Page: 3-32 (30)
Author: Yann Hérault, Arnaud Duchon, Damien Maréchal and Véronique Brault
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Changes in the number of chromosomes and variations in the copy number of chromosomal regions are described in various pathological conditions, such as cancer and aneuploidy, but also in normal physiological condition. Our initial view of DNA replication and mitotic preservation of chromosomal integrity is now challenged as new technologies allow the observation of mosaic somatic changes in copy numbers of chromosome regions of different sizes. In the mouse various engineering strategies are available to better understand the significance of copy numbers in normal physiological condition. For example, inducing recombination during the G2 phase will allow the generation of deletions and duplications of regions of interest prior to mitosis. The effects of copy number variation and segmental aneuploidy can be observed now in daughter cells and explored in somatic mosaics for large chromosomal regions.
Page: 33-82 (50)
Author: Tissa T. Manavalan and Carolyn M. Klinge
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Estrogens have a wide variety of physiological functions as sex steroid hormones in women and in men. Estrogens have apparent anti-aging properties in brain, cardiovascular tissues, and bone. Estrogens regulate genes directly through binding to estrogen receptors alpha and beta (ERα and ERβ) that are ligand-activated transcription factors and indirectly by activating plasma membrane-associated ER which, in turns, activates intracellular signaling cascades leading to altered gene expression. Estrogens may also impact cellular signaling by binding to GPR30/GPER. MicroRNAs (miRNAs) are short (19-25 nucleotides), naturally-occurring, non-coding RNA molecules that base-pair with the 3’ untranslated region of target mRNAs. This interaction either blocks translation of the mRNA or targets the mRNA transcript to be degraded. The human genome contains ~2,578 miRNAs. Aberrant patterns of miRNA expression are implicated in human diseases including estrogen-related diseases including breast cancer. miRNAs regulated by estrogens have been identified Zebrafish, mouse tissues, and in human cells and tissues including breast and myometrial tumors. The mechanism for estrogen regulation of miRNA expression and the role of estrogen-regulated miRNAs in normal homeostasis, reproduction, lactation, and in cancer is only beginning to be explored.
Update on Basic and Applied Aspects of Genome Analysis of Lactic Acid-Producing Bacteria, Including Bifidobacteria
Page: 83-126 (44)
Author: Baltasar Mayo, Douwe van Sinderen and Marco Ventura
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The rapidly increasing number of genome sequences provides an important resource to study the genetics, physiology and biochemical capabilities of lactic acid bacteria (LAB) and bifidobacteria. Despite the fact that they are phylogenitally unrelated, bifidobacteria are usually included under the term of LAB, as they are found within the same natural environments and are frequently used for the same purpose, i.e. as probiotics to exert health-promoting effects on the gastrointestinal and/or genitourinary tracts of animals and humans. The most updated sequence information (GOLD genome online database; http://www.genomesonline.org) summarizes 280 completed LAB genomes (14 Lactococcus, 165 Lactobacillus, 18 Leuconostoc, 6 Streptococcus thermophilus, 13 Oenococcus, 6 Pediococcus, 4 Weissella, and 54 Bifidobacterium) and more than 500 in progress. The typical LAB genome is relatively small (from 1.7 Mb in the case of S. thermophilus to 3.9 Mb for Lactobacillus pentosus), thus harboring a limited assortment of genes (from around 1,600 to over 3,000). These small genomes code for a broad array of transporters for efficient carbon and nitrogen assimilation from the nutritionally-rich niches they usually inhabit, and specify a rather limited range of biosynthetic and catabolic capabilities. The variation in the number of genes even within strains of the same species suggests that the genome of LAB is rather plastic and dynamic. The genome diversification of LAB from their ancestors is thought to be driven by niche adaptation through extensive gene loss, gene duplication, and acquisition of key functions via lateral gene transfer. The availability of genome sequences is expected to revolutionize the exploitation of the metabolic potential of LAB, improving their use in bioprocessing and their utilization in biotechnological and health-related applications.
Page: 127-142 (16)
Author: David Horvath
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Numerous genomic-based studies have provided insight to the physiological and evolutionary processes involved in developmental and environmental processes of model plants such as arabidopsis and rice. However, far fewer efforts have been attempted to use genomic resources to study physiological and evolutionary processes of weedy plants. Genomics-based tools such as extensive EST databases and microarrays have been developed for a limited number of weedy species, although application of information and resources developed for model plants and crops are possible and have been exploited. These tools have just begun to provide insights into the response of these weeds to herbivore and pathogen attack, survival of extreme environmental conditions, and interaction with crops. The potential of these tools to illuminate mechanisms controlling the traits that allow weeds to invade novel habitats, survive extreme environments, and that make weeds difficult to eradicate have potential for both improving crops and developing novel methods to control weeds.
Page: 143-160 (18)
Author: Sara Donzelli, Francesca Biagioni, Francesca Fausti, Sabrina Strano, Giulia Fontemaggi and Giovanni Blandino
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Cancer is caused by the spatial and temporal accumulation of alterations in the genome of a given cell. This leads to the deregulation of key signaling pathways that play a pivotal role in the control of cell proliferation and cell fate. The p53 tumor suppressor gene is the most frequent target in genetic alterations in human cancers. The primary selective advantage of such mutations is the elimination of cellular wild type p53 activity. In addition, many evidences in vitro and in vivo have demonstrated that at least certain mutant forms of p53 may possess a gain of function, whereby they contribute positively to cancer progression. The fine mapping and deciphering of specific cancer phenotypes is taking advantage of molecular-profiling studies based on genome-wide approaches. Currently, high-throughput methods such as array-based comparative genomic hybridization (CGH array), single nucleotide polymorphism array (SNP array), expression arrays and ChIP-on-chip arrays are available to study mutant p53-associated alterations in human cancers. Here we will mainly focus on the integration of the results raised through oncogenomic platforms that aim to shed light on the molecular mechanisms underlying mutant p53 gain of function activities and to provide useful information on the molecular stratification of tumor patients.
Page: 161-188 (28)
Author: Laura W. Dillon, Allison B. Weckerle and Yuh-Hwa Wang
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Human chromosomal fragile sites are specific genomic regions which exhibit gaps or breaks on metaphase chromosomes following conditions of partial replication stress. Fragile sites often coincide with genes that are frequently rearranged or deleted in human cancers, with over half of cancer-specific translocations containing breakpoints within fragile sites. But until recently, little direct evidence existed linking fragile site breakage to the formation of cancer-causing chromosomal aberrations. Studies have revealed that DNA breakage at fragile sites can induce formation of RET/PTC rearrangements, and deletions within the FHIT gene, resembling those observed in human tumors. These findings demonstrate the important role of fragile sites in cancer development, suggesting that a better understanding of the molecular basis of fragile site instability is crucial to insights in carcinogenesis. It is hypothesized that under conditions of replication stress, stable secondary structures form at fragile sites and stall replication fork progress, ultimately resulting in DNA breaks. A study examining an FRA16B fragment confirmed the formation of secondary structure and DNA polymerase stalling within this sequence in vitro, as well as reduced replication efficiency and increased instability in human cells. Polymerase stalling during synthesis of FRA16D has also been demonstrated. A recent study of endogenous FRA16C in human cells showed that replication fork stalling occurs at AT-rich sequences, and under mild replication stress, the frequency of stalling is increased. The ATR DNA damage checkpoint pathway plays a critical role in maintaining stability at fragile sites. Recent findings have confirmed binding of the ATR protein to three regions of FRA3B under conditions of mild replication stress. This review will discuss recent advances made in understanding the role and mechanism of fragile sites in cancer development.
Page: 189-212 (24)
Author: Diddier Prada, Marco A. Andonegui and Luis A. Herrera
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Theodore Boveri, eminent German biologist, embryologist and pathologist, observed aneuploidy in cancer cells more than a century ago and suggested that cancer cells derived from a single progenitor cell that acquires the potential for uncontrolled continuous proliferation. Currently, it is well known that aneuploidy is observed in virtually all cancers. Gain and loss of chromosomal material in neoplastic cells is considered a process of diversification that leads to survival of the fittest clones. According to Darwin’s theory of evolution, the environment determines the grounds upon which selection takes place and the genetic characteristics necessary for better adaptation. This concept can be applied to the carcinogenesis process, connecting the ability of cancer cells to adapt to different environments and to resist chemotherapy, genomic instability being the driving force of tumor development and progression. What causes this genome instability? Mutations have been recognized for a long time as the major source of genome instability in cancer cells. Nevertheless, an alternative hypothesis suggests that aneuploidy is a primary cause of genome instability rather than solely a simple consequence of the malignant transformation process. Whether genome instability results from mutations or from aneuploidy is not a matter of discussion in this review. It is most likely both phenomena are intimately related; however, we will focus on the mechanisms involved in aneuploidy formation and more specifically on the epigenetic origin of aneuploid cells. Epigenetic inheritance is defined as cellular information—other than the DNA sequence itself—that is heritable during cell division. DNA methylation and histone modifications comprise two of the main epigenetic modifications that are important for many physiological and pathological conditions, including cancer. Aberrant DNA methylation is the most common molecular cancer-cell lesion, even more frequent than gene mutations; global hypomethylation and aberrant local hypermethylation are perhaps the most frequent epigenetic modifications in cancer cells. Epigenetic characteristics of cells may be modified by several factors including environmental exposure, certain nutrient deficiencies, radiation, etc. Some of these alterations have been correlated with the formation of aneuploid cells in vivo. A growing body of evidence suggests that aneuploidy is produced and caused by chromosome instability. We propose and support in this manuscript that not only genetics but also epigenetics, and specifically alterations in DNA methylation, contribute in a major fashion to aneuploid cell formation.
Page: 213-232 (20)
Author: Cláudia S. Baptista, Sara Santos, Estela Bastos, Henrique Guedes-Pinto, Ivo G. Gut, Fátima Gärtner and Raquel Chaves
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TWIST1 is thought to be a novel oncogene. Understanding the molecular mechanisms regulating the TWIST1 gene expression profiles in tumor cells may give new insights regarding prognostic factors and novel therapeutic targets in veterinary oncology. In the present study we partially isolated the TWIST1 gene in Felis catus and performed comparative studies. Several primer combinations were used based on the alignments of homologous DNA sequences. After PCR amplification, three bands were obtained, purified and sequenced. Several bioinformatic tools were utilized to carry out the comparative studies. Higher similarity was found between the isolated TWIST1 gene in Felis catus and Homo sapiens (86%) than between Homo sapiens and Rattus norvegicus or Mus musculus (75%). Partial amino acid sequence showed no change in the four species analyzed. This confirmed that coding sequences presented high similarity (~96%) between man and cat. These results give the first insights regarding the TWIST1 gene in cat but further studies are required in order to establish, or not, its role in tumor formation and progression in veterinary oncology.
Advances in the Study of Brain Aging and Alzheimer’s Disease Using Microarray and Next-Generation Sequencing: Focus on Selective Neuronal Vulnerability
Page: 233-270 (38)
Author: Xinkun Wang, Mary L. Michaelis and Elias K. Michaelis
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Pivotal brain functions, such as neurotransmission, cognition, and memory, decline with advancing age and, especially, in neurodegenerative conditions associated with aging, such as Alzheimer’s disease (AD). Yet, deterioration in structure and function of the nervous system during aging or in AD is not uniform throughout the brain. Selective neuronal vulnerability (SNV) is a general but sometimes overlooked characteristic of brain aging and AD. There is little known at the molecular level to account for the phenomenon of SNV. Functional genomic analyses, through unbiased whole genome expression studies, could lead to new insights into a complex process such as SNV. Microarray and next-generation sequencing (RNA-Seq) data generated thus far (as of March 2012) using both human brain tissue and brains from animal models of aging and AD were analyzed in this chapter. Convergent trends that have emerged from these data sets were considered in identifying possible molecular and cellular pathways involved in SNV. It appears that during normal brain aging and in AD, neurons vulnerable to injury or cell death are characterized by significant decreases in the expression of genes related to mitochondrial metabolism and energy production. In AD, vulnerable neurons also exhibit down-regulation of genes related to synaptic neurotransmission and vesicular transport, cytoskeletal structure and function, and neurotrophic factor activity. A prominent category of genes that are up-regulated in AD are those related to inflammatory response and some components of calcium signaling. These genomic differences between sensitive and resistant neurons can now be used to explore the molecular underpinnings of previously suggested mechanisms of cell injury in aging and AD.
Investigating Molecular Mechanisms of Chronic Pain in the Anterior Cingulate Cortex Through Genetically Engineered Mice
Page: 271-287 (17)
Author: Susan S. Kim, Giannina Descalzi and Min Zhuo
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Recent advances into the understanding of molecular mechanism of chronic pain have been largely developed through the use of genetic manipulations. This is in part due to the scarcity of selective pharmacological tools, which can be readily solved by creating knockout or transgenic mice. By identifying new genes that are of import, our efforts can then be aimed at studying relevant signaling pathways, and combination of pharmacological manipulations with genetic models can be used to further examine the specific mechanisms involved in chronic pain. In this review, we will examine the genetic models that are currently in use to study chronic pain in the anterior cingulate cortex: knockout mice; transgenic mice; and the strength of combining pharmacology with these genetic models.
Genome science or genomics is essential to advancing knowledge in the fields of biology and medicine. Specifically, researchers learn about the molecular biology behind genetic expression in living organisms and related methods of treating human genetic diseases (including gene therapy). Advances in Genome Science is an e-book series which provides a multi-disciplinary view of some of the latest developments in genome research, allowing readers to capture the essence and diversity of genomics in contemporary science. The third volume of this ebook series features a variety of articles exploring oncogenomics, mouse genetics, feline genetics, genetic mechanism for pain, the genetics of weeds and much more.