Current Genomics

ISSN: 1389-2029

Abstracts


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Non-Mendelian Phenomena in Allopolyploid Genome Evolution
Bao Liu and Jonathan F. Wendel

Perhaps all flowering plants have experienced one or more episodes of polyploidization at some time in their evolutionary history. Recent evidence indicates that this genome doubling may be accompanied by a variety of non-Mendelian phenomena, some of which operate during hybridization and polyploid formation while others manifest more gradually on an evolutionary timescale. Here we review these phenomena, drawing attention to recent paradigm shifts necessitated by new insights from model plant systems. Allopolyploid formation in some plant groups is associated with an unexplained and in some cases directed process of genomic alteration leading to non-additivity with respect to parental genomes. Novel intergenomic interactions become possible as a consequence of the merger of two previously isolated diploid genomes, variously leading to intergenomic colonization and/or homogenization of formerly diverged sequences. Several epigenetic processes may accompany nascent allopolyploidy, such as nucleolar dominance, gene silencing and mobile element activation, the latter also resulting in genetic change. These myriad phenomena do not characterize all polyploid systems, and some nascent allopolyploids appear to be genomically quiescent. Although a direct connection to adaptation remains to be established, the diversity of genetic responses to allopolyploid formation and their apparent high frequency suggest that non-Mendelian phenomena contribute directly to polyploid stabilization and diversification.


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Human Kallikreins: Common Structural Features, Sequence Analysis and Evolution
George M. Yousef and Eleftherios P. Diamandis

Kallikreins are a subgroup of serine proteases with diverse physiological functions. The human kallikrein gene family has now been fully characterized and includes 15 members tandemly located on chromosome 19q13.4 In this review, we discuss the common structural features of kallikreins at the DNA, mRNA and protein levels and summarize their tissue expression and hormonal regulation. Kallikreins are expressed in a wide range of tissues including the salivary gland, endocrine tissues including testis, prostate, breast, endometrium, and the central nervous system. Most, if not all genes are under steroid hormone regulation. The classical kallikreins (KLK1-3) are thought to represent a distinct evolutionary subgroup of kallikreins. The occurrence of several splice variants is a very common phenomenon among kallikreins, and some of the splice variants appear to be tissue-specific and might be related to certain pathological conditions. We also provide a summary of predicted and experimentally confirmed promoter elements of kallikrein genes and describe repeat elements and polymorphisms within this genomic region.


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Nonsense-Mediated mRNA Decay: A Comparative Analysis of Different Species
L.E. Maquat

Nonsense-mediated mRNA decay (NMD) functions to ensure quality gene expression by degrading mRNAs that prematurely terminate translation. By so doing, it eliminates the production of potentially deleterious truncated proteins. NMD also degrades certain naturally occurring transcripts as a means of achieving proper levels of gene expression. With the exception of prokaryotes, NMD typifies all organisms that have been examined. As an example of its importance, NMD is required for the viability of mammalian blastocysts in culture as well as mammalian embryos in utero. The repertoire of factors that mediate NMD is larger in C. elegans, D. melanogaster, mammalian cells and, possibly, A. thaliana, than it is in S. cerevisiae and S. pombe. NMD requires not only a premature termination codon but also a downstream element. Whereas this element in S. cerevisiae, S. pombe, C. elegans, D. melanogaster and plants is debatably either a short cis-acting mRNA sequence or an abnormal 3’ untranslated region, it is a splicing-generated exon junction complex of proteins in mammalian cells. In fact, NMD may have provided a selective pressure for where introns colonize within mammalian genes. There also appear to be differences among different eukaryotes as to whether NMD is restricted to newly synthesized mRNA or can also target steady-state mRNA. In summary, despite the conservation of NMD in eukaryotes, different mechanisms have evolved to define those premature termination codons that elicit NMD.


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The Use of Phylogenetic Profiles for Gene Predictions
David A. Liberles, Anna Thorén, Gunnar von Heijne and Arne Elofsson

Determining gene functions from genomic sequences is a central goal of bioinformatics. Most purely computational approaches to this problem are based on the detection of genes with similar sequences. With the completion of fully sequenced genomes alternative approaches have become feasible. One such method is that of phylogenetic profiles. In this method a gene is described by its phylogenetic profile, i.e. a string that encodes the presence or absence of a homologous gene in other genomes. This string is then used to search for other genes with similar profiles. In this paper we briefly review the field as well as present an analysis on the performance of the method. We also discuss variations on this theme including inverse phylogenetic profiles and non-exact profiles using phylogenetic trees. In conclusion this indicates that phylogenetic profiles might be useful for some, but not all functional annotations. Functional annotation of genomes remains an important problem in genomics when no close homologs exist.


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Nucleolar Dominance: A ‘David and Goliath’ Chromatin Imprinting Process
W. Viegas, N. Neves, M. Silva, A. Caperta and L. Morais-Cecílio

Nucleolar dominance is an enigma. The puzzle of differential amphiplasty has remained unresolved since it was first recognised and described in Crepis hybrids by Navashin in 1934. Here we review the body of knowledge that has grown out of the many models that have tried to find the genetic basis for differential rRNA gene expression in hybrids, and present a new interpretation. We propose and discuss a chromatin imprinting model which re-interprets differential amphiplasty in terms of two genomes of differing size occupying a common space within the nucleus, and with heterochromatin as a key player in the scenario. Difference in size between two parental genomes induces an inherited epigenetic mark in the hybrid that allows patterns of chromatin organization to have positional effects on the neighbouring domains. This chromatin imprinting model can be also used to explain complex genomic interactions which transcend nucleolar dominance and which can account for the overall characteristics of hybrids. Gene expression in hybrids, relative to parentage, is seen as being based on the nuclear location of the sequences concerned within their genomic environment, and where the presence of particular repetitive DNA sequences are ‘sensed’, and render silent the adjacent information.


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Multicolor-FISH Approaches for the Characterization of Human Chromosomes in Clinical Genetics and Tumor Cytogenetics
Thomas Liehr and Uwe Claussen

A variety of multicolor fluorescence in situ hybridization (FISH) assays have been developed in the last decade. Routine application of such techniques started in 1996 with the simultaneous use of all the 24 human whole chromosome painting probes (i.e. multiplex-FISH = M-FISH and spectral karyotyping = SKY). Since that time different approaches for chromosomal differentiation based on multicolor-FISH (mFISH) assays have been published with the purpose to characterize structurally abnormal chromosomes and supernumerary marker chromosomes of unknown origin after conventional karyotypic analysis. Their characterization is of high clinical impact and is the requisite condition for further molecular investigations aimed at identification of disease related genes. We present an overview of the available different mFISH methods, highlighting their advantages and limitations, as well as their applications in clinical and tumor cytogenetics. Finally, an outlook is given on further possible developments of this special field of molecular cytogenetics.


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The CLCA Gene Family: A Novel Family of Putative Chloride Channels
A.D. Gruber*, C.M. Fuller, R.C. Elble, D.J. Benos, and B.U. Pauli

Several families of functionally and structurally distinct ion channels have been identified throughout the last decade, resulting in a growing complexity in our understanding of ion transport across biological membranes. Here, we introduce a novel family of putative chloride channel proteins with nine bovine, murine, and human homologs identified to date. The gene family has been termed CLCA family (chloride channels, calcium-activated) based on observations that heterologous expression of several family members is associated with the appearance of a novel anion channel activity that depends on the concentration of intracellular calcium. The family members identified so far are the bovine calcium-activated chloride channel (CaCC or bCLCA1), the bovine lung endothelial cell adhesion molecule-1 (LuECAM-1), the murine calcium-activated chloride channels mCLCA1, mCLCA2, and mCLCA3 (previously termed gob-5), and four human homologs (hCLCA1, hCLCA2, hCLCA3, and hCaCC2). Each of these homologs is characterized by a unique cellular and tissue expression pattern with most consistent expression in secretory epithelia of the digestive, respiratory, and reproductive organs. Of special interest is the observation that several of these molecules seem to combine cell-cell adhesion properties with ion channel function. Structural analyses have revealed that a four- or five-transmembrane topography is conserved throughout the family. Their functional features as well as the cellular coexpression of several CLCA homologs with the cystic fibrosis transmembrane conductance regulator (CFTR) in numerous tissues raises the question whether CLCA family members may participate in the complex ion channel disorder of cystic fibrosis.


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Telomeres and Centromeres in Plants
M. Murata

The prolongation of skeletal muscle strength in aging and neuromuscular disease has been the objective of numerous studies employing a variety of approaches. To date however, efforts to prevent or attenuate age- or disease-related muscle degeneration have been largely unsuccessful. Cell-based therapies have been stalled by the difficulty in obtaining sufficient numbers of autologous myoblasts and by inefficient incorporation into host muscle. Administration of growth hormone prevents age-related loss of muscle mass, but has failed to increase muscle strength. In this context, where direct therapeutic approaches to redress the primary disease are still suboptimal, it may be more effective to focus on strategies for improving skeletal muscle function. Experimental models of muscle growth and regeneration have implicated Insulin-like Growth Factor-1 (IGF-1) as an important mediator of anabolic pathways in skeletal muscle cells. Two major IGF-1 transcripts are characterized: the locally acting isoform with an autocrine/paracrine action and the circulating isoform with endocrine effects. The physiological differences between the function of local and circulating isoform of IGF-1 are not completely established. However the selective expression of the muscle-specific IGF-1 isoform avoids hypertrophic effects on distal organs such as the heart, and eliminates risk of possible neoplasms induced by inappropriate high expression levels of circulating IGF-1. In this review we discuss the roles of IGF-1 isoforms in myogenesis and the potential therapeutic role of local IGF-1 isoform on muscle aging and diseases.


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The Role of local Insulin-like Growth Factor-1 Isoforms in the Pathophysiology of Skeletal Muscle
A. Musarò and N. Rosenthal

The prolongation of skeletal muscle strength in aging and neuromuscular disease has been the objective of numerous studies employing a variety of approaches. To date however, efforts to prevent or attenuate age- or disease-related muscle degeneration have been largely unsuccessful. Cell-based therapies have been stalled by the difficulty in obtaining sufficient numbers of autologous myoblasts and by inefficient incorporation into host muscle. Administration of growth hormone prevents age-related loss of muscle mass, but has failed to increase muscle strength. In this context, where direct therapeutic approaches to redress the primary disease are still suboptimal, it may be more effective to focus on strategies for improving skeletal muscle function. Experimental models of muscle growth and regeneration have implicated Insulin-like Growth Factor-1 (IGF-1) as an important mediator of anabolic pathways in skeletal muscle cells. Two major IGF-1 transcripts are characterized: the locally acting isoform with an autocrine/paracrine action and the circulating isoform with endocrine effects. The physiological differences between the function of local and circulating isoform of IGF-1 are not completely established. However the selective expression of the muscle-specific IGF-1 isoform avoids hypertrophic effects on distal organs such as the heart, and eliminates risk of possible neoplasms induced by inappropriate high expression levels of circulating IGF-1. In this review we discuss the roles of IGF-1 isoforms in myogenesis and the potential therapeutic role of local IGF-1 isoform on muscle aging and diseases.


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Molecular Mechanisms Regulating mRNA Stability: Physiological and Pathological Significance
Anna M. Knapinska, Patricia Irizarry-Barreto, Sri Adusumalli, Ioannis Androulakis and Gary Brewer

The cytoplasmic level of a messenger RNA, and hence protein, depends not only upon its rates of synthesis, processing, and transport, but its decay rate as well. mRNA decay rates are frequently not static, but vary in response to extracellular stimuli and viral infections. Sequence elements within an mRNA, together with the protein and/or small non-coding RNA factors that bind these elements, dictate its decay rate. Not surprisingly, genetic alterations in mRNA stability can lead to various diseases, including cancer, heart disease, and immune disorders. However, we now have the capacity to alter selective aspects of the mRNA decay machinery by design in order to tune expression of any given gene to desired levels as a means of achieving therapeutic results. Our intent in this review is to introduce the reader to the intricacies of regulated gene expression at the level of mRNA stability, describe the roles of mRNA stability in pathology and drug development, and discuss some recent developments in the field of computational biology that are providing novel tools for understanding specific protein-RNA interactions, which drive the mRNA degradation machinery.