Telomeres play a vital role in protecting the ends of chromosomes and preventing chromosome fusion. The failure of cancer cells to properly maintain telomeres can be an important source of the chromosome instability involved in cancer cell progression. Telomere loss results in sister chromatid fusion and prolonged breakage/fusion/bridge (B/F/B) cycles, leading to extensive DNA amplification and large deletions. These B/F/B cycles end primarily when the unstable chromosome acquires a new telomere by translocation of the ends of other chromosomes. Many of (...) these translocations are nonreciprocal, resulting in the loss of the telomere from the donor chromosome, providing a mechanism for transfer of instability from one chromosome to another until a chromosome acquires a telomere by a mechanism other than nonreciprocal translocation. B/F/B cycles can also result in other forms of chromosome rearrangements, including double‐minute chromosomes and large duplications. Thus, the loss of a single telomere can result in instability in multiple chromosomes, and generate many of the types of rearrangements commonly associated with human cancer. BioEssays 26:1164–1174, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

A combination of cytogenetic and molecular analyses has shown that several different transposable elements are involved in the restructuring of Drosophila chromosomes. Two kinds of elements, P and hobo, are especially prone to induce chromosome rearrangements. The mechanistic details of this process are unclear, but, at least some of the time, it seems to involve ectopic recombination between elements inserted at different chromosomal sites; the available data suggest that these ectopic recombination events are much more likely to occure between (...) elements in the same chromosome than between elements in different chromosomes. Other Drosophila transposons also appear to mediate chromosome restructuring by ectopic recombination; these include the retrotransposons BEL, roo, Docand I and the foldback element FB. In addition, two retrotransposons, HeT‐A and TART, have been found to be associated specifically with the ends of Drosophila chromosomes. Very limited data indicate that transposon‐mediated chromosome restructuring is occurring in natural populations of Drosophila. This suggests that transposable elements may help to shape the structure of the Drosophila genome and implies that they may have a similar role in other organisms. (shrink)

Recent mutagenesis studies have demonstrated that the chemotherapeutic agent, chlorambucll (CHL), is highly mutagenic in male germ cells of the mouse. Post‐melotic germ cells, and especially early spermatids, are the most sensitive to the cytotoxic and mutagenic effects of this agent. Genetic, cytogenetic and molecular analyses of many induced mutations have shown that, in these germ‐cell stages, CHL induces predominantly chromosomal rearrangements (deletions and translocations), and mutation‐rate studies show that, in terms of tolerated doses, CHL is perhaps five to (...) ten times more efficient in inducing rearrangements than is radiation exposure. Appropriate breeding protocols, along with knowledge of the advantages and limitations associated with the use of CHL, can be used to expand the current resource of chromosomal rearrangements in the mouse and to provide new phenotype‐associated mutations amenable to positional‐cloning techniques. The analysis of CHL‐induced mutations has also contributed to understanding the factors that affect the yield and nature of chemically induced germline mutations in mammals. (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)

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)

Comparative mapping and sequencing show that turnover of sex determining genes and chromosomes, and sex chromosome rearrangements, accompany speciation in many vertebrates. Here I review the evidence and propose that the evolution of therian mammals was precipitated by evolution of the male‐determining SRY gene, defining a novel XY sex chromosome pair, and interposing a reproductive barrier with the ancestral population of synapsid reptiles 190 million years ago (MYA). Divergence was reinforced by multiple translocations in monotreme sex chromosomes, the first of (...) which supplied a novel sex determining gene. A sex chromosome‐autosome fusion may have separated eutherians (placental mammals) from marsupials 160 MYA. Another burst of sex chromosome change and speciation is occurring in rodents, precipitated by the degradation of the Y. And although primates have a more stable Y chromosome, it may be just a matter of time before the same fate overtakes our own lineage. (shrink)

DNA damage repair within telomeres are suppressed to maintain the integrity of linear chromosomes, but the accidental activation of repairs can lead to genome instability. This review develops the concept that mechanisms to repair DNA damage in telomeres contribute to genetic variability and karyotype evolution, rather than catastrophe. Spontaneous breaks in telomeres can be repaired by telomerase, but in some cases DNA repair pathways are activated, and can cause chromosomal rearrangements or fusions. The resultant changes can also affect subtelomeric (...) regions that are adjacent to telomeres. Subtelomeres are actively involved in such chromosomal changes, and are therefore the most variable regions in the genome. The case of Caenorhabditis elegans in the context of changes of subtelomeric structures revealed by long‐read sequencing is also discussed. Theoretical and methodological issues covered in this review will help to explore the mechanism of chromosome evolution by reconstruction of chromosomal ends in nature. (shrink)

A team of US researchers recently reported the design, assembly and in vivo functionality of a synthetic chromosome III (SynIII) for the yeast Saccharomyces cerevisiae. The synthetic chromosome was assembled bottom‐up from DNA oligomers by teams of students working over several years with researchers as the first part of an international synthetic yeast genome project. Embedded into the sequence of the synthetic chromosome are multiple design changes that include a novel in‐built recombination scheme that can be induced to catalyse intra‐ (...) class='Hi'>chromosomal rearrangements in a variety of different conditions. This system, along with the other synthetic sequence changes, is intended to aid researchers develop a deeper understanding of how genomes function and find new ways to exploit yeast in future biotechnologies. The landmark of the first synthesised designer eukaryote chromosome, and the power of its massively parallel recombination system, provide new perspectives on the future of synthetic biology and genome research. (shrink)

In this review, we focus on the evolutionary and biomedical aspects of the architecture of human chromosome 3 (HSA3) by analyzing chromosomal regions that have been conserved during the evolutionary process, compared to those that have been involved in the genomic restructuring of different placental lineages. Given that the organization of human chromosome 3 is derived when compared to the ancestral primate karyotype, and is an autosome that is commonly implicated in human tumour formation, we examined the patterns of (...) change and the genomic consequences that have resulted from its complex evolutionary history. The data show four discrete chromosomal regions that are frequently implicated in chromosomal rearrangements (3p25, 3p22, 3p12 and 3q21). These are rich in repetitive elements and are commonly implicated in structural rearrangements that underpin human genomic disorders and neoplasias. Additional Supporting Information may be found in the online version of this article. BioEssays 30:1126–1137, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

The focus of this study was to analyze the content, distribution, and comparative genome relationships of 996 chromosome bin-mapped expressed sequence tags accounting for 2266 restriction fragments on the homoeologous group 3 chromosomes of hexaploid wheat. Of these loci, 634, 884, and 748 were mapped on chromosomes 3A, 3B, and 3D, respectively. The individual chromosome bin maps revealed bins with a high density of mapped ESTs in the distal region and bins of low density in the proximal region of the (...) chromosome arms, with the exception of 3DS and 3DL. These distributions were more localized on the higher-resolution group 3 consensus map with intermediate regions of high-mapped-EST density on both chromosome arms. Gene ontology classification of mapped ESTs was not significantly different for homoeologous group 3 chromosomes compared to the other groups. A combined analysis of the individual bin maps using 537 of the mapped ESTs revealed rearrangements between the group 3 chromosomes. Approximately 232 of the consensus mapped ESTs matched sequences on rice chromosome 1 and revealed large- and small-scale differences in gene order. Of the group 3 mapped EST unigenes ∼21 and 32% matched the Arabidopsis coding regions and proteins, respectively, but no chromosome-level gene order conservation was detected. (shrink)

Two reports have shown that mammalian artificial chromosomes (MAC) can be constructed from cloned human centromere DNA and telomere repeats, proving the principle that chromosomes can form from naked DNA molecules transfected into human cells. The MACs were mitotically stable, low copy number and bound antibodies associated with active centromeres. As a step toward second-generation MACs, yeast and bacterial cloning systems will have to be adapted to achieve large MAC constructs having a centromere, two telomeres, and genomic copies of mammalian (...) genes. Available construction techniques are discussed along with a new P1 artificial chromosome (PAC)-derived telomere vector (pTAT) that can be joined to other PACs in vitro, avoiding a cloning step during which large repetitive arrays often rearrange. The PAC system can be used as a route to further define the optimal DNA elements required for efficient MAC formation, to investigate the expression of genes on MACs, and possibly to develop efficient MAC-delivery protocols. BioEssays 1999;21:76–83. © 1999 John Wiley & Sons, Inc. (shrink)

Enzymatic misrepair of ionizing‐radiation‐induced DNA damage can produce large‐scale rearrangements of the genome, such as translocations and dicentrics. These and other chromosome exchange aberrations can cause major phenotypic alterations, including cell death, mutation and neoplasia. Exchange formation requires that two (or more) genomic loci come together spatially. Consequently, the surprisingly rich aberration spectra uncovered by recently developed techniques, when combined with biophysically based computer modeling, help characterize large‐scale chromatin architecture in the interphase nucleus. Most results are consistent with a picture (...) whereby chromosomes are mainly confined to territories, chromatin motion is limited, and interchromosomal interactions involve mainly territory surfaces. Aberration spectra and modeling also help characterize DNA repair/misrepair mechanisms. Quantitative results for mammalian cells are best described by a breakage‐and‐reunion model, suggesting that the dominant recombinational mechanism during the G0/G1 phase of the cell cycle is non‐homologous end‐joining of radiogenic DNA double strand breaks. In turn, better mechanistic and quantitative understanding of aberration formation gives new insights into health‐related applications. BioEssays 24:714–723, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

Two reports have shown that mammalian artificial chromosomes (MAC) can be constructed from cloned human centromere DNA and telomere repeats, proving the principle that chromosomes can form from naked DNA molecules transfected into human cells. The MACs were mitotically stable, low copy number and bound antibodies associated with active centromeres. As a step toward second-generation MACs, yeast and bacterial cloning systems will have to be adapted to achieve large MAC constructs having a centromere, two telomeres, and genomic copies of mammalian (...) genes. Available construction techniques are discussed along with a new P1 artificial chromosome (PAC)-derived telomere vector (pTAT) that can be joined to other PACs in vitro, avoiding a cloning step during which large repetitive arrays often rearrange. The PAC system can be used as a route to further define the optimal DNA elements required for efficient MAC formation, to investigate the expression of genes on MACs, and possibly to develop efficient MAC-delivery protocols. BioEssays 1999;21:76–83. © 1999 John Wiley & Sons, Inc. (shrink)

Replication protein A (RPA) is the main eukaryotic single‐stranded DNA (ssDNA) binding protein, having essential roles in all DNA metabolic reactions involving ssDNA. RPA binds ssDNA with high affinity, thereby preventing the formation of secondary structures and protecting ssDNA from the action of nucleases, and directly interacts with other DNA processing proteins. Here, we discuss recent results supporting the idea that one function of RPA is to prevent annealing between short repeats that can lead to chromosome rearrangements by microhomology‐mediated end (...) joining or the formation of hairpin structures that are substrates for structure‐selective nucleases. We suggest that replication fork catastrophe caused by depletion of RPA could result from cleavage of secondary structures by nucleases, and that failure to cleave hairpin structures formed at DNA ends could lead to gene amplification. These studies highlight the important role RPA plays in maintaining genome integrity. (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)

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)

Chromosomal rearrangements frequently occur at specific places (“hot spots”) in the genome. These recombination hot spots are usually separated by 50–100 kb regions of DNA that are rarely involved in rearrangements. It is quite likely that there is a correlation between the above‐mentioned distances and the average size of DNA loops fixed at the nuclear matrix. Recent studies have demonstrated that DNA loop anchorage regions can be fairly long and can harbor DNA recombination hot spots. We previously proposed that (...) chromosomal DNA loops may constitute the basic units of genome organization in higher eukaryotes. In this review, we consider recombination between DNA loop anchorage regions as a possible source of genome evolution. (shrink)

Mammalian cells frequently depend on homologous recombination (HR) to repair DNA damage accurately and to help rescue stalled or collapsed replication forks. The essence of HR is an exchange of nucleotides between identical or nearly identical sequences. Although HR fulfills important biological roles, recombination between inappropriate sequence partners can lead to translocations or other deleterious rearrangements and such events must be avoided. For example, the recombination machinery must follow stringent rules to preclude recombination between the many repetitive elements in a (...) mammalian genome that share significant but imperfect homology. This paper takes a conceptual approach in addressing the homology requirements for recombination in mammalian genomes as well as the general strategy used by cells to reject recombination between similar but imperfectly matched sequences. A mechanism of heteroduplex rejection that involves the unwinding of recombination intermediates that may form between mismatched sequences is discussed. BioEssays 30:1163–1171, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

The use of Drosophila chromosomal rearrangements and transposon constructs involving the white gene reveals the existence of repressive chromatin domains that can spread over considerable genomic distances. One such type of domain is found in heterochromatin and is responsible for classical position‐effect variegation. Another type of repressive domain is established, beginning at specific sequences, by complexes of Polycomb Group proteins. Such complexes, which normally regulate the expression of many genes, including the homeotic loci, are responsible for silencing, white gene (...) variegation, pairing‐dependent effects and insertional targeting. (shrink)

Fusion genes formed by chromosomal rearrangements are common drivers of cancer. Recent innovations in the field of next‐generation sequencing (NGS) have seen a dynamic shift from traditional fusion detection approaches, such as visual characterization by fluorescence, to more precise multiplexed methods. There are many different NGS‐based approaches to fusion gene detection and deciding on the most appropriate method can be difficult. Beyond the experimental approach, consideration needs to be given to factors such as the ease of implementation, processing time, (...) associated costs, and the level of expertise required for data analysis. Here, the different NGS‐based methods for fusion gene detection, the basic principles underlying the techniques, and the benefits and limitations of each approach are reviewed. This article concludes with a discussion of how NGS will impact fusion gene detection in a clinical context and from where the next innovations are evolving. (shrink)

Genetics was established on a strict particulate conception of heredity. Genetic linkage, the deviation from independent segregation of Mendelian factors, was conceived as a function of the material allocation of the factors to the chromosomes, rather than to the multiple effects (pleiotropy) of discrete factors. Although linkage maps were abstractions they provided strong support for the chromosomal theory of inheritance. Direct Cytogenetic evidence was scarce until X-ray induced major chromosomal rearrangements allowed direct correlation of genetic and cytological rearrangements. (...) Only with the discovery of the polytenic giant chromosomes in Drosophila larvae in the 1930s were the virtual maps backed up by physical maps of the genetic loci. Genetic linkage became a pivotal experimental tool for the examination of the integration of genetic functions in development and in evolution. Genetic mapping has remained a hallmark of genetic analysis. The location of genes in DNA is a modern extension of the notion of genetic linkage. (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)

This article proposes that cancers can be initiated by retrotransposon (RTN) activation through changes in the transcriptional regulation of nearby genes. I first detail the hypothesis and then discuss the nature of physiological stress(es) in RTN activation; the role of DNA demethylation in the initiation and propagation of new RTN states; the connection between ageing and cancer incidence and the involvement of activated RTNs in the chromosomal aberrations that feature in cancer progression. The hypothesis neither replaces nor invalidates other (...) theories of cancer, in particular the somatic mutation theory, but helps clarify and unify much of the hitherto poorly integrated, complex phenomenology of cancer. (shrink)

Transposons are ubiquitous genetic elements discovered so far in all investigated prokaryotes and eukaryotes. In remarkable contrast to all other genes, transposable elements are able to move to new locations within their host genomes. Transposition of transposons into coding sequences and their initiation of chromosome rearrangements have tremendous impact on gene expression and genome evolution. While transposons have long been known in bacteria, plants, and animals, only in recent years has there been a significant increase in the number of transposable (...) elements discovered in filamentous fungi. Like those of other eukaryotes, each fungal transposable element is either of class I or of class II. While class I elements transpose by a RNA intermediate and employ reverse transcriptases, class II elements transpose directly at the DNA level. We present structural and functional features for such transposons that have been identified so far in filamentous fungi. Emphasis is given to specific advantages or unique features when fungal systems are used to study transposable elements, e.g., the evolutionary impact of transposons in coenocytic organisms and possible experimental approaches toward horizontal gene transfer. Finally, we focus on the potential of transposons for tagging and identifying fungal genes. BioEssays 20:652–659, 1998.© 1998 John Wiley & Sons Inc. (shrink)

Genome instability has been associated with progression of transformed cells to high tumorigenicity. Although genome instability may result from a variety of factors, some studies suggest that DNA in the region of a chromosome rearrangement can subsequently have much higher rates of DNA deletions or gene amplification. One approach to studying the factors that produce these high rates of DNA rearrangement is by analysis of unstable integration sites for DNA transfected into mammalian cells. Integrated sequences commonly show a (...) temporary instability, and at rare locations this instability is continuous and can be observed even after multiple subclonings. These continuously unstable locations undergo DNA amplification of both the integrated sequences and the surrounding cell DNA, and it can occur either at the original site or on episomes after looping out from the chromosome. Because the adjacent cell DNA plays a role in this instability, and the region can be shown to be stable before integration, the results indicate that these recombinational hotspots can be formed de novo by the process of integration. Current studies are attempting to determine which sequences are responsible for the high rates of recombination and whether similar types of event are involved in the instability associated with endogenous cellular genes in cancer cells. (shrink)

The genetic stability of living cells is continuously threatened by the presence of endogenous reactive oxygen species and other genotoxic molecules. Of particular threat are the thousands of DNA single-strand breaks that arise in each cell, each day, both directly from disintegration of damaged sugars and indirectly from the excision repair of damaged bases. If un-repaired, single-strand breaks can be converted into double-strand breaks during DNA replication, potentially resulting in chromosomal rearrangement and genetic deletion. Consequently, cells have adopted (...) multiple pathways to ensure the rapid and efficient removal of single-strand breaks. A general feature of these pathways appears to be the extensive employment of protein–protein interactions to stimulate both the individual component steps and the overall repair reaction. Our current understanding of DNA single-strand break repair is discussed, and testable models for the architectural coordination of this important process are presented. BioEssays 23:447–455, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Homologous recombination (HR) is essential for the accurate repair of DNA double‐strand breaks and damaged replication forks. However, inappropriate or aberrant HR can also result in genome rearrangements. The maintenance of cell viability is, therefore, a careful balancing act between the benefits of HR (the error‐free repair of DNA strand breaks) and the potential detrimental outcomes of HR (chromosomal rearrangements). Two papers have recently provided a mechanistic insight into how HR may be tempered by RecQ helicases to prevent genome (...) instability and diseases that are a consequence of this, such as cancer.1,2 BioEssays 30:291–295, 2008. © 2008 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)

Variation or rearrangement of regulatory genes is responsible for cellular malignant change. These types of chromosomal variations also produce heterochrony or paedomorphic evolution at the organismal level. Analogously, neoplasia represents a cellular macroevolutionary event, and a tumour can be said to be an evolved population of cells. To understand this cellular evolution to malignancy, it may be necessary to go beyond a clonal selection (adaptationist) explanation of neoplastic alteration. In the pericellular environment natural selection consists of the organizational (...) restraints of surrounding cells as well as the host's immunological surveillance and non-specific monocyte-macrophage systems. Indirect evidence suggests that success for the neoplasm depends not upon clonal selection, but solely upon a genetic methodology—the function of which is to elude selection.The author has coined the term cellular heterochrony to illustrate analogic similarities in the molecular modes of speciation between anaplastic cancer cells and the heterochronic evolution of organisms. By reverting to a juvenile (embryonic) repertoire of cellular behaviour a tumour secures its own tenure or niche by usurping the host's armamentarium of selection forces, employing many of the same or similar methods by which implanting and invading tissues of the mammalian embryo forestall maternal detection and rejection. A number of ways by which the tumour blocks, subverts or evades selection are discussed. (shrink)

In vertebrates it is often found that if one considers a group of genes clustered on a certain chromosome, then the homologues of those genes often form another cluster on a different chromosome. There are four explanations, not necessarily mutually exclusive, to explain how such homologous clusters appeared. Homologous clusters are expected at a low probability even if genes are distributed at random. The duplication of a subset of the genome might create homologous clusters, as would a duplication of the (...) entire genome. Alternatively, it may be adaptive for certain combinations of genes to cluster, although clearly the genes must have duplicated prior to rearrangement into clusters. Molecular phylogenetics provides a means to examine the origins of homologous clusters, although it is difficult to discriminate between the different explanations using current data. However, with more extensive sequencing and mapping of vertebrate genomes, especially those of the early diverging chordates, it should soon become possible to resolve the origins of homologous clusters. BioEssays 21:697–703, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

Tumour‐associated genetic changes frequently involve DNA translocation or deletion. Many of these events will have arisen from initial genomic damage, induced by either the activity of endogenous metabolic processes or from exposure to environmental genotoxic agents. Although initial genomic damage will have been widely distributed, tumorigenic events are confined to certain DNA target sites. Furthermore, within these target sites there appear to be regions of preferential DNA rearrangement, and examination of these sites implies that the location and extent of (...) such rearrangement may be influenced by DNA primary and secondary structure rather than simply by the point of damage. We selectively review evidence relating to DNA structures that may predispose certain regions of the genome to damage‐induced rearrangement, and discuss the possible role of interstitial, inverted telomere‐like sequence arrays in promoting chromosomal events of a type known to be associated with some human and animal tumours. (shrink)

Monoallelic gene expression has played a significant role in the evolution of mammals enabling the expansion of a vast repertoire of olfactory receptor types and providing increased sensitivity and diversity. Monoallelic expression of immune receptor genes has also increased diversity for antigen recognition, while the same mechanism that marks a single allele for preferential rearrangement also provides a distinguishing feature for directing hypermutations. Random monoallelic expression of the X chromosome is necessary to balance gene dosage across sexes. In marsupials (...) only the maternal X chromosome is expressed, while in eutherian mammals the paternal X genes are silenced in the developing placenta and early blastocyst. These examples of epigenetic gene regulation commonly employ asynchrony of replication, the binding of polycomb proteins and antisense RNA, and histone modifications to chromatin structure. The same is true for genomic imprinting which among vertebrates is unique to mammals and represents a special kind of epigenetic modification that is heritable according to parent of origin. Genomic imprinting pervades many aspects of mammalian growth and evolution but in particular has played a significant role in the co‐adaptive evolution of the mother and foetus. (shrink)

Polyploid cells contain multiple copies of all chromosomes. Polyploidization can be developmentally programmed to sustain tissue barrier function or to increase metabolic potential and cell size. Programmed polyploidy is normally associated with terminal differentiation and poor proliferation capacity. Conversely, non‐programmed polyploidy can give rise to cells that retain the ability to proliferate. This can fuel rapid genome rearrangements and lead to diseases like cancer. Here, the mechanisms that generate polyploidy are reviewed and the possible challenges upon polyploid cell division are (...) discussed. The discussion is framed around a recent study showing that asynchronous cell cycle progression (an event that is named “chronocrisis”) of different nuclei from a polyploid cell can generate DNA damage at mitotic entry. The potential mechanisms explaining how mitosis in non‐programmed polyploid cells can generate abnormal karyotypes and genetic instability are highlighted. (shrink)

Malignant tumours are often characterised by significant rearrangement of the genome. This may be visible in the form of a deranged karyotype with both loss and gain of DNA sequences extending from chromosomal regions to whole chromosomes. In several tumour types, however, gross genomic derangements are minimal, and tumour cells contain one or more additional (supernumerary) chromosomes that may be unrecognisable in terms of a single origin. In this review we term such chromosomes cancer‐associated neochromosomes (CaNCs). In the (...) absence of other identified genomic abnormalities, and because the CaNC is a common feature of the cancer type, it is hypothesised that the genetic alterations required for cell transformation are contained within its structure. In this review, we discuss the potential impact of modern genomic technologies on our understanding of the nature and causes of CaNC formation, which is central to several cancer types, exemplified here by well‐differentiated liposarcoma. (shrink)

Biochemical and genetical analysis of plant transposons has shown that these elements can induce unstable mutations and also that the transposon structure can be altered in different ways. Upon insertion, a transposon can give rise to a variety of chromosomal changes in the vicinity of the insertion site. The alterations range from the nucleotide level to large‐scale rearrangements.

The process of chromatin diminution in Parascaris and Ascaris is a developmentally controlled genome rearrangement, which results in quantitative and qualitative differences in DNA content between germ line and somatic cells. Chromatin diminution involves chromosomal breakage, new telomere formation and DNA degradation. The programmed elimination of chromatin in presomatic cells might serve as an alternative way of gene regulation. We put forward a new hypothesis of how an ancient partial genome duplication and chromatin diminution may have served to (...) maintain the genetic balance in somatic cells and simultaneously endowed the germ line cells with a selective advantage. (shrink)

The presence of small polydisperse extrachromosomal circular (spc) DNAs composed entirely of chromosomal sequences seems to reflect the plasticity of eukaryotic genomes. The size distribution and number of spc DNAs is found to vary with development, growth state and mitotic capacity. In particular, spc DNAs are observed to be several fold smaller in established immortal cell lines than in diploid cells with a limited life span. Analysis of cloned spc DNA fragments revealed that: (1) most of the spc DNAs (...) thus far investigated contain repetitive sequences; (2) some of the repetitive sequences are enriched in spc DNA clones relative to their representation in the chromosome; (3) various repetitive sequences of different reiteration frequency were found in spc DNA from immortal cell lines while a particular sequence of retroposon was predominant in primary lymphoid tissue cells and stem cells; (4) most of these spc DNAs appear to represent the extra copies generated by replicon‐misfiring in immortal cell lines or by retrotranscription in stem cells, and intermediates or by‐products produced by abortive rearrangement in diploid cells with a finite replicative capacity. (shrink)

The Y chromosome in the XY sex-determination system is often shorter than its X counterpart, a condition attributed to degeneration after Y recombination ceases. Contrary to the traditional view of continuous, gradual degeneration, our study reveals stabilization within large mating populations. In these populations, we demonstrate that both mutant and active alleles on the Y chromosome can reach equilibrium through a mutation-selection balance. However, the emergence of a new species, particularly through the founder effect, can disrupt this equilibrium. Specifically, if (...) the male founders of a new species carry only a mutant allele for a particular Y-linked gene, this allele becomes fixed, leading to the loss of the corresponding active gene on the Y chromosome. Our findings suggest that the rate of Y-chromosome degeneration may be linked to the frequency of speciation events associated with single-male founder events. (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)

The rearrangement inequality states that the sum of products of permutations of 2 sequences of real numbers are maximized when the terms are similarly ordered and minimized when the terms are ordered in opposite order. We show that similar inequalities exist in algebras of multi-valued logic when the multiplication and addition operations are replaced with various T-norms and T-conorms respectively. For instance, we show that the rearrangement inequality holds when the T-norms and T-conorms are derived from Archimedean copulas.

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)

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)

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)

With the new and highly accurate noninvasive prenatal test, new options for screening become available. I contend that the current state of the art of NIPT is already in need of a thorough ethical investigation and that there are different points to consider before any chromosomal or subchromosomal condition is added to the screening panel of a publicly funded screening program. Moreover, the application of certain ethical principles makes the inclusion of some conditions unethical in a privately funded scheme, (...) even if such screening would enhance a woman’s reproductive autonomy. On the one hand, a screening program aimed solely at the detection of Down syndrome is subject to the technological imperative and should be reassessed in the light of technologies that allow for the detection of conditions that are at least as severe. On the other hand, some chromosomal conditions should not be included in any screening programs, because this would violate certain ethical principles, such as the right of the future child to genetic privacy. (shrink)

According to Peter van Inwagen, there are, from the point of view of serious metaphysics, no composites, only simples. Saying that we have built a ship is a misleading way of saying that we have rearranged some simples ship- wise. However, the notion of rearranging simples is problematic, and van Inwagen’s resort to “honorary simples” does not make it less so. Simples can be rearranged only by way of rearranging these, making talk of them not merely a convenient facon de (...) parler, as van Inwagen claims, but ineliminable even when we are in the “ontology room.”. (shrink)

Sex chromosomes are advantageous to mammals, allowing them to adopt a genetic rather than environmental sex determination system. However, sex chromosome evolution also carries a burden, because it results in an imbalance in gene dosage between females (XX) and males (XY). This imbalance is resolved by X dosage compensation, which comprises both X chromosome inactivation and X chromosome upregulation. X dosage compensation has been well characterized in the soma, but not in the germ line. Germ cells face a special challenge, (...) because genome wide reprogramming erases epigenetic marks responsible for maintaining the X dosage compensated state. Here we explain how evolution has influenced the gene content and germ line specialization of the mammalian sex chromosomes. We discuss new research uncovering unusual X dosage compensation states in germ cells, which we postulate influence sexual dimorphisms in germ line development and cause infertility in individuals with sex chromosome aneuploidy. (shrink)

Here we discuss a “chromosome separation checkpoint” that might regulate the anaphase‐telophase transition. The concept of cell cycle checkpoints was originally proposed to account for extrinsic control mechanisms that ensure the order of cell cycle events. Several checkpoints have been shown to regulate major cell cycle transitions, namely at G1‐S and G2‐M. At the onset of mitosis, the prophase‐prometaphase transition is controlled by several potential checkpoints, including the antephase checkpoint, while the spindle assembly checkpoint guards the metaphase‐anaphase transition. Our hypothesis (...) is based on the recently uncovered feedback control mechanism that delays chromosome decondensation and nuclear envelope reassembly until effective separation of sister chromatids during anaphase is achieved. A central player in this potential checkpoint is the establishment of a constitutive, midzone‐based Aurora B phosphorylation gradient that monitors the position of chromosomes along the spindle axis. We propose that this surveillance mechanism represents an additional step towards ensuring mitotic fidelity. (shrink)

X‐chromosome inactivation refers to the coordinate regulation of almost all genes on the mammalian × chromosome. Most models for × chromosome inactivation suppose a role for methylation of × chromosome DNA sequences and/or the heterochromatinization of large «domains» of the × chromosome containing many genes.1 Some recent work concerning the expression of X‐linked transgenes, and parallels between regulated expression of sex‐linked genes in invertebrates and mammals, suggest that × chromosome inactivation may be a gene‐by‐gene event mediated by the interaction between (...) regulatory sequences common to all X‐linked genes and soluble activators and repressors. (shrink)