Genome dynamics最新文献

Despite a late start, analysis of the horse genome has progressed rapidly during the past ten years. With synteny, genetic linkage, radiation hybrid, cytogenetic and comparative maps presently generated for all equine chromosomes including the Y chromosome, the map of the equine genome contains approximately 4,000 markers. The average resolution of the mapped markers is approximately 700 kb, which makes the horse gene map the densest among the domestic animal species hitherto not sequenced. This map is currently used by researchers worldwide to discover genes associated with various traits of significance in the horse including overall health, disease resistance, reproduction, fertility, athletic performance, phenotypic characteristics like coat color, etc. Efforts are currently underway to initiate functional studies of the equine genome. Despite in its infancy, the expression based analysis of the equine genome using cDNA or oligoarrays is expected to be an integral part of genome analysis in the horse. More recently, a physical map of approximately 150,000 overlapping bacterial artificial chromosome (BAC) clones is being generated by end-sequencing and subsequent assembly of the BACs. Collectively, the wide range of genomic tools/resources presently available in the horse makes it the next ideal candidate for whole genome sequencing. The motivation and support of the ultimate benefactors - the equine industry - from this huge endeavor will however be pivotal.

The proto-oncogene c-myc has been the subject of intensive research since its discovery. It is already known that this oncogene targets multiple pathways for the initiation and promotion of tumor formation, and that deregulation of this protein is observed in numerous cancers. However, despite the plethora of information gathered, the exact role and mechanism of action of the protein still remains enigmatic. This review focuses on the role of the c-Myc protein in the induction of genomic instability and its link with the development of cancer. We briefly describe c-Myc protein, its binding partners and downstream targets as well as its role in inducing genomic instability and the c-myc-related diseases in humans and mice with regard to genomic instability. This review emphasizes the notions that c-Myc is a multifunctional protein which also affects the stability of the whole genome and triggers the initiation of a complex network of genomic instability and therefore acts beyond the characteristics of classical transcription factors that only regulate a limited number of downstream targets. We propose that c-Myc is a structural modifier of the genome that affects the nuclear organization and an important molecule in tumor cell progression through the induction of genomic instability.

Medaka (Oryzias latipes) is widely used in research in the fields of biology, medicine, environmental science and fisheries. Zebrafish and medaka are well established as genetic model systems in which large-scale mutagenesis has been successfully performed, and for which EST data, BAC libraries, and fine linkage maps have been accumulated. Among rayfinned fish, there is a large evolutionary distance between medaka and zebrafish. In contrast, the evolutionary distance between medaka and two species of pufferfish, fugu (Takifugu rubripes), and tetraodon (Tetraodon nigroviridis), is almost comparable to that between humans and rodents, and the current genome project is showing that their genome organization is well conserved. Comparison of genome structure among teleosts and mammals helps our understanding of the orthologous gene structure and the evolution of gene families in vertebrates. In addition, gene functions have to be analyzed by both forward and reverse genetics. The Targeting Induced Local Lesions IN Genome (TILLING) system, which includes random mutagenesis, followed by screening for induced mutations in the target genes, is a powerful tool for studying the functional genomics of both medaka and zebrafish.

Cell cycle checkpoints induced by telomere dysfunction represent one of the major in vivo tumor suppressor mechanisms preventing cancer but at the same time provoking age dependent decline in self-renewal and regeneration of tissues and organs. On the other hand, telomere shortening contributes to the initiation of cancer by inducing chromosomal instability. Telomere function and telomerase activity are mainly associated with actively proliferating cells. Since stem cells are continuously proliferating throughout lifetime, it is of great interest to explore the role of telomeres and telomerase in stem cells. Although most stem cell compartments express telomerase, the level of telomerase activity is not sufficient to maintain telomere length of stem cells during aging. Stem cells appear to have tighter DNAdamage checkpoint control in comparison to somatic cells, which may reflect the need to protect this long lasting cell compartment against malignant transformation. These enhanced checkpoint responses may have a detrimental impact on stem cell function, by causing increased sensitivity towards senescence or apoptosis induced by telomere shortening. This review summarizes our knowledge on telomere dynamics and its functional impact on stem cells during aging and transformation.

The mouse is a key model organism for the study of mammalian genetics, development, physiology and biochemistry. The determination of the mouse genome sequence was therefore an early priority in the genome project. A draft sequence became available in 2002 and many chromosomes are now close to being finished. Comparative analysis of the mouse genome sequence with that of the human and other genomes has revealed a wealth of information on genome evolution in the mammalian lineage and assisted in the annotation of both genomes. With the availability of a well-annotated mouse genome sequence, mouse geneticists are now poised to undertake the challenge of generating mutations at every gene in the mouse genome. Systematic mutagenesis of the mouse genome will be an important step towards the first comprehensive functional annotation of a mammalian genome and the identification and characterisation of models for the study of human genetic disease.

Over the last few centuries, several hundred dog breeds have been artificially selected through intense breeding, resulting in the modern dog population having the widest polymorphism spectrum in terms of body shape, behavior and aptitude among mammals. Unfortunately, this diversification has predisposed most breeds to specific diseases of genetic origin. The highly fragmented nature of the dog population offers a great opportunity to track the genes and alleles responsible for these diseases as well as for the various phenotypic traits. This has led to a thorough analysis of the dog genome. Here, we report the main results obtained during the last ten years, culminating in the recent publication of a complete dog genome sequence.

The chicken has long been an important model organism for developmental biology, as well as a major source of protein with billions of birds used in meat and egg production each year. Chicken genomics has been transformed in recent years, with the characterisation of large EST collections and most recently with the assembly of the chicken genome sequence. Since the chicken shared a common ancestor with mammals 310 million years ago it fills a gap in our knowledge in the evolution and conservation of vertebrate genomes. As the first livestock genome to be fully sequenced it leads the way for others to follow. The genome sequence and the availability of 3 million genetic polymorphisms are expected to aid the identification of genes that control traits of importance in poultry. As the first bird genome to be sequenced it is a model for the remaining 9,600 species thought to exist today. Many of the features of avian biology and organisation of the chicken genome make it an ideal model organism for phylogenetics and embryology, along with applications in agriculture and medicine. In this report these advances are reviewed and the implications of the chicken genome in current and future applications are discussed.

Upon genotoxic stress, checkpoint machinery in eukaryotic cells induces cell-cycle arrest, thus allowing the cells to repair damaged DNA or stalled replication forks. The checkpoint machinery is mediated by phosphorylation cascades involving protein kinases and their target proteins. Since the genome is under constant threat from DNA damage due to radiation, chemicals and replication errors, checkpoint dysregulation can cause catastrophic DNA damage, resulting in chromosome instability, aneuploidy, and even tumorigenesis. Two parallel pathways that respond to DNA-damage stress have been extensively studied. The first is the ATM pathway, which responds to double-stranded DNA breaks, while the second is the ATR pathway, which primarily responds to agents that interfere with normal DNA replication. The ATM and ATR kinases activate their downstream target proteins by phosphorylating specific serine or threonine residues. Dephosphorylation by protein phosphatase (PP2A) also participates in the regulation of these phosphorylation signals. Of the target proteins, the two effector kinases CHK1 and CHK2 are particularly important because they phosphorylate additional substrates to maintain chromosome stability after various DNA damaging insults. Recent observations indicate that other protein kinases that control centrosome duplication and chromosome segregation during the cell cycle also play essential roles in maintaining genomic stability.

Nucleotide excision repair (NER) of DNA-lesions is the most versatile DNA repair mechanism involved in genome maintenance, cell and organismal preservation. Deciphering the stepwise mechanism of NER has mostly relied on cells from rare patients presenting photosensitive, recessively inherited genetic disorders such as xeroderma pigmentosum (XP), trichothiodystrophy (TTD) and Cockayne (CS) syndromes. Cells from these patients share various extents of impaired capacity of repairing UV-induced DNA lesions (cyclobutane pyrimidine dimers, 6-4 pyrimidine-pyrimidone photo products) located either in transcribed DNA strands or in inactive DNA. We review here the essentials of NER actors and how impairment of their activity may lead to distinct and characteristic human disorders whose presentation may be limited to developmental trait (TTD; CS), or cumulate with cancer susceptibility toward genotoxic aggressions, most notably short wavelength ultraviolets.

Oxidative damage to DNA has been examined in many non-malignant conditions, in most cases for its utility as a marker of oxidative stress. Whilst this may prove useful, attempts to answer the question - why might oxidative damage be important in this disease? - would provide added value to the biomarker data, as well as give clues to pathogenesis and perhaps therapy. In this chapter, data from the scientific literature are considered broadly, where oxidative damage to DNA has been analysed either in tissues or in extracellular matrices, such as urine, in various groups of non-malignant disease. The lesion of primary focus is 8-hydroxy-7,8-dihydro-2'-deoxyguanosine, only because this is the most widely measured lesion. By coupling biomarker information with the characteristics of the disease and a set of general mechanisms whereby DNA oxidation may be pathogenic (retrospectively derived from the literature examined), we can ascribe pathogenic roles for DNA oxidation in various diseases. Based on available experimental evidence, for a wide range of conditions, such mechanisms would include prominent roles for the induction of mitochondrial dysfunction, promotion of cytotoxicity and modulation of inflammatory responses. Our general conclusion is that, dependent on the disease, oxidative DNA damage may be a biomarker, biohazard or both of these.