenetic relations hips. We dated the origin of insects to the Early Ordovician [~479 million years ago (Ma)], of insect flight to the Early Devonian (~406 Ma), of major extant lineages to the Mississippian (~345 Ma), and the major diversification of holometabolous insects to the Early Cretaceous. Our phylogenomic study provides a comprehensive reliable scaffold for future comparative analyses of evolutionary innovations among insects. (Abstract)

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