Darwinian evolutionary theory has two key terms, variations and biological selection, which finally lead to survival of the fittest variant. With the rise of molecular genetics, variations were explained as results of error replications out of the genetic master templates. For more than half a century, it has been accepted that new genetic information is mostly derived from random error-based events. But the error replication narrative has problems explaining the sudden emergence of new species, new phenotypic traits, and (...) genome innovations as a sudden single event. Meanwhile, it is recognized that errors cannot explain the evolution of genetic information, genetic novelty, and complexity. Now, empirical evidence establishes the crucial role of non-random genetic content editors, such as viruses, diversity generating retroelements, and other RNA networks, to produce new genetic information, complex regulatory control, inheritance vectors, genetic identity, immunity, new sequence space, evolution of complex organisms, and evolutionary transitions. (shrink)

Homologous recombination (HR) is required to protect and restart stressed replication forks. Paradoxically, the Mrc1 branch of the S phase checkpoints, which is activated by replicative stress, prevents HR repair at breaks and arrested forks. Indeed, the mechanisms underlying HR can threaten genome integrity if not properly regulated. Thus, understanding how cells avoid genetic instability associated with replicative stress, a hallmark of cancer, is still a challenge. Here I discuss recent results that support a model by which HR responds (...) to replication stress through replicative and repair activities that operate at different stages of the cell cycle (S and G2, respectively) and in distinct subnuclear structures. Remarkably, the replication checkpoint appears to control this scenario by inhibiting the assembly of HR repair centers at stressed forks during S phase, thereby avoiding genetic instability. (shrink)

Complexity is pleased to announce the installment of Prof Hiroki Sayama as its new Chief Editor. In this Editorial, Prof Sayama describes his feelings about his recent appointment, discusses some of the journal’s journey and relevance to current issues, and shares his vision and aspirations for its future.

Artificial genetic constructs that direct the synthesis of self‐replicating RNA molecules are used widely to induce gene silencing, for bioproduction, and for vaccination. Interestingly, one variant of the self‐replicon has not been discussed in the literature: namely, transgenic organisms that synthesise alien replicons. For example, plant cells may be easily genetically modified to produce bacteriophages or insect viruses. Alien replicon‐producing organisms (ARPOs) may serve as a unique tool for biocontrol or to selectively influence the characteristics of a target organism. (...) The ARPO approach would have to meet strict biosafety criteria, and its practical applications are problematic. However, a discussion on ARPO applicability would be valuable to outline the full set of options available in the bioengineering toolbox. In this paper, RNA replicons for bioengineering are reviewed briefly, and the ARPO approach is discussed. (shrink)

This paper evaluates and criticises the developmental systems conception of evolution and develops instead an extension of the gene's eye conception of evolution. We argue (i) Dawkin's attempt to segregate developmental and evolutionary issues about genes is unsatisfactory. On plausible views of development it is arbitrary to single out genes as the units of selection. (ii) The genotype does not carry information about the phenotype in any way that distinguishes the role of the genes in development from that other factors. (...) (iii) There is no simple and general causal criterion which distinguishes the role of genes in development and evolution. (iv) There is, however, an important sense in which genes but not every other developmental factor represent the phenotype. (v) The idea that genes represent features of the phenotype forces us to recognise that genes are not the only, or almost the only, replicators. Many mechanisms of replication are involved in both development and evolution. (vi) A conception of evolutionary history which recognises both genetic and non-genetic replicators, lineages of replicators and interactors has advantages over both the radical rejection of the replicator/interactor distinction and the conservative restriction of replication to genetic replication. (shrink)

Replication forks inevitably stall at damaged DNA in every cell cycle. The ability to overcome DNA lesions is an essential feature of the replication machinery. A variety of specialized polymerases have recently been discovered, which enable cells to replicate past various forms of damage by a process termed translesion synthesis. Alternatively, homologous recombination can be used to restart DNA replication across the lesion. Genetic and biochemical studies have shed light on the impact of these two post‐replication repair pathways in (...) bacteria and yeast. In vertebrates, however, a genetic approach to study post‐replication repair has been compromised because many of the genes involved appear to be essential for embryonic development. We have taken advantage of the chicken cell line DT40 to perform a genetic analysis of translesion synthesis and homologous recombination and to characterize genetic interactions between these two pathways in vertebrates. In this article, we aim to summarize our current understanding of post‐replication repair in DT40 in the perspective of bacterial, yeast and mammalian genetics. BioEssays 26:151–158, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

DNA replication initiates at many sites in eukaryotic chromosomes. It has been difficult to isolate such replication origins, but a family of sequences from the yeast genome have properties which suggest that they may serve this function. The identification of these sequences together with sophisticated methods of genetic analysis, make yeast a useful organism for the study of eukaryotic DNA replication.

Understanding community-level selection using Lewontin’s criteria requires both community-level inheritance and community-level heritability, and in the discipline of community and ecosystem genetics, these are often conflated. While there are existing studies that show the possibility of both, these studies impose community-level inheritance as a product of the experimental design. For this reason, these experiments provide only weak support for the existence of community-level selection in nature. By contrast, treating communities as interactors (in line with Hull’s replicator-interactor framework or Dawkins’s idea (...) of the “extended phenotype”) provides a more plausible and empirically supportable model for the role of ecological communities in the evolutionary process. (shrink)

Hereditary breast and ovarian cancers are frequently attributed to germline mutations in the tumor suppressor genes BRCA1 and BRCA2. BRCA1/2 act to repair double‐strand breaks (DSBs) and suppress the demise of unstable replication forks. Our work elucidated a dynamic interplay between BRCA2 and the WRN DNA helicase/exonuclease defective in the premature aging disorder Werner syndrome. WRN and BRCA2 participate in complementary pathways to stabilize replication forks in cancer cells, allowing them to proliferate. Whether the functional overlap of WRN and BRCA2 (...) is relevant to replication at gaps between newly synthesized DNA fragments, protection of telomeres, and/or metabolism of secondary DNA structures remain to be determined. Advances in understanding the mechanisms elicited during replication stress have prompted the community to reconsider avenues for cancer therapy. Insights from studies of PARP or topoisomerase inhibitors provide working models for the investigation of WRN's mechanism of action. We discuss these topics, focusing on the implications of the WRN‐BRCA2 genetic interaction under conditions of replication stress. (shrink)

There are many layers of regulation governing DNA replication to ensure that genetic information is accurately transmitted from mother cell to daughter cell. While much of the control occurs at the level of origin selection and firing, less is known about how replication fork progression is controlled throughout the genome. In Drosophila polytene cells, specific regions of the genome become repressed for DNA replication, resulting in underreplication and decreased copy number. Importantly, underreplicated domains share properties with common fragile sites. (...) The Suppressor of Underreplication protein SUUR is essential for this repression. Recent work established that SUUR functions by directly inhibiting replication fork progression, raising several interesting questions as to how replication fork progression and stability can be modulated within targeted regions of the genome. Here we discuss potential mechanisms by which replication fork inhibition can be achieved and the consequences this has on genome stability and copy number control. (shrink)

Excerpt from Genetic Philosophy of Education: An Epitome of the Published Educational Writings, of President G Stanley Hall, of Clark University All must admit that there is a lack at the present time, at least among the rank and file of teachers, and in the public mind generally, of any adequate philoso phy of education, or even Of a point of view from which the themes of school and home can be dis cussed broadly and intelligently. The older philoso (...) phies of F roebel, Hegel, and Herbart are certainly in sufficient to meet present needs, and especially in the training of teachers is this painfully felt. They are not only obscure, and little inspiring, either Of breadth of thought or intelligent practice but they fail en tirely to connect with the teacher 3 daily life, unless they be taught in a very shallow and formal way. About the Publisher Forgotten Books publishes hundreds of thousands of rare and classic books. Find more at www.forgottenbooks.com This book is a reproduction of an important historical work. Forgotten Books uses state-of-the-art technology to digitally reconstruct the work, preserving the original format whilst repairing imperfections present in the aged copy. In rare cases, an imperfection in the original, such as a blemish or missing page, may be replicated in our edition. We do, however, repair the vast majority of imperfections successfully; any imperfections that remain are intentionally left to preserve the state of such historical works. (shrink)

Mitochondria contain a molecular genetic system to express the 13 protein components of the electron transport system encoded in the mitochondrial genome (mtDNA). Defects in the function of this system result in some diaseases, many of which are multisystem disorders, prominently involving highly aerobic, postmitotic tissues. These defects can be caused by large‐scale rearrangements of mtDNA, by point mutations, or by nuclear gene mutations resulting in abnormalities in mtDNA. Although any of these mutations would be expected to produce a (...) similar clinical phenotype by compromising oxidative phosphorylation, the surprising and puzzling result is that different clinical phenotypes are generally associated with specific mtDNA mutations. Moreover, the same mutation can produce a distinct clinical phenotype in different individuals or pedigrees. MtDNA rearrangements are also found in aged individuals, but at a subclinical level, suggesting that normal and pathological processes can differ by the effect of genetic or environmental factors on the error rate of mtDNA replication. (shrink)

The dynamics of eukaryotic DNA polymerases has been difficult to establish because of the difficulty of tracking them along the chromosomes during DNA replication. Recent work has addressed this problem in the yeasts Schizosaccharomyces pombe and Saccharomyces cerevisiae through the engineering of replicative polymerases to render them prone to incorporating ribonucleotides at high rates. Their use as tracers of the passage of each polymerase has provided a picture of unprecedented resolution of the organization of replicons and replication origins in the (...) two yeasts and has uncovered important differences between them. Additional studies have found an overlapping distribution of DNA polymorphisms and the junctions of Okazaki fragments along mononucleosomal DNA. This sequence instability is caused by the premature release of polymerase δ and the retention of non proof‐read DNA tracts replicated by polymerase α. The possible implementation of these new experimental approaches in multicellular organisms opens the door to the analysis of replication dynamics under a broad range of genetic backgrounds and physiological or pathological conditions. (shrink)

Integrative mobile genetic elements (MGEs), such as transposons and insertion sequences, propagate within bacterial genomes, but persistence times in individual lineages are short. For long‐term survival, MGEs must continuously invade new hosts by horizontal transfer. Theoretically, MGEs that persist for millions of years in single lineages, and are thus subject to vertical inheritance, should not exist. Here we draw attention to an exception – a class of MGE termed REPIN. REPINs are non‐autonomous MGEs whose duplication depends on non‐jumping RAYT (...) transposases. Comparisons of REPINs and typical MGEs show that replication rates of REPINs are orders of magnitude lower, REPIN population size fluctuations correlate with changes in available genome space, REPIN conservation depends on RAYT function, and REPIN diversity accumulates within host lineages. These data lead to the hypothesis that REPINs form enduring, beneficial associations with eubacterial chromosomes. Given replicative nesting, our hypothesis predicts conflicts arising from the diverging effects of selection acting simultaneously on REPINs and host genomes. Evidence in support comes from patterns of REPIN abundance and diversity in two distantly related bacterial species. Together this bolsters the conclusion that REPINs are the genetic counterpart of mutualistic endosymbiotic bacteria. (shrink)

Faithful DNA replication and accurate chromosome segregation are the key machineries of genetic transmission. Disruption of these processes represents a hallmark of cancer and often results from loss of tumor suppressors. PTEN is an important tumor suppressor that is frequently mutated or deleted in human cancer. Loss of PTEN has been associated with aneuploidy and poor prognosis in cancer patients. In mice, Pten deletion or mutation drives genomic instability and tumor development. PTEN deficiency induces DNA replication stress, confers stress (...) tolerance, and disrupts mitotic spindle architecture, leading to accumulation of structural and numerical chromosome instability. Therefore, PTEN guards the genome by controlling multiple processes of chromosome inheritance. Here, we summarize current understanding of the PTEN function in promoting high-fidelity transmission of genetic information. We also discuss the PTEN pathways of genome maintenance and highlight potential targets for cancer treatment. PTEN is a guardian of the genome. However, the role of PTEN in guarding the genome has not been revealed until recently. PTEN controls multiple fundamental processes of genomic transmission. By physically interacting with key molecules in DNA replication, DNA repair/decatenation, and chromosome segregation during the cell cycle, PTEN maintains genomicintegrity and fitness. (shrink)

Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR and SPINK1 variants were associated with pancreatitis risk. We now report two associations at genome-wide significance identified and replicated at PRSS1-PRSS2 and X-linked CLDN2 through a two-stage genome-wide study. The PRSS1 variant likely affects disease susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele (...) is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men. © 2012 Nature America, Inc. All rights reserved. (shrink)

The information contained within the linear sequence of bases (the genome) must be faithfully replicated in each cell cycle, with a balance of constancy and variation taking place over the course of evolution. Recently, it has become clear that additional information important for genetic regulation is contained within the chromatin proteins associated with DNA (the epigenome). Epigenetic information also must be faithfully duplicated in each cell cycle, with a balance of constancy and variation taking place during the course of (...) development to achieve differentiation while maintaining identity within cell lineages. Both the genome and the epigenome are synthesized at the replication fork, so the events occurring during S‐phase provide a critical window of opportunity for eliciting change or maintaining existing genetic states. Cells discriminate between different states of chromatin through the activities of proteins that selectively modify the structure of chromatin. Several recent studies report the localization of certain chromatin modifying proteins to replication forks at specific times during S‐phase. Since transcriptionally active and inactive chromosome domains generally replicate at different times during S‐phase, this spatiotemporal regulation of chromatin assembly proteins may be an integral part of epigenetic inheritance. BioEssays 25:647–656, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Precise DNA replication is fundamental for genetic inheritance. In eukaryotes, replication initiates at multiple origins that are first “licensed” and subsequently “fired” to activate DNA synthesis. Despite the success in identifying origins with specific DNA motifs in Saccharomyces cerevisiae, no consensus sequence or sequences with a predictive value of replication origins have been recognized in metazoan genomes. Rather, epigenetic rules and chromatin structures are believed to play important roles in governing the selection and activation of replication origins. We propose (...) that replication initiation is facilitated by a group of sequence‐specific “replication pioneer factors,” which function to increase chromatin accessibility and foster a chromatin environment that is conducive to the loading of the prereplication complex. Dysregulation of the function of these factors may lead to gene duplication, genomic instability, and ultimately the occurrence of pathological conditions such as cancer. (shrink)

We present SASC, Self-Adaptive Semantic Crossover, a new class of crossover operators for genetic programming. SASC operators are designed to induce the emergence and then preserve good building-blocks, using metacontrol techniques based on semantic compatibility measures. SASC performance is tested in a case study concerning the replication of investment funds.

Intrachromosomal recombination between direct repeats can occur either as gene conversion events, which maintain exactly the number of repeat units, or as deletions, which reduce the number of repeat units. Gene conversions are classical recombination events that utilize the standard chromosome recombination machinery. Spontaneous deletions between direct repeats are generally recA‐independent in E. coli and RAD52‐independent in S. cerevisiae. This independence from the major recombination genes does not mean that deletions form through a nonrecombinational process. Deletions have been suggested to (...) result from sister chromatid exchange at the replication fork in a recA‐independent process. The same type of exchange is proposed to be RAD52‐independent in Saccharomyces cerevisiae. RAD52‐dependent events encompass all events that involve the initial steps of a recombination reaction, which include strand invasion to form a heteroduplex intermediate. (shrink)

Conventional methods of genetic engineering and more recent genome editing techniques focus on identifying genetic target sequences for manipulation. This is a result of historical concept of the gene which was also the main assumption of the ENCODE project designed to identify all functional elements in the human genome sequence. However, the theoretical core concept changed dramatically. The old concept of genetic sequences which can be assembled and manipulated like molecular bricks has problems in explaining the natural (...) genome-editing competences of viruses and RNA consortia that are able to insert or delete, combine and recombine genetic sequences more precisely than random-like into cellular host organisms according to adaptational needs or even generate sequences de novo. Increasing knowledge about natural genome editing questions the traditional narrative of mutations (error replications) as essential for generating genetic diversity and genetic content arrangements in biological systems. This may have far-reaching consequences for our understanding of artificial genome editing. (shrink)

Gene discovery reveals new biology, expands the utility of marker‐assisted selection, and enables targeted mutagenesis. Still, such discoveries can take over a decade. We present a general strategy, “Agile Genetics,” that uses nested, structured populations to overcome common limits on gene resolution. Extensive simulation work on realistic genetic architectures shows that, at population sizes of >5000 samples, single gene‐resolution can be achieved using bulk segregant pools. At this scale, read depth and technical replication become major drivers of resolution. Emerging (...) enrichment methods to address coverage are on the horizon; we describe one possibility – iterative depth sequencing (ID‐seq). In addition, graph‐based pangenomics in experimental populations will continue to maximize accuracy and improve interpretation. Based on this merger of agronomic scale with molecular and bioinformatic innovation, we predict a new age of rapid gene discovery. (shrink)

Bayesian learning theory and evolutionary theory both formalize adaptive competition dynamics in possibly high‐dimensional, varying, and noisy environments. What do they have in common and how do they differ? In this paper, we discuss structural and dynamical analogies and their limits, both at a computational and an algorithmic‐mechanical level. We point out mathematical equivalences between their basic dynamical equations, generalizing the isomorphism between Bayesian update and replicator dynamics. We discuss how these mechanisms provide analogous answers to the challenge of adapting (...) to stochastically changing environments at multiple timescales. We elucidate an algorithmic equivalence between a sampling approximation, particle filters, and the Wright‐Fisher model of population genetics. These equivalences suggest that the frequency distribution of types in replicator populations optimally encodes regularities of a stochastic environment to predict future environments, without invoking the known mechanisms of multilevel selection and evolvability. A unified view of the theories of learning and evolution comes in sight. (shrink)

Post‐translational modifications regulate each step of DNA replication to ensure the faithful transmission of genetic information. In this context, we recently showed that deubiquitination of SUMO2/3 and SUMOylated proteins by USP7 helps to create a SUMO‐rich and ubiquitin‐low environment around replisomes that is necessary to maintain the activity of replication forks and for new origin firing. We propose that a two‐flag system mediates the collective concentration of factors at sites of DNA replication, whereby SUMO and Ubiquitinated‐SUMO would constitute “stay” (...) or “go” signals respectively for replisome and accessory factors. We here discuss the findings that led to this model, which have implications for the potential use of USP7 inhibitors as anticancer agents. (shrink)

We advocate for an integrative long-term perspective on time, noting that culture changes on timescales amenable to behavioral genetic study with appropriate design and modeling extensions. We note the need for replications of behavioral genetic studies to examine model invariance across long-term timescales, which would afford examination of specified as well as unspecified cultural moderators of behavioral genetic effects.

Genomic instability is a hallmark of cancer. Cancer cells that exhibit abnormal chromosomes are characteristic of most advanced tumours, despite the potential threat represented by accumulated genetic damage. Carcinogenesis involves a loss of key components of the genetic and signalling molecular networks; hence some authors have suggested that this is part of a trend of cancer cells to behave as simple, minimal replicators. In this study, we explore this conjecture and suggest that, in the case of cancer, (...) genomic instability has an upper limit that is associated with a minimal cancer cell network. Such a network would include (for a given microenvironment) the basic molecular components that allow cells to replicate and respond to selective pressures. However, it would also exhibit internal fragilities that could be exploited by appropriate therapies targeting the DNA repair machinery. The implications of this hypothesis are discussed. (shrink)

An assessment is offered of the recent debate on information in the philosophy of biology, and an analysis is provided of the notion of information as applied in scientific practice in molecular genetics. In particular, this paper deals with the dependence of basic generalizations of molecular biology, above all the ‘central dogma’, on the so-called ‘informational talk’ (Maynard Smith [2000a]). It is argued that talk of information in the ‘central dogma’ can be reduced to causal claims. In that respect, the (...) primary aim of the paper is to consider a solution to the major difficulty of the causal interpretation of genetic information: how to distinguish the privileged causal role assigned to nucleic acids, DNA in particular, in the processes of replication and protein production. A close reading is proposed of Francis H. C. Crick's On Protein Synthesis (1958) and related works, to which we owe the first explicit definition of information within the scientific practice of molecular biology. Introduction 1.1 The basic questions of the information debate 1.2 The causal interpretation (CI) of biological information and Crick's ‘central dogma’ Crick's definitions of genetic information The main requirement for (CI) Types of causation in molecular biology 4.1 Structural causation in molecular biology 4.2 Nucleic acids as correlative causal factors The ‘central dogma’ without the notion of information Concluding remarks This is a new version of this article as there were errors in the abstract and full text in the previous version. (shrink)

Although neither the genome nor the environment can be manipulated in research on human behaviour, some of the new tools of molecular genetics can be brought to bear on human behavioural disorders (e.g. cognitive disabilities) and quantitative traits (e.g. cognitive abilities). The inability to manipulate the human genome experimentally has had the positive effect of focusing attention on naturally occuring genetic variation responsible for behavioural differences among individuals in all their complex multifactorial splendour. Genes in such complex multiple‐gene systems (...) are called quantitative trait loci (QTLs), which merge the two worlds of genetic research, quantitative genetics and molecular genetics. Although most genetic research on complex human behaviour has focused on severe mental disorders, cognitive abilities and disabilities may be even more immediately relevant to neuroscience. For example, verbal ability and spatial ability are two of the most heritable cognitive abilities, and reading disability is the first behavioural disability for which replicated QTL linkage has been found. The purpose of this essay is to provide an overview of the genetics of cognitive abilities and disabilities as an example of the impending merger of quantitative genetics and molecular genetics in QTL analysis of complex traits. (shrink)

A general case about the insights and oversights of molecular genetics is argued for by considering two specific cases: the first concerns the bearing of molecular genetics on Mendelian genetics, and the second concerns the bearing of molecular genetics on the replicability of the genetic material. As in the first case, it is argued that Mendel's law of segregation cannot be explained wholly in terms of molecular genetics--the law demands evolutionary scrutiny as well. In the second case, it is (...) argued that an account of the replicability of the genetic material in terms of molecular genetics is not entirely independent of evolutionary considerations, in the sense that it raises further evolutionary questions. The limitations of the molecular-genetic approach in these cases point to the limitations of that approach in general. (shrink)

A diploid human genome contains approximately six billion nucleotides. This enormous amount of genetic information can be replicated with great accuracy in only a few hours. However, because DNA strands are oriented antiparallel while DNA polymerization only occurs in the 5′ → 3′ direction, semi‐conservative replication of double‐stranded DNA is an asymmetric process, i.e., there is a leading and a lagging strand. This provides a considerable opportunity for non‐random error rates, because the architecture of the two strands as well (...) as the DNA polymerases that replicate them may be different. In addition, the proteins that start or finish chains may well be different from those that perform the bulk of chain elongation. Furthermore, while replication fidelity depends on the absolute and relative concentrations of the four deoxyribonucleotide precursors, these are not equal in vivo, not constant throughout the cell cycle, and not necessarily equivalent in all cell types. Finally, the fidelity of DNA synthesis is sequence‐dependent and the eukaryotic nuclear genome is a heterogeneous substrate. It contains repetitive and non‐repetitive sequences and can actually be considered as two subgenomes that differ in nucleotide composition and gene content and that replicate at different times. The effects that each of these asymmetries may have on error rates during replication of the eukaryotic genome are discussed. (shrink)

The RecQ family of DNA helicases have been shown to be important for the maintenance of genomic integrity in all organisms analysed to date. In human cells, representatives of this family include the proteins defective in the cancer predisposition disorder Bloom's syndrome and the premature ageing condition, Werner's syndrome. Several pieces of evidence suggest that RecQ family helicases form associations with one or more of the cellular topoisomerases, and together these heteromeric complexes manipulate DNA structure to effect efficient DNA replication, (...) genetic recombination, or both. Here, we propose that RecQ helicases are required for ensuring that structural abnormalities arising during replication, such as at sites where replication forks encounter DNA lesions, are corrected with high fidelity. In mutants defective in these proteins, not only is replication abnormal, but cells display aberrant responses to DNA-damaging agents or inhibitors of DNA synthesis. We suggest that RecQ helicases may be important for the integration of cellular responses to these insults, such as by linking cell cycle checkpoint responses to recombinational repair. BioEssays 21:286–294, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

We focus here on the intercalary heterochromatin (IH) of Drosophila melanogaster and, in particular, its molecular properties. In the polytene chromosomes of Drosophila, IH is represented by a reproducible set of dense bands scattered along the euchromatic arms. IH contains mainly unique DNA sequences, and shares certain features with other heterochromatin types such as pericentric, telomeric, and PEV‐induced heterochromatin, the inactive mammalian X‐chromosome and the heterochromatized male chromosome set in coccids. These features are transcriptional silencing, chromatin compactness, late DNA replication, (...) underrreplication or elimination in somatic cells, and formation of the heterochromatin state in early embryogenesis. Post‐translational modification of histones and the specific nonhistone protein complexes are shown to participate in the establishment and maintenance of silencing for all heterochromatin types. Many IH regions contain binding sites for HP1 and/or Pc‐G proteins and all the regions are sites of heterochromatin‐associated SuUR protein. Some IH regions are known to contain homeotic genes. Summarizing these data, we suggest that IH regions comprise stable inactivated genes, whose silencing is developmentally programmed. BioEssays 25:1040–1051, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Recent data show that catastrophic events during one cell cycle can cause massive genome damage producing viable clones with unstable genomes. This is in contrast with the traditional view that tumorigenesis requires a long‐term process in which mutations gradually accumulate over decades. These sudden events are likely to result in a large increase in genomic diversity within a relatively short time, providing the opportunity for selective advantages to be gained by a subset of cells within a population. This genetic (...) diversity amplification, arising from a single aberrant cell cycle, may drive a population conversion from benign to malignant. However, there is likely a period of relative genome stability during the clonal expansion of tumors – this may provide an opportunity for therapeutic intervention, especially if mechanisms that limit tolerance of aneuploidy are exploited. (shrink)

Contingency-theorists have gestured to a series of phenomena such as random mutations or rare Armageddon-like events as that which accounts for evolutionary contingency. These phenomena constitute a class, which may be aptly called the ‘sources of contingency’. In this paper, I offer a probabilistic conception of what it is to be a source of contingency and then examine two major candidates: chance variation and genetic drift, both of which have historically been taken to be ‘chancy’ in a number of (...) different senses. However,contrathe gesturing of contingency-theorists, chance variation and genetic drift are not always strong sources of contingency, as they can be non-chancy in at least one sense that opposes evolutionary contingency. The probabilistic conception offered herein allows for sources of contingency to appropriately vary in strength. To this end, I import Shannon’sinformation entropyas a statistical measure for systematically assessing the strength of a source of contingency, which is part and parcel of identifying sources of contingency. In brief, the higher the entropy, the greater the strength. This is also empirically significant because molecular, mutational, and replicative studies often contain sufficient frequency or probability data to allow for entropies to be calculated. In this way, contingency-theorists can evaluate the strength of a source of contingency in real-world cases. Moreover, the probabilistic conception also makes conceptual room for the converse of sources of contingency: ‘sources of directionality’, which ought to be recognised, as they can interact with genuine sources of contingency in undermining evolutionary contingency. (shrink)

When one takes the evolution of operant behavior as prototype, one sees that the term replication is too tied to the peculiarities of genetic evolution. A more general term is recurrence. The important problem raised by recurrence is not “information” but relationship: deciding when two occurrences belong to the same lineage. That is solved by looking at common environmental effects.

It is commonly presumed that abiotic membranes were colonized by proteins later on. Yet, hydrophobic peptides could have formed primordial protein‐dominated membranes on their own. In a metabolism‐first context, “autocatalytically closed” sets of statistical peptides could organize a self‐maintaining protometabolism, assisted by an unfolding set of ribotide‐related cofactors. Pairwise complementary ribotide cofactors may have formed docking guides for stochastic peptide formation, before replicating RNA emerged from this subset. Tidally recurring wet‐drying cycles and an early onset of photosynthetic activities are considered (...) most likely to meet the thermodynamic requirements. Conceivably, the earliest peptide‐dominated vesicles were engaged in light harvesting, together with isoprenoid‐tethered pigments, rather than providing an external boundary. Early on, the bulk of prebiotic organic matter can have formed a contiguous layer covering the mineral sediment, held in place by colloidal coherence of a hydrogel matrix. This unconventional scenario assumes a late onset of cellular individualization – perhaps from within, resembling endosporogenesis. (shrink)

We advance two objections to the selfish gene theory formulated by Richard Dawkins, which states that natural selection operates on genetic replicators. These objections target three of the essential features of the theory. The first feature is the exclusivity that the theory ascribes to genetic replicators as objects of natural selection. We call it “the exclusivity clause”. The second and third features correspond to two criteria that genetic replicators must satisfy for Dawkins’ theory to (...) hold. We call them “the stability criterion” and “the fidelity criterion”. The first objection we advance is that, given the findings of transgenerational epigenetics, genetic replicators do not appear to satisfy the exclusivity clause and some of them do not seem to meet the stability criterion. The second objection is that the existence of the molecular phenomena known as alternative splicing and trans-splicing seems to entail that many genetic replicators do not satisfy neither the stability criterion nor the fidelity criterion. (shrink)

Many psychometricians and behavioral geneticists believe that high heritability of IQ test scores within racial groups coupled with environmental hypotheses failing to account for the differences between the mean scores for groups lends plausibility to explanations of mean differences in terms of genetic factors. I show that heritability estimates and the statistical analysis of variance on which they are based have limited relevance in exposing genetic and environmental factors operating within any single group or population. I begin with (...) agricultural investigations, where replication of genetic types and control over environmental factors are possible, and highlight the difficulties of moving from AOV of observed traits to investigation of measurable genetic factors. The difficulties can only be exacerbated for human data sets, which are equivalent to a crop trial in which each variety is replicated in only one or two of the locations. (shrink)

FOREWORD. Gilbert Gottlieb and the Developmental Point of View. I. INTRODUCTION. 1. Developmental Systems, Nature-Nurture, and the Role of Genes in Behavior and Development: On the Legacy of Gilbert Gottlieb. 2. Normally Occurring Environmental and Behavioral Influences on Gene Activity: From Central Dogma to Probabilistic Epigenesis. II. THEORETICAL FOUNDATIONS FOR THE DEVELOPMENTAL STUDY OF BEHAVIOR AND GENETICS. 3. Historical and Philosophical Perspectives on Behavioral Genetics and Developmental Science. 4. Development and Evolution Revisited. 5. Probabilistic Epigenesis and Modern Behavioral and Neural (...) Genetics. 6. The Roles of Environment, Experience, and Learning in Behavioral Development. 7. Contemporary Ideas in Physics and Biology in Gottlieb’s Psychology. III. EMPIRICAL STUDIES OF BEHAVIORAL DEVELOPMENT AND GENETICS. 8. Behavioral Development during the Mother-Young Interaction in Placental Mammals: The Development of Behavior in the Relationship with the Mother. 9. Amniotic Fluid as an Extended Milieu Interieur. 10. Developmental Effects of Selective Breeding for an Infant Trait. 11. Emergence and Constraint in Novel Behavioral Adaptations. 12. Nonhuman Primate Research Contributions to Understanding Genetic and Environmental Influences on Phenotypic Outcomes across Development. 13. Interactive Contributions of Genes and Early Experience to Behavioural Development: Sensitive Periods and Lateralized Brain and Behaviour. 14. Trans-Generational Epigenetic Inheritance. 15. The Significance of Non-Replication of Gene-Phenotype Associations. 16. Canalization and Malleability Reconsidered: The Developmental Basis of Phenotypic Stability and Variability. IV. APPLICATIONS TO DEVELOPMENT. 17. Gene-Parenting Interplay in the Development of Infant Emotionality. 18. Genetic Research in Psychiatry and Psychology: A Critical Overview. 19. On the Limits of Standard Quantitative Genetic Modeling of Inter-Individual Variation: Extensions, Ergodic Conditions and a New Genetic Factor Model of Intra-Individual Variation. 20. Songs My Mother Taught Me: Gene-Environment Interactions, Brain Development and the Auditory System: Thoughts on Non-Kin Rejection, Part II. 21. Applications of Developmental Systems Theory to Benefit Human Development: On the Contributions of Gilbert Gottlieb to Individuals, Families, and Communities. (shrink)

Mutations in specific genes result in birth defects, cancer, inherited diseases or lethality. The frequency with which DNA damage is converted to mutations increases dramatically when the cellular genome is replicated. Although DNA damage poses special problems to the fidelity of DNA replication, efficient mechanisms exist in mammalian cells which function to replicate their genome despite the presence of many damaged sites. These mechanisms operate in either error‐prone or error‐free modes of DNA synthesis, and frequently involve DNA strand‐pairing reactions. (...) class='Hi'>Genetic studies in yeast and other eukaryotes suggest that replication through DNA damage is highly regulated and catalysed by complex biochemical machineries composed of many specialised gene products. Knowledge of the molecular details by which such factors facilitate the replication of damaged DNA in mammalian cells should reveal basic rules about how DNA damage induces mutagenesis and carcinogenesis. (shrink)

DNA and RNA are the only known natural genetic materials. Systematic modification of each of their chemical building blocks (nucleobase, sugar, and phosphate) has enabled the study of the key properties that make those nucleic acids genetic materials. All three moieties contribute to replication and, significantly, all three moieties can be replaced by synthetic analogs without loss of function. Synthetic nucleic acid polymers capable of storing and propagating information not only expand the central dogma, but also highlight that (...) DNA and RNA are not unique chemical solutions for genetic information storage. By considering replication as a question of information transfer, we propose that any polymer that can be replicated could serve as a genetic material.Editor's suggested further reading in BioEssays Xenobiology: A new form of life as the ultimate biosafety tool Abstract. (shrink)

Werner syndrome (WS) is an inherited disorder that produces somatic stunting, premature ageing and early onset of degenerative and neoplastic diseases. Cultured fibroblasts derived from subjects with WS are found to undergo premature replicative senescence and thus provide a cellular model system to study the disorder. Recently, several overexpressed gene sequences isolated from a WS fibroblast cDNA library have been shown to possess the capacity to inhibit DNA synthesis and disrupt many normal biochemical processes. Because a similar constellation of genes (...) is overexpressed in WS and senescent normal fibroblasts, these data suggest the existence of a common molecular genetic pathway for replicative senescence in both types of cell. We propose that the primary defect in WS is a mutation in a gene for a trans‐acting repressor protein that reduces its binding affinity for shared regulatory regions of several genes, including those that encode inhibitors of DNA synthesis (IDS). The mutant WS repressor triggers a sequence of premature expression of IDS and other genes, with resulting inhibition of DNA synthesis and early cellular senescence, events which occur much later in normal cells. (shrink)

This research looks what happens to human reproduction when human genetic information is digitized. By employing speculative design as a transdisciplinary strategy to construct such an alternative future to open up public dialogues, it aims to stimulate audiences in an artistic way to deliberate two key questions: (1) how will biotechnology recondition and recontextualize the natural processes of genetic information (i.e. expression, replication, transmission and mutation) and our physiological processes (e.g. reproduction)? And (2) what might be the ethical, (...) legal and social implications (ELSI) for using such biotechnology? To this end, this practice-based research introduces the ‘e-gamete Digital Procreation Service’ (2019) – a speculative design project that has been developed as an approach to invite audiences to a future scenario of network-transmitted genetic information and computer-simulated human procreation. The carefully designed future service (an ironic practice of commercialization) allows human reproduction to take place outside of the human body. Audiences are encouraged to contemplate what novel situations might occur within their own futures and to consider broader questions like how family, parenthood, marriage, etc. are redefined and what new social relationships might emerge. By employing speculative design as an artistic research tool/tactic to step outside the technical limitations and craft the future service, the project asks vital question about the future in a provocative and quasi-realistic manner. Thus, the research forms a unique entanglement of sensitive topics by dealing with future biotechnology and human reproduction. (shrink)

Health policy is increasingly confronted with the demand for financing genetic testing on inherited susceptibility to disease. Tests on polymorphism/snp associated with multicausal and chronic conditions are already offered in private commercial institutions or in academic hospitals. The increasing pressure on public health services to offer SNP testing leads to first methodological approaches for a generally valid regulatory framework applicable for inclusion or refusal of genetic tests into the public health services. Systematic search in Medline, Embase and the (...) Web for methodological papers or guidelines for the assessment of polymorphism-screening. Since genetic testing has not only clinical and economic effects on health care, but also primarily ethical consequences by profiling our understanding of “health” and “disease”, this paper gives an overview of relevant aspects and background information to consider in the assessment of genetic tests. Although 2–3 million SNPs are identified and the journals are full of reported “significant” associations between disease and mutation, only a few can be replicated unequivocally. The ACCE -framework was developed by the Center of Disease Control for the assessment of genetic testing. This standardised appraisal approach proposes collecting and evaluating: Prevalence, genotype-/phenotype-relation. Clinical presentation: natural history; the different expressions of disease. Performance of the genetic test. Implications for therapy and prevention. Conclusion for clinical applications of risk-profiling of health on their susceptibility to disease and/or for clarification of disease for therapy planning. Since genetic testing is urging its way into the health care system, the actual danger is, that population screening starts before valid evidence from big prospective studies have been carried out and delivered proofs of direct causal associations. Before diffusing into the health care system we are suggesting to take a cautious and standardised approach. (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)

A secondary analysis was performed on preliminary data from an ongoing cross-cultural study on assortative pairing. Independently sampled pairs of opposite-sex romantic partners and of same-sex friends rated themselves and each other on Life History (LH) strategy and mate value. Data were collected in local bars, clubs, coffeehouses, and other public places from three different cultures: Tucson, Arizona; Hermosillo, Sonora; and San José, Costa Rica. The present analysis found that slow LH individuals assortatively pair with both sexual and social partners (...) more strongly than fast LH individuals. We interpret this phenomenon as representing (1) an adaptation for preserving coadapted genomes in slow LH strategists to maintain high copying fidelity genetic replication while producing a lower number of offspring in stable, predictable, and controllable environments and (2) a bet-hedging adaptation in fast LH strategists, favoring the genetic diversification of a higher number of offspring in unstable, unpredictable, and uncontrollable environments. (shrink)

Memes are hypothetical cultural units passed on by imitation; although nonbiological, they undergo Darwinian selection like genes. Cognitive study of multimodular human minds undermines memetics: unlike in genetic replication, high-fidelity transmission of cultural information is the exception, not the rule. Constant, rapid 'mutation' of information during communication generates endlessly varied creations that nevertheless adhere to modular input conditions. The sort of cultural information most susceptible to modular processing is that most readily acquired by children, most easily transmitted across individuals, (...) most apt to survive within a culture, most likely to recur in different cultures, and most disposed to cultural variation and elaboration. (shrink)