The chromosomes undergo a condensation‐decondensation cycle within the life cycle of mammalian cells. Chromosome condensation is a complex and critical event that is necessary for the equal distribution of genetic material between the two daughter cells. Although chromosome condensation‐decondensation and segregation is mechanistically complex, it proceeds with high fidelity during the eukaryotic cell division cycle. Cell fusion studies have indicated the presence of chromosome condensation factors in mammalian cells during mitosis. If extracts from (...) mitotic cells are injected into immature oocytes of Xenopus laevis, they induce meiotic maturation (i.e. germinal vesicle breakdown and chromosome condensation) within 2–3 hours. Recently, we showed that the maturation‐promoting activity of the mitotic cell extracts is inactivated by certain protein factors present in cells during the G1 period. The activity of the G1 factors coincides with the process of chromosome decondensation that begins at telophase and continues throughout the G1 period. These studies have revealed that the mitotic factors and the G1 factors play a pivotal role in the regulation of condensation and decondensation of chromosomes. Furthermore, our studies strongly suggest that nonhistone protein phosphorylation and dephosphorylation may mediate chromosome condensation and decondensation, respectively. (shrink)

At metaphase, DNA in a human chromosome is estimated to be compacted at least 10,000 fold in length.1,2 However, the higher order mechanisms by which the chromosomes are organized in interphase and subsequently further condensed in mitosis have largely remained elusive. One generally overlooked participant in chromosome condensation is DNA replication. Many early studies of eukaryotic chromosome organization and cell fusions have suggested that DNA replication plays a role in chromosome compaction. Recent phenotypic analysis of (...) Drosophila DNA replication mutants has revitalized this old idea. In this review, the role of DNA replication in chromosome condensation will be examined. BioEssays 24:411–418, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

Recent studies indicate that mammalian chromosomes contain discretecis‐acting loci that control replication timing, mitotic condensation, and stability of entire chromosomes. Disruption of the large non‐coding RNA gene ASAR6 results in late replication, an under‐condensed appearance during mitosis, and structural instability of human chromosome 6. Similarly, disruption of the mouse Xist gene in adult somatic cells results in a late replication and instability phenotype on the X chromosome. ASAR6 shares many characteristics with Xist, including random mono‐allelic expression and (...) asynchronous replication timing. Additional “chromosome engineering” studies indicate that certain chromosome rearrangements affecting many different chromosomes display this abnormal replication and instability phenotype. These observations suggest that all mammalian chromosomes contain “inactivation/stability centers” that control proper replication, condensation, and stability of individual chromosomes. Therefore, mammalian chromosomes contain four types ofcis‐acting elements, origins, telomeres, centromeres, and “inactivation/stability centers”, all functioning to ensure proper replication, condensation, segregation, and stability of individual chromosomes. (shrink)

This review deals with the condensation–decondensation cycle of chromatin. This cycle can be analysed in increasing detail because of the availability of well‐characterized temperature‐sensitive cell‐cycle mutants in which the control for condensation is aberrant at the non‐permissive temperature. DNA transfection and gene cloning techniques using one such mutant have resulted in the identification of a gene involved in the normal regulation of entry into mitosis.

Sister chromatid separation in anaphase is an important event in the cell's transmission of genetic information to a descendent. It has been investigated from different aspects: cell cycle regulation, spindle and chromosome dynamics within the three‐dimensional cell architecture, transmission fidelity control and cellular signaling. Integrated studies directed toward unified understanding are possible using multidisciplinary methods with model organisms. Ubiquitin‐dependent proteolysis, protein dephosphorylation, an unknown function by the TPR repeat proteins, chromosome transport by microtubule‐based motors and DNA topological change (...) by DNA topoisomerase II are all necessary for progression from metaphase to anaphase. Chromosome condensation, mitotic kinetochore function and spindle formation require a large number of proteins, which are prerequisites for successful sister chromatid separation. Factors that help to retain sister chromatid connection after replication and prevent premature separation remain to be determined. Although sister chromatid separation occurs in anaphase, gene functions in other cell cycle stages also ensure the progression of correct chromatid separation. (shrink)

Recent progress in our understanding of mitotic chromosome dynamics has been accelerated by the identification of two essential protein complexes, cohesin and condensin. Cohesin is required for holding sister chromatids (duplicated chromosomes) together from S phase until the metaphase‐to‐anaphase transition. Condensin is a central player in chromosome condensation, a process that initiates at the onset of mitosis. The main focus of this review is to discuss how the mitotic metaphase chromosome is assembled and shaped by a (...) precise balance between the cohesion and condensation machineries. We argue that, in different eukaryotic organisms, the balance of cohesion and condensation is adjusted in such a way that the size and shape of the resulting chromosomes are best suited for their accurate segregation. BioEssays 23:924–935, 2001. © 2001 John Wiley & Sons, Inc. (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)

How eukaryotic genomes are packaged into compact cylindrical chromosomes in preparation for cell divisions has remained one of the major unsolved questions of cell biology. Novel approaches to study the topology of DNA helices inside the nuclei of intact cells, paired with computational modeling and precise biomechanical measurements of isolated chromosomes, have advanced our understanding of mitotic chromosome architecture. In this Review Essay, we discuss – in light of these recent insights – the role of chromatin architecture and the (...) functions and possible mechanisms of SMC protein complexes and other molecular machines in the formation of mitotic chromosomes. Based on the information available, we propose a stepwise model of mitotic chromosome condensation that envisions the sequential generation of intra‐chromosomal linkages by condensin complexes in the context of cohesin‐mediated inter‐chromosomal linkages, assisted by topoisomerase II. The described scenario results in rod‐shaped metaphase chromosomes ready for their segregation to the cell poles. (shrink)

Genome maintenance requires various nucleoid-associated factors in prokaryotes. Among them, the SMC protein has been thought to play a static role in the organization and segregation of the chromosome during cell division. However, recent studies have shown that the bacterial SMC is required to align left and right arms of the emerging chromosome and that the protein dynamically travels from origin to Ter region. A rod form of the SMC complex mediates DNA bridging and has been recognized as (...) a machinery responsible for DNA loop extrusion, like eukaryotic condensin or cohesin complexes, which act as chromosome organizers. Attention is now turning to how the prototype of the complex is loaded on the entry site and translocated on chromosomal DNA, explaining its overall conformational changes at atomic levels. Here, we review and highlight recent findings concerning the prokaryotic SMC complex and discuss possible mechanisms from the viewpoint of protein architecture. Recent studies show dynamic movements of the prokaryotic SMC protein complex: initial loading, translocation on DNA for bacterial chromosome organization. The recent structural models of the protein also provide a new vision for the structure-function relationship. (shrink)

A complex structure, visible by electron microscopy, surrounds each chromosome during mitosis. The organization of this structure is distinct from that of the chromosomes and the cytoplasm. It forms a perichromosomal layer that can be isolated together with the chromosomes. This layer covers the chromosomes except in centromeric regions. The perichromosomal layer includes nuclear and nucleolar proteins as well as ribonucleoproteins (RNPs). The list of proteins and RNAs identified includes nuclear matrix proteins (perichromin, peripherin), nucleolar proteins (perichro‐monucleolin, Ki‐67 antigen, (...) B23 protein, fibrillarin, p103, p52), ribosomal proteins (S1) and snRNAs (U3 RNAs). Only limited information is available about how and when the perichromosomal layer is formed. During early prophase, the proteins extend from the nucleoli towards the periphery of the nucleus. Thin cordon‐like structures reach the nuclear envelope delimiting areas in which chromosomes condense. At telophase, the proteins are associated with the part of the chromosomes remaining condensed and accumulate in newly formed nucleoli in regions where chromatin is already decondensed. The perichromosomal layer contains several different classes of proteins and RNPs and it has been attributed various roles: (1) in chromosome organization, (2) as a barrier around the chromosomes, (3) involvement in compartmentation of the cells in prophase and telophase and (4) a binding site for chromosomal passenger proteins necessary to the early process of nuclear assembly. (shrink)

We may now ask the question: In what historical perspective should we place the work of Richard Goldschmidt? There is no doubt that in the period 1910–1950 Goldschmidt was an important and prolific figure in the history of biology in general, and of genetics in particular. His textbook on physiological genetics, published in 1938, was an amazing compendium of ideas put forward in the previous half-century about how genes influence physiology and development. His earlier studies on the genetic and geographic (...) distribution of the various species and races of Lymantria contributed soundly to an understanding of the inheritance and development of sex, as well as the genetics of speciation. He was a curious mixture of the experimentalist, empiricist, and theorizer, who could grasp both the large and the small at once and wrap them into the same integrated and coherent package.In insisting on trying to relate genetics to development, Goldschmidt was continually forced to speculate and to forsake experimental fact for generalized theory. In refusing to reconcile a physiological and developmental conception with a corpuscular theory of the gene, he forced himself to substitute for a large body of experimentally verified evidence, vague and general speculations which did not lead in any precise direction. L. C. Dunn summarizes succinctly the effect of Goldschmidt's thinking on the development of genetic theory: Although Goldschmidt's ideas had a considerable influence in directing attention to the developmental processes intervening between genes and characters, they did not lead to the establishment of a general theory of development in genetical terms. In fact, at the end of the period, as signalized by Goldschmidt's book of 1938 [Physiological Gentics] doubt remained whether there was a field with a defined problem which could be identified as developmental genetics.Yet the frequency with which Goldschmidt is cited by later writers suggests that there is a more positive side to his contribution than this. The early Mendelians had recognized the genic constitution of organisms and the Drosophila workers had uncovered in detail the chromosomal mechanism of heredity. These great discoveries were of classical character, solidly based on a multitude of well established facts. By themselves, however, they would not have been sufficient to place genetics in the central position within biology which it was to assume. Beyond the “static” analysis of gene transmission an insight was needed into the dynamic role of genes in cellular physiology, biochemistry, and development. Goldschmidt recognized this aspect and outlined in brilliant generalizations a physiological theory of genetics. Necessarily the prophetic nature of this achievement — romantic in the sense of Ostwald's classification of great scientists and their discoveries — transcended its factual basis. It was the audacity of the theoretician unimpeded by the still scanty data which gave a new focus to biological thought.Some have called Goldschmidt an “obstructionist” in the history of genetics—one whose efforts were largely directed toward useless and continual criticism — challenge for the sake of challenge. As this line of argument goes, time wasted answering Goldschmidt's poorly conceived criticisms could have been better used to pursue new lines of thought within the classical gene theory. Sometimes historians are upbraided for studying the work of such “obstructionists,” or even the work of those whose ideas have later proved to be inadequate. This argument misses the point of history and the lessons which it can teach. Perhaps Goldschmidt did take the time of a number of the classical geneticists who tried to answer his objections to the gene theory; and perhaps many of his own ideas about genes were, by today's view, “wrong.” These are always easier judgments to make by hindsight than at the moment. But that is not the point. Goldschmidt had a considerable influence on his contemporaries, and to dismiss him as an obstructionist because his opponents later proved to be more nearly right, distorts history and obscures significant questions which we might well be asking. It might be valuable to know why Goldschmidt felt compelled to be an iconoclast —and how that impulse, psychological in orgin, led him to overlook critical items of evidence which his opponents considered more carefully. It might also be valuable to try and understand how a contemporary of Goldschmidt or. Morgan really viewed the gene theory — what were its strong and weak point? Such questions are not readily answered by studying the work of only those men who were correct by later standards.Answers to some of the above questions can be gleaned from this study of Goldschmidt — though the first, and most psychologically oriented, question is largely untouched here.On the one hand, Goldschmidt forced classical geneticists to reexamine the foundation of their ideas about the nature, inviolability, and even physical dimensions of genes. He also kept alive the very real problems of gene physiology and its relations to development — a relationship that was given less attention by the Drosophila school in their pursuit of the transmission process. On a broader level he emphasized to the biological community a principle that was in danger of being lost in the enthusiasm surrounding the expansion of the Mendelian-chromosome theory. The point was that all theories in science are transient, logical constructs which should not be held as sacred. Time and again, as the history of science has shown, theories become rigid structures which retard new modes of thought. From Goldschmidt's perspective, the gene theory was in danger of performing just that function, for it was preventing workers from viewing the gene in a functional as well as a structural light.On the other hand, examining the work of critics (or even of outright “obstructionists”) gives the historian an opportunity to observe how the more established community of scholars at some point in time reacts to challenges of its cherished ideas. The fact that many workers in his own day (such as Beadle, Luria, Delbruck, Sturtevant, Bridges, and others), as well as most geneticists today, saw Goldschmidt as having been largely “obstructionist” is useful historical (and/or sociological) data. Clearly, as this paper has tried to show, Goldschmidt's ideas were not all obstructionist, and his viewpoint that genes must be considered functionally was one which was clearly valid, premature as it may have been from an experimental and technique point of view. Perhaps Goldschmidt's major fault was that he developed alternative theories which were not easily testable. Nonetheless, his challenge to a fundamental and established idea brought forth a reaction from many members of the genetic community which indicates how unwilling they were to reconsider the formalized theory on which their work was based. While many of Goldschmidt's criticisms — and particularly his way of making them — arose out of his own idiosyncrasies, they were also a product of his times. His view of the nature of theory-construction, and his rejection of old-style reductionism and mechanism, were part of a growing awareness within the world scientific community that explanations based on reducing complex phenomena to ultimate particles or units were clearly inadequate. The success of the Mendelian-chromosome theory had obscured that fact for many geneticists, but to Goldschmidt it was a point that could not be allowed to pass unnoticed. (shrink)

The mechanism of chromosome condensation is one of the classic mysteries of mitosis. A number of years ago, it was suggested that nonhistone proteins of the chromosome scaffold fraction might help chromosomes to condense, possibly by constructing a framework for the condensed structure. Recent results have shown that topoisomerase II and the SMC proteins, two abundant members of the scaffold fraction, are required for chromosome condensation and segregation during mitosis. Topoisomerase II is a well‐characterized enzyme. (...) In contrast, nothing is yet known about the function of the SMC proteins. We summarize evidence suggesting that these proteins may be enzymes whose activity is somehow involved in the establishment and maintenance of mitotic chromosome morphology. (shrink)

During the eukaryotic cell cycle, chromosomes undergo large structural transitions and spatial rearrangements that are associated with the major cell functions of genome replication, transcription and chromosome condensation to metaphase chromosomes. Eukaryotic cells have evolved cell cycle dependent processes that modulate histone:DNA interactions in chromosomes. These are; (i) acetylations of lysines; (ii) phosphorylations of serines and threonines and (iii) ubiquitinations of lysines. All of these reversible modifications are contained in the well‐defined very basic N‐ and C‐ terminal domains (...) of histones. Acetylations and phosphorylations markedly affect the charge densities of these domains whereas ubiquitination adds a bulky globular protein, ubiquitin, to lysines in the C‐terminal tails of H2A and H2B. Histone acetylations are strictly associated with genome replication and transcription; histone H1 and H3 phosphorylations correlate with the process of chromosome condensation. The subunits of histone H1 kinase have now been shown to be cyclins and the p34CDC2 kinase product of the cell cycle control gene CDC2. It is probable that all of the processes that control chromosome structure:function relationships are also involved in the control of the cell cycle. (shrink)

DNA topoisomerase II (topo II) is involved in chromosome structure and function, although its exact location and role in mitosis are somewhat controversial. This is due in part to the varied reports of its localization on mitotic chromosomes, which has been described at different times as uniformly distributed, axial on the chromosome arms and predominantly centromeric. These disparate results are probably due to several factors, including use of different preparation and fixation techniques, species differences and changes in distribution (...) during the cell cycle. Recently, several papers have re‐investigated the distribution of topo II on chromosomes as a function of cell cycle and species(1–3). The new studies suggest that Topo II has a dynamic pattern of distribution on the chromosomes, in general becoming axial as chromosomes condense during prophase and then concentrating at centromeres during metaphase. These experiments suggest a novel role for topo II in centromere structure and function. (shrink)

A hypothesis for the control of eukaryotic DNA replication at the chromosomal level is proposed. The specific regulatory problem arises from the subdivision of the genome into thousands of individually replicating units, each of which must be duplicated a single time during S‐phase. The hypothesis is based on the finding of direct repeats at replication origins. Such repeats can adopt, beyond the full‐length double helical structure, another configuration exposing two single‐stranded loops that provide suitable templates for the initiation of DNA (...) replication. Any further initiation at the same origin is excluded as the single strandedness is eliminated by the replication process. Restoration of the initiable loop structure is proposed to occur by DNA‐protein rearrangements involved in chromosome condensation and duplication of the chromosomal protein backbone during mitosis. A possible role of the maturation promoting factor (MPF) is suggested. (shrink)

This essay presents the early days of human cytogenetics, from the late 1950s until the mid 1970s, as a historical series of images. I propose a chronology moving from photographs of bodies to chromosome sets, to be joined by ultrasound images, which provided a return to bodies, by then focused on the unborn. Images carried ontological significance and, as I will argue, are principal characters in the history of human cytogenetics. Inspired by the historiography of heredity and genetics, studies (...) on visual cultures, the conceptualization of circulation, and the sociology of pregnancy, I suggest that cytogenetics, through its focus on pregnancy, pregnant women, and their offspring, found strategic living materials that stabilized human chromosome studies as a biomedical, post-eugenics practice. The historicity of each path displays a wide circulation of objects, tools, and methods that condensed on images that shared in the centuries-old visual expertise that medicine and botany had manufactured. (shrink)

Research over the last two decades has identified a group of meiosis‐specific proteins, consisting of budding yeast Spo13, fission yeast Moa1, mouse MEIKIN, and Drosophila Mtrm, with essential functions in meiotic chromosome segregation. These proteins, which we call meiosis I kinase regulators (MOKIRs), mediate two major adaptations to the meiotic cell cycle to allow the generation of haploid gametes from diploid mother cells. Firstly, they promote the segregation of homologous chromosomes in meiosis I (reductional division) by ensuring that sister (...) kinetochores face towards the same pole (mono‐orientation). Secondly, they safeguard the timely separation of sister chromatids in meiosis II (equational division) by counteracting the premature removal of pericentromeric cohesin, and thus prevent the formation of aneuploid gametes. Although MOKIRs bear no obvious sequence similarity, they appear to play functionally conserved roles in regulating meiotic kinases. Here, the known functions of MOKIRs are reviewed and their possible mechanisms of action are discussed. Also see the video abstract here https://youtu.be/tLE9KL89bwk. (shrink)

Type II DNA topoisomerase activity is required to change DNA topology. It is important in the relaxation of DNA supercoils generated by cellular processes, such as transcription and replication, and it is essential for the condensation of chromosomes and their segregation during mitosis. In mammals this activity is derived from at least two isoforms, termed DNA topoisomerase IIα and β. The α isoform is involved in chromosome condensation and segregation, whereas the role of the β isoform is (...) not yet clear. DNA topoisomerase IIβ was first reported in 1987. Here we review the research on DNA topoisomerase IIβ over the last 10 years. BioEssays 20:215–226, 1998.© 1998 John Wiley & Sons, Inc. (shrink)

Type II DNA topoisomerase activity is required to change DNA topology. It is important in the relaxation of DNA supercoils generated by cellular processes, such as transcription and replication, and it is essential for the condensation of chromosomes and their segregation during mitosis. In mammals this activity is derived from at least two isoforms, termed DNA topoisomerase IIα and β. The α isoform is involved in chromosome condensation and segregation, whereas the role of the β isoform is (...) not yet clear. DNA topoisomerase IIβ was first reported in 1987. Here we review the research on DNA topoisomerase IIβ over the last 10 years. BioEssays 20:215–226, 1998.© 1998 John Wiley & Sons, Inc. (shrink)

Linear chromosomes shorten in every round of replication. In Drosophila, telomere‐specialized long interspersed retrotransposable elements (LINEs) belonging to the jockey clade offset this shortening by forming head‐to‐tail arrays at Drosophila telomere ends. As such, these telomeric LINEs have been considered adaptive symbionts of the genome, protecting it from premature decay, particularly as Drosophila lacks a conventional telomerase holoenzyme. However, as reviewed here, recent work reveals a high degree of variation and turnover in the telomere‐specialized LINE lineages across Drosophila. There (...) appears to be no absolute requirement for LINE activity to maintain telomeres in flies, hence the suggestion that the telomere‐specialized LINEs may instead be neutral or in conflict with the host, rather than adaptive. (shrink)

Degradation of eukaryotic RNAs that contain premature termination codons (PTC) during nonsense‐mediated mRNA decay (NMD) is initiated by RNA decapping or endonucleolytic cleavage driven by conserved factors. Models for NMD mechanisms, including recognition of PTCs or the timing and role of protein phosphorylation for RNA degradation are challenged by new results. For example, the depletion of the SMG5/7 heterodimer, thought to activate RNA degradation by decapping, leads to a phenotype showing a defect of endonucleolytic activity of NMD complexes. This (...) phenotype is not correlated to a decreased binding of the endonuclease SMG6 with the core NMD factor UPF1, suggesting that it is the result of an imbalance between active (e.g., in polysomes) and inactive (e.g., in RNA‐protein condensates) states of NMD complexes. Such imbalance between multiple complexes is not restricted to NMD and should be taken into account when establishing causal links between gene function perturbation and observed phenotypes. (shrink)

There is an emerging consensus within Natural Law that explains transgender identity as an “embodied misunderstanding.” The basic line of argument is that our sexual identity as male or female refers to our possible reproductive roles of begetting or conceiving. Since these two possibilities are determined early on by the presence or absence of a Y chromosome, our sexual identity cannot be changed or reassigned. I develop an argument from analogy, comparing gender and language, to show that this consensus (...) is premature. Language and gender imbue our body with further social meaning and so, I conclude, that just as we can learn multiple languages, so too can we learn multiple genders. Since language and gender each constitutively contribute to our wellbeing as a “second nature,” I argue against this consensus to show that the reason people who are transgender struggle to flourish is not because of a “troubled trans psyche,” but because there are conceptual, interpersonal, and institutional obstacles stacked against them. (shrink)

Variegated phenotypes often result from chromosomal rearrangements that place euchromatic genes next to heterochromatin. In such rearrangements, the condensed structure of heterochromatin can spread into euchromatic regions, which then assume the morphology of heterochromatin and become transcriptionally inactive. In position‐effect variegation (PEV) therefore, gene inactivation results from a change in chromatin structure. PEV has been intensively investigated in the fruitfly Drosophila, where the phenomenon allows a genetic dissection of chromatin components. Consequently, many genes have been identified which, when mutated, act (...) as dominant modifiers (suppressors or enhancers) of PEV. Data available already demonstrate that genetic, molecular and developmental analysis of these genes provides an avenue to the identification of regulatory and structural chromatin components, and hence to fundamental aspects of chromosome structure and function. (shrink)

There is an emerging consensus within Natural Law that explains transgender identity as an “embodied misunderstanding.” The basic line of argument is that our sexual identity as male or female refers to our possible reproductive roles of begetting or conceiving. Since these two possibilities are determined early on by the presence or absence of a Y chromosome, our sexual identity cannot be changed or reassigned. I develop an argument from analogy, comparing gender and language, to show that this consensus (...) is premature. Language and gender imbue our body with further social meaning and so, I conclude, that just as we can learn multiple languages, so too can we learn multiple genders. Since language and gender each constitutively contribute to our wellbeing as a “second nature,” I argue against this consensus to show that the reason people who are transgender struggle to flourish is not because of a “troubled trans psyche,” but because there are conceptual, interpersonal, and institutional obstacles stacked against them. (shrink)

The formation of a highly condensed chromosome structure (heterochromatin) in a region of a eukaryotic chromosome can inactivate the genes within that region. Genetic studies using the fruitfly Drosophila melanogaster have identified several essential genes which influence the formation of heterochromatin. My purpose in this review is to summarize some recent work on the genetics of heterochromatin assembly in Drosophila and a recent model for how chromosomal proteins may interact to form a heterochromatic structure.

Despite advances in treatments over the last decades, a uniformly reliable and free of side effects therapy of human cancers remains to be achieved. During chromosome replication, a premature halt of two converging DNA replication forks would cause incomplete replication and a cytotoxic chromosome nondisjunction during mitosis. In contrast to normal cells, most cancer cells bear numerous DNA deletions. A homozygous deletion permanently marks a cell and its descendants. Here, we propose an approach to cancer therapy in (...) which a pair of sequence‐specific roadblocks is placed solely at two cancer‐confined deletion sites that are located ahead of two converging replication forks. We describe this method, termed “replication blocks specific for deletions” (RBSD), and another deletions‐based approach as well. RBSD can be expanded by placing pairs of replication roadblocks on several different chromosomes. The resulting simultaneous nondisjunctions of these chromosomes in cancer cells would further increase the cancer‐specific toxicity of RBSD. (shrink)

It has become apparent that difficulties to replicate telomeres concern not only the very ends of eukaryotic chromosomes. The challenges already start when the replication fork enters the telomeric repeats. The obstacles encountered consist mainly of noncanonical nucleic acid structures that interfere with replication if not resolved. Replication stress at telomeres promotes the formation of so‐called fragile telomeres displaying an abnormal appearance in metaphase chromosomes though their exact molecular nature remains to be elucidated. A substantial number of factors is required (...) to counteract fragility. In this review we promote the hypothesis that telomere fragility is not caused directly by an initial insult during replication but it results as a secondary consequence of DNA repair of damaged replication forks by the homologous DNA recombination machinery. Incomplete DNA synthesis at repair sites or partial chromatin condensation may become apparent as telomere fragility. Fragility and DNA repair during telomere replication emerges as a common phenomenon which exacerbates in multiple disease conditions. (shrink)

The eukaryotic genome is organized into different domains by cis‐acting elements, such as boundaries/insulators and matrix attachment regions, and is packaged with different degrees of condensation. In the M phase, the chromatin becomes further highly condensed into chromosomes. The first step for transcriptional activation of a given gene, at a particular time during development, in any locus, is the opening of its chromatin domain. This locus needs to be kept in this state in each early G1 phase during every (...) cell cycle. Certain distal enhance elements, including locus control regions (LCRs) and enhancers, are believed to perform this target chromatin domain opening process and several models have been proposed to explain distal enhance action. But they did not explain precisely how a given chromatin domain is opened. Based on various studies, we propose a hypothesis for the mechanism of opening chromatin on a large scale. One important mechanism may involved breaking one or two DNA strands and reducing the linking numbers within chromatin domain. The topological changes can overpass some complexes formed on DNA strands and can be transmitted from specific localized points over a broad region, until boundary elements or insulators are reached. These may initiate downstream events such as propagation of histone acetylation and the binding of transcription factors to proximal promoters and may further augment the action mediated by distal enhancer elements. BioEssays 25:507–514, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

A central characteristic of people with Prader-Willi Syndrome (PWS) is an apparent insatiable appetite leading to severe overeating and the potential for marked obesity and associated serious health problems and premature death. This behaviour may be due to the effects of the genetic defect resulting from the chromosome 15 abnormalities associated with the syndrome. We examine the ethical and legal dilemmas that can arise in the care of people with PWS. A tension exists between a genetic deterministic perspective (...) and that of individual choice. We conclude that the determination of the capacity of a person with PWS to make decisions about his/her eating behaviour and to control that behaviour is of particular importance in resolving this dilemma. If the person is found to lack capacity, the common law principles of acting in a person's "best interests" using the "least restrictive alternative" may be helpful. Allowing serious weight gain in the absence of careful consideration of these issues is an abdication of responsibility. (shrink)

This study identified the influences of maternal socio-demographic and antenatal factors on stillbirths and neonatal deaths in New South Wales, Australia. Bivariate and multivariate analyses were used to explore the association of selected antenatal and maternal characteristics with stillbirths and neonatal deaths. The findings of this study showed that stillbirths and neonatal deaths significantly varied by infant sex, maternal age, Aboriginality, maternal country of birth, socioeconomic status, parity, maternal smoking behaviour during pregnancy, maternal diabetes mellitus, maternal hypertension, antenatal care, plurality (...) of birth, low birth weight, place of birth, delivery type, maternal deaths and small gestational age. First-born infants, twins and infants born to teenage mothers, Aboriginal mothers, those who smoked during the pregnancy and those of lower socioeconomic status were at increased risk of stillbirths and neonatal deaths. The most common causes of stillbirths were conditions originating in the perinatal period: intrauterine hypoxia and asphyxia. Congenital malformations, including deformities and chromosomal abnormalities, and disorders related to slow fetal growth, short gestation and low birth weight were the most common causes of neonatal deaths. The findings indicate that very low birth weight (less than 2000 g) contributed 75·6% of the population-attributable risks to stillbirths and 59·4% to neonatal deaths. Low gestational age (less than 32 weeks) accounted for 77·7% of stillbirths and 87·9% of neonatal deaths. The findings of this study suggest that in order to reduce stillbirths and neonatal deaths, it is essential to include strategies to predict and prevent prematurity and low birth weight, and that there is a need to focus on anti-smoking campaigns during pregnancy, optimizing antenatal care and other healthcare programmes targeted at the socially disadvantaged populations identified in this study. (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)

This essay considers the prospects of modeling spacetime as a phenomenon that emerges in the low-energy limit of a quantum liquid. It evaluates three examples of spacetime analogues in condensed matter systems that have appeared in the recent physics literature, indicating the extent to which they are viable, and considers what they suggest about the nature of spacetime.

In this paper, we hypothesize that X chromosome‐associated mechanisms, which affect X‐linked genes and are behind the immunological advantage of females, may also affect X‐linked microRNAs. The human X chromosome contains 10% of all microRNAs detected so far in the human genome. Although the role of most of them has not yet been described, several X chromosome‐located microRNAs have important functions in immunity and cancer. We therefore provide a detailed map of all described microRNAs located on human (...) and mouse X chromosomes, and highlight the ones involved in immune functions and oncogenesis. The unique mode of inheritance of the X chromosome is ultimately the cause of the immune disadvantage of males and the enhanced survival of females following immunological challenges. How these aspects influence X‐linked microRNAs will be a challenge for researchers in the coming years, not only from an evolutionary point of view, but also from the perspective of disease etiology. (shrink)

In this paper, we hypothesize that X chromosome-associated mechanisms, which affect X-linked genes and are behind the immunological advantage of females, may also affect X-linked microRNAs. The human X chromosome contains 10% of all microRNAs detected so far in the human genome. Although the role of most of them has not yet been described, several X chromosome-located microRNAs have important functions in immunity and cancer. We therefore provide a detailed map of all described microRNAs located on human (...) and mouse X chromosomes, and highlight the ones involved in immune functions and oncogenesis. The unique mode of inheritance of the X chromosome is ultimately the cause of the immune disadvantage of males and the enhanced survival of females following immunological challenges. How these aspects influence X-linked microRNAs will be a challenge for researchers in the coming years, not only from an evolutionary point of view, but also from the perspective of disease etiology. (shrink)

Obstetricians face difficult decisions when the interests of fetus and mother conflict. An example is the problem of choosing the delivery method when labour begins prematurely and the fetus is breech. Vaginal delivery involves risks for the breech fetus of brain damage or death caused by umbilical cord compression and head entrapment. Caesarean section might avoid these dangers but involves risks for the mother, including infection, haemorrhage and even death in a small percentage of cases. If a caesarean section is (...) performed the infant might die anyway, due to complications of prematurity. Thus, decisions about delivery method involve balancing the risks to mother and fetus. Uncertainty about the frequency of fetal injuries in vaginal breech deliveries adds to the difficulty of these decisions. (shrink)

Mammal sex determination depends on an XY chromosome system, a gene for testis development and a means of activating the X chromosome. The duckbill platypus challenges these dogmas.1,2 Gutzner et al.1 find no recognizable SRY sequence and question whether the mammalian X was even the original sex chromosome in the platypus. Instead they suggest that the original platypus sex chromosomes were derived from the ZW chromosome system of birds and reptiles. Unraveling the puzzles of sex determination (...) and dosage compensation in the platypus has been complicated by the fact that it has a surplus of sex chromosomes. Rather than a single X and Y chromosome, the male platypus has five Xs and five Ys. BioEssays 27:681–684, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

In this essay, I consider what condensed matter physics has to say about the nature of spacetime. In particular, I consider the extent to which spacetime can be modeled as a quantum liquid, with matter and force fields described by effective field theories of the low-energy excitations of the liquid. After a brief review of effective field theories in 2-dim highly-correlated condensed matter systems, I evaluate analogies in the recent physics literature between spacetime and superfluid Helium, and proposals that suggest (...) spacetime is an emergent phenomenon arising from the edge states of a 4-dim Quantum Hall liquid. KeyworCh: spacetime, effective field theory, condensed matter, quantum gravity.. (shrink)

With the assumption of inactivation of small traits in bacteriophages “chromosomes” by ultraviolet irradiation the probability of multiplicity reactivation of irradiated phages is calculated. The result appears to be in agreement with the experimental results ofDulbecco.In the mathematical treatment of the problem a distinction is made between ordinary genes, with probability of inactivation negligible relative to the probability of inactivation of the whole phage, and a few vulnerable centers or genes whose probability of inactivation is not negligible. The hypothesis of (...) the existence of vulnerable centers appears necessary in order to explainDulbecco's experimental results.Postulant que de petites sections des „chromosomes” du bactériophage sont inactivés par l'irradiation ultraviolette, on a calculé la probabilité de réactivation par infection multiple des bactériophages traités par les rayons ultraviolets. Les résultats obtenus s'accordent avec les résultats expérimentaux de M.Dulbecco.Dans la tractation mathématique des problèmes une distinction a été faite entre les gènes ordinaires — dont la probabilité d'inactivation prise individuellement peut Être négligée relativement à la probabilité d'inactivation du phage entier — et quelques centres vulnérables ou gènes dont la probabilité d'inactivation ne pourrait Être négligée.L'hypothèse de l'existance des centres vulnérables s'est démontrée nécessaire à l'explication des résultats expérimentaux de M.Dulbecco.Die Wahrscheinlichkeit der Reaktivation durch multiplen Infektionen ist unter Voraussetzung, dass die Ultraviolett-Bestrahlung kleine Teile der Bakteriophagenchromosomen inaktiviert, berechnet. Das Ergebnis entspricht den experimentellen ResultatenDulbecco's.In der mathematischen Behandlung des Problems ist ein Unterschied gemacht worden zwischen gewöhnlichen Genen — wovon jeder eine geringe Wahrscheinlichkeit der Inaktivierung hat, in Bezug auf die Wahrscheinlichkeit der Inaktivierung der ganzen Bakteriophage — und einige verletzbare Stellen oder Genen, wovon die Wahrscheinlichkeit der Inaktivierung grössenordnungsmÄssig höher liegt. Die Hypothese über die verletzbaren Stellen war notwendig um die experimentellen ResultateDulbecco's zu erklÄren. (shrink)

Mammals have a very complex, tightly controlled, and developmentally regulated process of dosage compensation. One form of the process equalizes expression of the X‐linked genes, present as a single copy in males (XY) and as two copies in females (XX), by inactivation of one of the two X‐chromosomes in females. The second form of the process leads to balanced expression between the X‐linked and autosomal genes by transcriptional upregulation of the active X in males and females. However, not all X‐linked (...) genes are absolutely balanced. This review is focused on the recent advances in studying the dosage compensation phenomenon in mammals. (shrink)

The objectives of this study were to develop a high-density chromosome bin map of homoeologous group 7 in hexaploid wheat, to identify gene distribution in these chromosomes, and to perform comparative studies of wheat with rice and barley. We mapped 2148 loci from 919 EST clones onto group 7 chromosomes of wheat. In the majority of cases the numbers of loci were significantly lower in the centromeric regions and tended to increase in the distal regions. The level of duplicated (...) loci in this group was 24% with most of these loci being localized toward the distal regions. One hundred nineteen EST probes that hybridized to three fragments and mapped to the three group 7 chromosomes were designated landmark probes and were used to construct a consensus homoeologous group 7 map. An additional 49 probes that mapped to 7AS, 7DS, and the ancestral translocated segment involving 7BS also were designated landmarks. Landmark probe orders and comparative maps of wheat, rice, and barley were produced on the basis of corresponding rice BAC/PAC and genetic markers that mapped on chromosomes 6 and 8 of rice. Identification of landmark ESTs and development of consensus maps may provide a framework of conserved coding regions predating the evolution of wheat genomes. (shrink)

It is widely hoped that quantum gravity will shed light on the question of the origin of time in physics. The currently dominant approaches to a candidate quantum theory of gravity have naturally evolved from general relativity, on the one hand, and from particle physics, on the other hand. A third important branch of twentieth century ‘fundamental’ physics, condensed-matter physics, also offers an interesting perspective on quantum gravity, and thereby on the problem of time. The bottomline might sound disappointing: to (...) understand the origin of time, much more experimental input is needed than what is available today. Moreover it is far from obvious that we will ever find out the true origin of physical time, even if we become able to directly probe physics at the Planck scale. But we might learn some interesting lessons about time and the structure of our universe in the process. A first lesson is that there are probably several characteristic scales associated with “quantum gravity” effects, rather than the single Planck scale usually considered. These can differ by several orders of magnitude, and thereby conspire to hide certain effects expected from quantum gravity, rendering them undetectable even with Planck-scale experiments. A more tentative conclusion is that the hierarchy between general relativity, special relativity and Newtonian physics, usually taken for granted, might have to be interpreted with caution. (shrink)

Extraordinary extended lampbrush chromosomes with thousands of transcription loops are favorable objects in chromosome biology. Chromosomes become lampbrushy due to unusually high rate of transcription during oogenesis. However, until recently, the information on the spectrum of transcribed sequences as well as genomic context of individual chromomeres was mainly limited to tandemly repetitive elements. Here we briefly outline novel findings and future directions in lampbrush chromosome studies in the post‐genomic era. We emphasize the fruitfulness of combining genome‐wide approaches with (...) microscopy imaging techniques using lampbrush chromosomes as a remarkable model object. We believe that new data on the spectrum of sequences transcribed on the lateral loops of lampbrush chromosomes and their structural organization push the boundaries in the discussion of their biological role. Also see the video abstract here: https://youtu.be/zexoHfzX9rM. (shrink)

Many organisms face a dilemma rooted in the unequal numbers of X chromosomes carried by the two sexes and the need to maintain equivalent expression of X‐linked genes. Several strategies have arisen to cope with this problem. All rely on accurately targeting epigenetic modifications to entire chromosomes. Targeting results from the action of recognition elements that attract modification and may rely on spreading of modification in cis along the affected chromosome. A recent report describing the first X chromosome (...) recognition element from C. elegans opens the way to defining the relative contributions of these factors to the compensation of X‐linked gene expression in worms.1 Extrachromosomal arrays composed of a C. elegans recognition element attract proteins that modify the C. elegans X chromosomes and interact genetically with mutations disrupting compensation. Moreover, examination of X:A translocations provides the first evidence for spreading of modification along C. elegans X chromosomes. BioEssays 26:707–710, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Studies on Neurospora chromosome segment duplications (Dps) performed since the publication of Perkins's comprehensive review in 1997 form the focus of this article. We present a brief summary of Perkins's seminal work on chromosome rearrangements, specifically, the identification of insertional and quasiterminal translocations that can segregate Dp progeny when crossed with normal sequence strains (i.e., T × N). We describe the genome defense process called meiotic silencing by unpaired DNA that renders Dp‐heterozygous crosses (i.e., Dp × N) barren, (...) which provides a basis for identifying Dps, and discuss whether other processes also might contribute to the barren phenotype of Dp × N and Dp × Dp crosses. We then turn to studies suggesting that large Dps (i.e., >300 kbp) can allow smaller gene‐sized duplications to escape another genome defense process called repeat‐induced point mutation (RIP), possibly by titration of the RIP machinery. Finally, we assess whether in natural populations dominant RIP suppressor Dps provide an “RIP‐free” niche for evolution of new genes following the duplication of existing genes. (shrink)