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Genes, Volume 2, Issue 3 (September 2011), Pages 397-660

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Research

Jump to: Review, Other

Open AccessArticle Delineating Chromosomal Breakpoints in Radiation-Induced Papillary Thyroid Cancer
Genes 2011, 2(3), 397-419; doi:10.3390/genes2030397
Received: 23 April 2011 / Revised: 23 May 2011 / Accepted: 16 June 2011 / Published: 28 June 2011
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Abstract
Recurrent translocations are well known hallmarks of many human solid tumors and hematological disorders, where patient- and breakpoint-specific information may facilitate prognostication and individualized therapy. In thyroid carcinomas, the proto-oncogenes RET and NTRK1 are often found to be activated through chromosomal rearrangements. [...] Read more.
Recurrent translocations are well known hallmarks of many human solid tumors and hematological disorders, where patient- and breakpoint-specific information may facilitate prognostication and individualized therapy. In thyroid carcinomas, the proto-oncogenes RET and NTRK1 are often found to be activated through chromosomal rearrangements. However, many sporadic tumors and papillary thyroid carcinomas (PTCs) arising in patients with a history of exposure to elevated levels of ionizing irradiation do not carry these known abnormalities. We developed a rapid scheme to screen tumor cell metaphase spreads and identify candidate genes of tumorigenesis and neoplastic progression for subsequent functional studies. Using a series of overnight fluorescence in situ hybridization (FISH) experiments with pools comprised of bacterial artificial chromosome (BAC) clones, it now becomes possible to rapidly refine breakpoint maps and, within one week, progress from the low resolution Spectral Karyotyping (SKY) maps or Giemsa-banding (G-banding) karyotypes to fully integrated, high resolution physical maps including a list of candiate genes in the critical regions. Full article
(This article belongs to the Special Issue Radiation-Related Cancer 25 Years After Chernobyl)
Open AccessArticle Reassessing Domain Architecture Evolution of Metazoan Proteins: Major Impact of Gene Prediction Errors
Genes 2011, 2(3), 449-501; doi:10.3390/genes2030449
Received: 24 May 2011 / Revised: 14 June 2011 / Accepted: 20 June 2011 / Published: 13 July 2011
Cited by 12 | PDF Full-text (3104 KB) | HTML Full-text | XML Full-text | Correction | Supplementary Files
Abstract
In view of the fact that appearance of novel protein domain architectures (DA) is closely associated with biological innovations, there is a growing interest in the genome-scale reconstruction of the evolutionary history of the domain architectures of multidomain proteins. In such analyses, [...] Read more.
In view of the fact that appearance of novel protein domain architectures (DA) is closely associated with biological innovations, there is a growing interest in the genome-scale reconstruction of the evolutionary history of the domain architectures of multidomain proteins. In such analyses, however, it is usually ignored that a significant proportion of Metazoan sequences analyzed is mispredicted and that this may seriously affect the validity of the conclusions. To estimate the contribution of errors in gene prediction to differences in DA of predicted proteins, we have used the high quality manually curated UniProtKB/Swiss-Prot database as a reference. For genome-scale analysis of domain architectures of predicted proteins we focused on RefSeq, EnsEMBL and NCBI’s GNOMON predicted sequences of Metazoan species with completely sequenced genomes. Comparison of the DA of UniProtKB/Swiss-Prot sequences of worm, fly, zebrafish, frog, chick, mouse, rat and orangutan with those of human Swiss-Prot entries have identified relatively few cases where orthologs had different DA, although the percentage with different DA increased with evolutionary distance. In contrast with this, comparison of the DA of human, orangutan, rat, mouse, chicken, frog, zebrafish, worm and fly RefSeq, EnsEMBL and NCBI’s GNOMON predicted protein sequences with those of the corresponding/orthologous human Swiss-Prot entries identified a significantly higher proportion of domain architecture differences than in the case of the comparison of Swiss-Prot entries. Analysis of RefSeq, EnsEMBL and NCBI’s GNOMON predicted protein sequences with DAs different from those of their Swiss-Prot orthologs confirmed that the higher rate of domain architecture differences is due to errors in gene prediction, the majority of which could be corrected with our FixPred protocol. We have also demonstrated that contamination of databases with incomplete, abnormal or mispredicted sequences introduces a bias in DA differences in as much as it increases the proportion of terminal over internal DA differences. Here we have shown that in the case of RefSeq, EnsEMBL and NCBI’s GNOMON predicted protein sequences of Metazoan species, the contribution of gene prediction errors to domain architecture differences of orthologs is comparable to or greater than those due to true gene rearrangements. We have also demonstrated that domain architecture comparison may serve as a useful tool for the quality control of gene predictions and may thus guide the correction of sequence errors. Our findings caution that earlier genome-scale studies based on comparison of predicted (frequently mispredicted) protein sequences may have led to some erroneous conclusions about the evolution of novel domain architectures of multidomain proteins. A reassessment of the DA evolution of orthologous and paralogous proteins is presented in an accompanying paper [1]. Full article
(This article belongs to the Special Issue Evolution and Structure of Proteins and Proteomes)
Open AccessArticle Chromatin Organization by Repetitive Elements (CORE): A Genomic Principle for the Higher-Order Structure of Chromosomes
Genes 2011, 2(3), 502-515; doi:10.3390/genes2030502
Received: 24 June 2011 / Revised: 21 July 2011 / Accepted: 25 July 2011 / Published: 2 August 2011
Cited by 10 | PDF Full-text (1131 KB) | HTML Full-text | XML Full-text
Abstract
Eukaryotic genomes contain a large amount of DNA repeats (also known as repetitive DNA, repetitive elements, and repetitive sequences). Here, I propose a role of repetitive DNA in the formation of higher-order structures of chromosomes. The central idea of this theory is [...] Read more.
Eukaryotic genomes contain a large amount of DNA repeats (also known as repetitive DNA, repetitive elements, and repetitive sequences). Here, I propose a role of repetitive DNA in the formation of higher-order structures of chromosomes. The central idea of this theory is that chromatin regions with repetitive sequences pair with regions harboring homologous repeats and that such somatic repeat pairing (RP) assembles repetitive DNA chromatin into compact chromosomal domains that specify chromatin folding in a site-directed manner. According to this theory, DNA repeats are not randomly distributed in the genome. Instead, they form a core framework that coordinates the architecture of chromosomes. In contrast to the viewpoint that DNA repeats are genomic ‘junk’, this theory advocates that repetitive sequences are chromatin organizer modules that determine chromatin-chromatin contact points within chromosomes. This novel concept, if correct, would suggest that DNA repeats in the linear genome encode a blueprint for higher-order chromosomal organization. Full article
Open AccessArticle Reassessing Domain Architecture Evolution of Metazoan Proteins: Major Impact of Errors Caused by Confusing Paralogs and Epaktologs
Genes 2011, 2(3), 516-561; doi:10.3390/genes2030516
Received: 7 June 2011 / Revised: 8 July 2011 / Accepted: 19 July 2011 / Published: 2 August 2011
Cited by 5 | PDF Full-text (18993 KB) | HTML Full-text | XML Full-text
Abstract
In the accompanying paper (Nagy, Szláma, Szarka, Trexler, Bányai, Patthy, Reassessing Domain Architecture Evolution of Metazoan Proteins: Major Impact of Gene Prediction Errors) we showed that in the case of UniProtKB/TrEMBL, RefSeq, EnsEMBL and NCBI’s GNOMON predicted protein sequences of Metazoan species [...] Read more.
In the accompanying paper (Nagy, Szláma, Szarka, Trexler, Bányai, Patthy, Reassessing Domain Architecture Evolution of Metazoan Proteins: Major Impact of Gene Prediction Errors) we showed that in the case of UniProtKB/TrEMBL, RefSeq, EnsEMBL and NCBI’s GNOMON predicted protein sequences of Metazoan species the contribution of erroneous (incomplete, abnormal, mispredicted) sequences to domain architecture (DA) differences of orthologous proteins might be greater than those of true gene rearrangements. Based on these findings, we suggest that earlier genome-scale studies based on comparison of predicted (frequently mispredicted) protein sequences may have led to some erroneous conclusions about the evolution of novel domain architectures of multidomain proteins. In this manuscript we examine the impact of confusing paralogous and epaktologous multidomain proteins (i.e., those that are related only through the independent acquisition of the same domain types) on conclusions drawn about DA evolution of multidomain proteins in Metazoa. To estimate the contribution of this type of error we have used as reference UniProtKB/Swiss-Prot sequences from protein families with well-characterized evolutionary histories. We have used two types of paralogy-group construction procedures and monitored the impact of various parameters on the separation of true paralogs from epaktologs on correctly annotated Swiss-Prot entries of multidomain proteins. Our studies have shown that, although public protein family databases are contaminated with epaktologs, analysis of the structure of sequence similarity networks of multidomain proteins provides an efficient means for the separation of epaktologs and paralogs. We have also demonstrated that contamination of protein families with epaktologs increases the apparent rate of DA change and introduces a bias in DA differences in as much as it increases the proportion of terminal over internal DA differences.We have shown that confusing paralogous and epaktologous multidomain proteins significantly increases the apparent rate of DA change in Metazoa and introduces a positional bias in favor of terminal over internal DA changes. Our findings caution that earlier studies based on analysis of datasets of protein families that were contaminated with epaktologs may have led to some erroneous conclusions about the evolution of novel domain architectures of multidomain proteins. A reassessment of the DA evolution of multidomain proteins is presented in an accompanying paper [1]. Full article
(This article belongs to the Special Issue Evolution and Structure of Proteins and Proteomes)
Open AccessArticle Aberrant Single Exon Skipping is not Altered by Age in Exons of NF1, RABAC1, AATF or PCGF2 in Human Blood Cells and Fibroblasts
Genes 2011, 2(3), 562-577; doi:10.3390/genes2030562
Received: 13 June 2011 / Revised: 21 July 2011 / Accepted: 25 July 2011 / Published: 2 August 2011
Cited by 3 | PDF Full-text (1759 KB) | HTML Full-text | XML Full-text
Abstract
In human pre-mRNA splicing, infrequent errors occur resulting in erroneous splice products as shown in a genome-wide approach. One characteristic subgroup consists of products lacking one cassette exon. The noise in the splicing process, represented by those misspliced products, can be increased [...] Read more.
In human pre-mRNA splicing, infrequent errors occur resulting in erroneous splice products as shown in a genome-wide approach. One characteristic subgroup consists of products lacking one cassette exon. The noise in the splicing process, represented by those misspliced products, can be increased by cold shock treatment or by inhibiting the nonsense mediated decay. Here, we investigated whether the splicing noise frequency increases with age in vivo in peripheral bloods cells or in vitro in cultured and aged fibroblasts from healthy donors. Splicing noise frequency was measured for four erroneously skipped NF1 exons and one exon of RABAC1, AATF and PCGF2 by RT-qPCR. Measurements were validated in cultured fibroblasts treated with cold shock or puromycin. Intragenic but not interpersonal differences were detected in splicing noise frequencies in vivo in peripheral blood cells of 11 healthy donors (15 y–85 y) and in in vitro senescent fibroblasts from three further donors. No correlation to the age of the donors was found in the splicing noise frequencies. Our data demonstrates that splicing error frequencies are not altered by age in peripheral blood cells or in vitro aged fibroblasts in the tested exons of the four investigated genes, indicating a high importance of correct splicing in these proliferating aged cells. Full article
Open AccessArticle Reassessing Domain Architecture Evolution of Metazoan Proteins: The Contribution of Different Evolutionary Mechanisms
Genes 2011, 2(3), 578-598; doi:10.3390/genes2030578
Received: 30 June 2011 / Revised: 13 July 2011 / Accepted: 2 August 2011 / Published: 5 August 2011
Cited by 8 | PDF Full-text (10413 KB) | HTML Full-text | XML Full-text
Abstract
In the accompanying papers we have shown that sequence errors of public databases and confusion of paralogs and epaktologs (proteins that are related only through the independent acquisition of the same domain types) significantly distort the picture that emerges from comparison of [...] Read more.
In the accompanying papers we have shown that sequence errors of public databases and confusion of paralogs and epaktologs (proteins that are related only through the independent acquisition of the same domain types) significantly distort the picture that emerges from comparison of the domain architecture (DA) of multidomain Metazoan proteins since they introduce a strong bias in favor of terminal over internal DA change. The issue of whether terminal or internal DA changes occur with greater probability has very important implications for the DA evolution of multidomain proteins since gene fusion can add domains only at terminal positions, whereas domain-shuffling is capable of inserting domains both at internal and terminal positions. As a corollary, overestimation of terminal DA changes may be misinterpreted as evidence for a dominant role of gene fusion in DA evolution. In this manuscript we show that in several recent studies of DA evolution of Metazoa the authors used databases that are significantly contaminated with incomplete, abnormal and mispredicted sequences (e.g., UniProtKB/TrEMBL, EnsEMBL) and/or the authors failed to separate paralogs and epaktologs, explaining why these studies concluded that the major mechanism for gains of new domains in metazoan proteins is gene fusion. In contrast with the latter conclusion, our studies on high quality orthologous and paralogous Swiss-Prot sequences confirm that shuffling of mobile domains had a major role in the evolution of multidomain proteins of Metazoa and especially those formed in early vertebrates. Full article
(This article belongs to the Special Issue Evolution and Structure of Proteins and Proteomes)
Open AccessArticle Protein Folding Absent Selection
Genes 2011, 2(3), 608-626; doi:10.3390/genes2030608
Received: 10 July 2011 / Revised: 5 August 2011 / Accepted: 11 August 2011 / Published: 16 August 2011
Cited by 8 | PDF Full-text (299 KB) | HTML Full-text | XML Full-text
Abstract
Biological proteins are known to fold into specific 3D conformations. However, the fundamental question has remained: Do they fold because they are biological, and evolution has selected sequences which fold? Or is folding a common trait, widespread throughout sequence space? To address [...] Read more.
Biological proteins are known to fold into specific 3D conformations. However, the fundamental question has remained: Do they fold because they are biological, and evolution has selected sequences which fold? Or is folding a common trait, widespread throughout sequence space? To address this question arbitrary, unevolved, random-sequence proteins were examined for structural features found in folded, biological proteins. Libraries of long (71 residue), random-sequence polypeptides, with ensemble amino acid composition near the mean for natural globular proteins, were expressed as cleavable fusions with ubiquitin. The structural properties of both the purified pools and individual isolates were then probed using circular dichroism, fluorescence emission, and fluorescence quenching techniques. Despite this necessarily sparse “sampling” of sequence space, structural properties that define globular biological proteins, namely collapsed conformations, secondary structure, and cooperative unfolding, were found to be prevalent among unevolved sequences. Thus, for polypeptides the size of small proteins, natural selection is not necessary to account for the compact and cooperative folded states observed in nature. Full article
(This article belongs to the Special Issue Evolution and Structure of Proteins and Proteomes)

Review

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Open AccessReview Understanding the Molecular Circuitry of Cell Lineage Specification in the Early Mouse Embryo
Genes 2011, 2(3), 420-448; doi:10.3390/genes2030420
Received: 2 June 2011 / Revised: 24 June 2011 / Accepted: 5 July 2011 / Published: 13 July 2011
Cited by 7 | PDF Full-text (623 KB) | HTML Full-text | XML Full-text
Abstract
Pluripotent stem cells hold great promise for cell-based therapies in regenerative medicine. However, critical to understanding and exploiting mechanisms of cell lineage specification, epigenetic reprogramming, and the optimal environment for maintaining and differentiating pluripotent stem cells is a fundamental knowledge of how [...] Read more.
Pluripotent stem cells hold great promise for cell-based therapies in regenerative medicine. However, critical to understanding and exploiting mechanisms of cell lineage specification, epigenetic reprogramming, and the optimal environment for maintaining and differentiating pluripotent stem cells is a fundamental knowledge of how these events occur in normal embryogenesis. The early mouse embryo has provided an excellent model to interrogate events crucial in cell lineage commitment and plasticity, as well as for embryo-derived lineage-specific stem cells and induced pluripotent stem (iPS) cells. Here we provide an overview of cell lineage specification in the early (preimplantation) mouse embryo focusing on the transcriptional circuitry and epigenetic marks necessary for successive differentiation events leading to the formation of the blastocyst. Full article
(This article belongs to the Special Issue The Early Mouse Embryo as a Model Organism for Reprogramming)
Open AccessReview Comparative Genomics of Erwinia amylovora and Related Erwinia Species—What do We Learn?
Genes 2011, 2(3), 627-639; doi:10.3390/genes2030627
Received: 7 August 2011 / Revised: 30 August 2011 / Accepted: 8 September 2011 / Published: 15 September 2011
Cited by 16 | PDF Full-text (177 KB) | HTML Full-text | XML Full-text
Abstract
Erwinia amylovora, the causal agent of fire blight disease of apples and pears, is one of the most important plant bacterial pathogens with worldwide economic significance. Recent reports on the complete or draft genome sequences of four species in the genus [...] Read more.
Erwinia amylovora, the causal agent of fire blight disease of apples and pears, is one of the most important plant bacterial pathogens with worldwide economic significance. Recent reports on the complete or draft genome sequences of four species in the genus Erwinia, including E. amylovora, E. pyrifoliae, E. tasmaniensis, and E. billingiae, have provided us near complete genetic information about this pathogen and its closely-related species. This review describes in silico subtractive hybridization-based comparative genomic analyses of eight genomes currently available, and highlights what we have learned from these comparative analyses, as well as genetic and functional genomic studies. Sequence analyses reinforce the assumption that E. amylovora is a relatively homogeneous species and support the current classification scheme of E. amylovora and its related species. The potential evolutionary origin of these Erwinia species is also proposed. The current understanding of the pathogen, its virulence mechanism and host specificity from genome sequencing data is summarized. Future research directions are also suggested. Full article
(This article belongs to the Special Issue Genes and Genomes of Plant Pathogenic Bacteria)
Open AccessReview Genes Involved in the Production of Antimetabolite Toxins by Pseudomonas syringae Pathovars
Genes 2011, 2(3), 640-660; doi:10.3390/genes2030640
Received: 16 August 2011 / Revised: 6 September 2011 / Accepted: 6 September 2011 / Published: 15 September 2011
Cited by 4 | PDF Full-text (408 KB) | HTML Full-text | XML Full-text
Abstract
Pseudomonas syringae is pathogenic in a wide variety of plants, causing diseases with economic impacts. Pseudomonas syringae pathovars produce several toxins that can function as virulence factors and contribute to disease symptoms. These virulence factors include antimetabolite toxins, such as tabtoxin, phaseolotoxin [...] Read more.
Pseudomonas syringae is pathogenic in a wide variety of plants, causing diseases with economic impacts. Pseudomonas syringae pathovars produce several toxins that can function as virulence factors and contribute to disease symptoms. These virulence factors include antimetabolite toxins, such as tabtoxin, phaseolotoxin and mangotoxin, which target enzymes in the pathways of amino acid metabolism. The antimetabolite toxins are generally located in gene clusters present in the flexible genomes of specific strains. These gene clusters are typically present in blocks of genes that appear to be integrated into specific sites in the P. syringae core genome. A general overview of the genetic organization and biosynthetic and regulatory functions of these genetic traits of the antimetabolite toxins will be given in the present work. Full article
(This article belongs to the Special Issue Genes and Genomes of Plant Pathogenic Bacteria)

Other

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Open AccessCorrection Correction: Nagy, A., et al. Reassessing Domain Architecture Evolution of Metazoan Proteins: Major Impact of Gene Prediction Errors. Genes 2011, 2, 449-501.
Genes 2011, 2(3), 599-607; doi:10.3390/genes2030599
Received: 9 August 2011 / Accepted: 16 August 2011 / Published: 16 August 2011
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Abstract We found some errors in the published versions of Figure S2, Figure S3 and Figure S8 of our paper [1]. The correct Figures are presented below. [...] Full article
(This article belongs to the Special Issue Evolution and Structure of Proteins and Proteomes)

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