RESUMO
Polystyrene-based nanoferric oxide composite is a representative nanomaterial successfully applied in scale-up water decontamination for arsenic and phosphorus. However, little is available on the effect of solution chemistry (for instance, the coexisting Ca2+) on the long-term performance of the nanocomposite. In this study, we carried out 20 cyclic runs of phosphate adsorption-desorption on a polymer-supported ferric nanocomposite HFO@201. Unexpectedly, an enhanced phosphate removal was observed in the presence of Ca2+, which is quite different from its adverse effect on phosphate capture by granular ferric oxide. Further mechanistic studies revealed that enhanced phosphate removal was mainly realized via the Ca-P coprecipitation inside the networking pores of HFO@201 as well as the possible formation of the multiple Fe-P-Ca-P complex. The complex formation led to a distinct increase in P adsorption, and the coprecipitation, driven by the accumulated OH- in confined pores during phosphate adsorption and alkaline regeneration, favored P removal via the formation of amorphous calcium phosphate (ACP) and hydroxyapatite inside. TEM-EDS spectra indicated that coprecipitation did not occur on the surface of loaded nano-HFO, greatly mitigating its adverse effect on P adsorption on the surface of nano-HFO. Fixed-bed column study showed that the presence of Ca2+ increased the effective treatable volume of HFO@201 toward P-containing influents by â¼70%. This study is believed to shed new insights into the effect of solution chemistry on similar nanocomposites for advanced water treatment.
Assuntos
Poluentes Químicos da Água , Purificação da Água , Adsorção , Compostos Férricos , Concentração de Íons de Hidrogênio , Fosfatos , Poliestirenos , PorosidadeRESUMO
Chromosome 11, although average in size, is one of the most gene- and disease-rich chromosomes in the human genome. Initial gene annotation indicates an average gene density of 11.6 genes per megabase, including 1,524 protein-coding genes, some of which were identified using novel methods, and 765 pseudogenes. One-quarter of the protein-coding genes shows overlap with other genes. Of the 856 olfactory receptor genes in the human genome, more than 40% are located in 28 single- and multi-gene clusters along this chromosome. Out of the 171 disorders currently attributed to the chromosome, 86 remain for which the underlying molecular basis is not yet known, including several mendelian traits, cancer and susceptibility loci. The high-quality data presented here--nearly 134.5 million base pairs representing 99.8% coverage of the euchromatic sequence--provide scientists with a solid foundation for understanding the genetic basis of these disorders and other biological phenomena.
Assuntos
Cromossomos Humanos Par 11 , Análise de Sequência de DNA , DNA , Expressão Gênica , Genes , Humanos , Dados de Sequência Molecular , Mapeamento Físico do Cromossomo , Receptores Odorantes/genéticaRESUMO
We present a global comparison of differences in content of segmental duplication between human and chimpanzee, and determine that 33% of human duplications (> 94% sequence identity) are not duplicated in chimpanzee, including some human disease-causing duplications. Combining experimental and computational approaches, we estimate a genomic duplication rate of 4-5 megabases per million years since divergence. These changes have resulted in gene expression differences between the species. In terms of numbers of base pairs affected, we determine that de novo duplication has contributed most significantly to differences between the species, followed by deletion of ancestral duplications. Post-speciation gene conversion accounts for less than 10% of recent segmental duplication. Chimpanzee-specific hyperexpansion (> 100 copies) of particular segments of DNA have resulted in marked quantitative differences and alterations in the genome landscape between chimpanzee and human. Almost all of the most extreme differences relate to changes in chromosome structure, including the emergence of African great ape subterminal heterochromatin. Nevertheless, base per base, large segmental duplication events have had a greater impact (2.7%) in altering the genomic landscape of these two species than single-base-pair substitution (1.2%).
Assuntos
Evolução Molecular , Duplicação Gênica , Genoma Humano , Genômica , Pan troglodytes/genética , Animais , Cromossomos de Mamíferos/genética , Biologia Computacional , Conversão Gênica , Humanos , Especificidade da Espécie , Fatores de TempoRESUMO
Complex eukaryotic genomes are now being sequenced at an accelerated pace primarily using whole-genome shotgun (WGS) sequence assembly approaches. WGS assembly was initially criticized because of its perceived inability to resolve repeat structures within genomes. Here, we quantify the effect of WGS sequence assembly on large, highly similar repeats by comparison of the segmental duplication content of two different human genome assemblies. Our analysis shows that large (> 15 kilobases) and highly identical (> 97%) duplications are not adequately resolved by WGS assembly. This leads to significant reduction in genome length and the loss of genes embedded within duplications. Comparable analyses of mouse genome assemblies confirm that strict WGS sequence assembly will oversimplify our understanding of mammalian genome structure and evolution; a hybrid strategy using a targeted clone-by-clone approach to resolve duplications is proposed.
Assuntos
Duplicação Gênica , Genoma Humano , Genômica/métodos , Mapeamento Físico do Cromossomo/métodos , Análise de Sequência de DNA/métodos , Animais , Cromossomos Humanos/genética , Biologia Computacional/métodos , Genes Duplicados/genética , Humanos , Camundongos , Sensibilidade e Especificidade , Alinhamento de SequênciaRESUMO
An understanding of how centromeric transition regions are organized is a critical aspect of chromosome structure and function; however, the sequence context of these regions has been difficult to resolve on the basis of the draft genome sequence. We present a detailed analysis of the structure and assembly of all human pericentromeric regions (5 megabases). Most chromosome arms (35 out of 43) show a gradient of dwindling transcriptional diversity accompanied by an increasing number of interchromosomal duplications in proximity to the centromere. At least 30% of the centromeric transition region structure originates from euchromatic gene-containing segments of DNA that were duplicatively transposed towards pericentromeric regions at a rate of six-seven events per million years during primate evolution. This process has led to the formation of a minimum of 28 new transcripts by exon exaptation and exon shuffling, many of which are primarily expressed in the testis. The distribution of these duplicated segments is nonrandom among pericentromeric regions, suggesting that some regions have served as preferential acceptors of euchromatic DNA.
Assuntos
Centrômero/química , Centrômero/genética , Evolução Molecular , Genoma Humano , Animais , Composição de Bases , DNA/química , DNA/genética , Eucromatina/química , Eucromatina/genética , Etiquetas de Sequências Expressas , Duplicação Gênica , Humanos , RNA Mensageiro/análise , RNA Mensageiro/genética , Transcrição Gênica/genéticaRESUMO
Chromosome 5 is one of the largest human chromosomes and contains numerous intrachromosomal duplications, yet it has one of the lowest gene densities. This is partially explained by numerous gene-poor regions that display a remarkable degree of noncoding conservation with non-mammalian vertebrates, suggesting that they are functionally constrained. In total, we compiled 177.7 million base pairs of highly accurate finished sequence containing 923 manually curated protein-coding genes including the protocadherin and interleukin gene families. We also completely sequenced versions of the large chromosome-5-specific internal duplications. These duplications are very recent evolutionary events and probably have a mechanistic role in human physiological variation, as deletions in these regions are the cause of debilitating disorders including spinal muscular atrophy.
Assuntos
Cromossomos Humanos Par 5/genética , Análise de Sequência de DNA , Animais , Composição de Bases , Caderinas/genética , Sequência Conservada/genética , Duplicação Gênica , Genes/genética , Doenças Genéticas Inatas/genética , Genômica , Humanos , Interleucinas/genética , Dados de Sequência Molecular , Atrofia Muscular Espinal/genética , Pan troglodytes/genética , Mapeamento Físico do Cromossomo , Pseudogenes/genética , Sintenia/genética , Vertebrados/genéticaRESUMO
Human chromosome 16 features one of the highest levels of segmentally duplicated sequence among the human autosomes. We report here the 78,884,754 base pairs of finished chromosome 16 sequence, representing over 99.9% of its euchromatin. Manual annotation revealed 880 protein-coding genes confirmed by 1,670 aligned transcripts, 19 transfer RNA genes, 341 pseudogenes and three RNA pseudogenes. These genes include metallothionein, cadherin and iroquois gene families, as well as the disease genes for polycystic kidney disease and acute myelomonocytic leukaemia. Several large-scale structural polymorphisms spanning hundreds of kilobase pairs were identified and result in gene content differences among humans. Whereas the segmental duplications of chromosome 16 are enriched in the relatively gene-poor pericentromere of the p arm, some are involved in recent gene duplication and conversion events that are likely to have had an impact on the evolution of primates and human disease susceptibility.
Assuntos
Cromossomos Humanos Par 16/genética , Duplicação Gênica , Mapeamento Físico do Cromossomo , Animais , Genes/genética , Genômica , Heterocromatina/genética , Humanos , Dados de Sequência Molecular , Polimorfismo Genético/genética , Análise de Sequência de DNA , Sintenia/genéticaRESUMO
The effect of Er on microstructure and mechanical properties of the 5052 aluminum alloy with a big width-to-thickness ratio was investigated by a metallurgical microscope, scanning electron microscope and tensile testing machine. The results showed that the precipitates were slightly refined after Er addition and Al3Fe was transformed into Al6Fe and AlEr with/without a small amount of Fe or Si. The effect of Er on grain refinement was related to its content. When Er content was lower or higher than 0.4%, the grain would coarsen. Homogenization could refine the grain by controlling Er content and distribution in the Al matrix. Long time homogenization at high temperature would significantly reduce the strength of the 5052 aluminum alloy and 5052 aluminum alloys with low Er content, but help to improve the plasticity of those with high Er content. The ultimate tensile strength, yield strength and elongation of the as-cast 5052 aluminum alloy were 197 MPa, 117 MPa and 22.5% respectively. The strength was the highest, when Er content was 0.4 wt. % and the elongation was the best at 0.1 wt. % Er content.
RESUMO
BACKGROUND: Housekeeping genes (HKG) are constitutively expressed in all tissues while tissue-enriched genes (TEG) are expressed at a much higher level in a single tissue type than in others. HKGs serve as valuable experimental controls in gene and protein expression experiments, while TEGs tend to represent distinct physiological processes and are frequently candidates for biomarkers or drug targets. The genomic features of these two groups of genes expressed in opposing patterns may shed light on the mechanisms by which cells maintain basic and tissue-specific functions. RESULTS: Here, we generate gene expression profiles of 42 normal human tissues on custom high-density microarrays to systematically identify 1,522 HKGs and 975 TEGs and compile a small subset of 20 housekeeping genes which are highly expressed in all tissues with lower variance than many commonly used HKGs. Cross-species comparison shows that both the functions and expression patterns of HKGs are conserved. TEGs are enriched with respect to both segmental duplication and copy number variation, while no such enrichment is observed for HKGs, suggesting the high expression of HKGs are not due to high copy numbers. Analysis of genomic and epigenetic features of HKGs and TEGs reveals that the high expression of HKGs across different tissues is associated with decreased nucleosome occupancy at the transcription start site as indicated by enhanced DNase hypersensitivity. Additionally, we systematically and quantitatively demonstrated that the CpG islands' enrichment in HKGs transcription start sites (TSS) and their depletion in TEGs TSS. Histone methylation patterns differ significantly between HKGs and TEGs, suggesting that methylation contributes to the differential expression patterns as well. CONCLUSION: We have compiled a set of high quality HKGs that should provide higher and more consistent expression when used as references in laboratory experiments than currently used HKGs. The comparison of genomic features between HKGs and TEGs shows that HKGs are more conserved than TEGs in terms of functions, expression pattern and polymorphisms. In addition, our results identify chromatin structure and epigenetic features of HKGs and TEGs that are likely to play an important role in regulating their strikingly different expression patterns.
Assuntos
Epigênese Genética , Perfilação da Expressão Gênica , Genoma Humano , Cromatina , Sequência Conservada , Ilhas de CpG , Metilação de DNA , Dosagem de Genes , Duplicação Gênica , Regulação da Expressão Gênica , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Sítio de Iniciação de TranscriçãoRESUMO
Composites of 7055 aluminum (Al) matrix reinforced with SiC particles were prepared using the spray deposition method. The volume fraction of the phase reinforced with SiC particles was 17%. The effect of the introduction of SiC particles on the deposited microstructure and properties of the composites was studied in order to facilitate the follow-up study. The structure and element enrichment zone of spray-deposited SiCp/7055 Al matrix composites were studied by Optical Microscope (OM), X-ray diffraction (XRD), Scanning Electronic Microscopy (SEM) and Transmission electron microscopy (TEM). The results show that the reinforcement phases of the SiC particles were uniformly distributed on the macro and micro levels, and a few SiC particles were segregated into annular closed regions. C and Si on the surface of SiC particles diffused to the Al matrix. The distribution of the two elements was gradient weakening with SiC particles as the center, and the enrichment zones of Si, Mg and Cu formed in the middle of the closed annular area of a few SiC particles. The enrichment zones were mainly composed of alpha-Al, SiC, Al2CuMg, Al2Cu and MgZn2. AlCu and AlMgCu phase precipitate on the surface of the SiC particles, beside the particle boundary, and had the characteristics of preferred nucleation. They tended to grow at the edges and corners of SiC particles. It was observed that the formation of nanoparticles in the alloy had a pinning effect on dislocations. The different cooling rates of the SiC particles and the Al matrix led to different aluminum liquid particle sizes, ranging from 20 to 150 µm. In the region surrounded by SiC particles, the phenomenon of large particles extruding small particles was widespread. Tearing edges and cracks continued to propagate around the SiC particles, increasing their propagation journey and delaying the fracture of the materials.
RESUMO
BACKGROUND: It has been suggested that chromosomal rearrangements harbor the molecular footprint of the biological phenomena which they induce, in the form, for instance, of changes in the sequence divergence rates of linked genes. So far, all the studies of these potential associations have focused on the relationship between structural changes and the rates of evolution of single-copy DNA and have tried to exclude segmental duplications (SDs). This is paradoxical, since SDs are one of the primary forces driving the evolution of structure and function in our genomes and have been linked not only with novel genes acquiring new functions, but also with overall higher DNA sequence divergence and major chromosomal rearrangements. RESULTS: Here we take the opposite view and focus on SDs. We analyze several of the features of SDs, including the rates of intraspecific divergence between paralogous copies of human SDs and of interspecific divergence between human SDs and chimpanzee DNA. We study how divergence measures relate to chromosomal rearrangements, while considering other factors that affect evolutionary rates in single copy DNA. CONCLUSION: We find that interspecific SD divergence behaves similarly to divergence of single-copy DNA. In contrast, old and recent paralogous copies of SDs do present different patterns of intraspecific divergence. Also, we show that some relatively recent SDs accumulate in regions that carry inversions in sister lineages.
Assuntos
Evolução Molecular , Duplicação Gênica , Rearranjo Gênico , Genoma Humano , Pan troglodytes/genética , Animais , Centrômero/genética , Biologia Computacional , Bases de Dados de Ácidos Nucleicos , Especiação Genética , Variação Genética , Humanos , Especificidade da Espécie , Telômero/genéticaRESUMO
Innovative strategies are needed to combat drug resistance associated with methicillin-resistant Staphylococcus aureus (MRSA). Here, we investigate the potential of wall teichoic acid (WTA) biosynthesis inhibitors as combination agents to restore ß-lactam efficacy against MRSA. Performing a whole-cell pathway-based screen, we identified a series of WTA inhibitors (WTAIs) targeting the WTA transporter protein, TarG. Whole-genome sequencing of WTAI-resistant isolates across two methicillin-resistant Staphylococci spp. revealed TarG as their common target, as well as a broad assortment of drug-resistant bypass mutants mapping to earlier steps of WTA biosynthesis. Extensive in vitro microbiological analysis and animal infection studies provide strong genetic and pharmacological evidence of the potential effectiveness of WTAIs as anti-MRSA ß-lactam combination agents. This work also highlights the emerging role of whole-genome sequencing in antibiotic mode-of-action and resistance studies.
Assuntos
Antibacterianos/farmacologia , Parede Celular/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Ácidos Teicoicos/biossíntese , beta-Lactamas/metabolismo , Substituição de Aminoácidos , Antibacterianos/química , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Avaliação Pré-Clínica de Medicamentos , Farmacorresistência Bacteriana , Genoma Bacteriano , Staphylococcus aureus Resistente à Meticilina/genética , Testes de Sensibilidade Microbiana , Concentração Osmolar , Fenótipo , Análise de Sequência de DNA , Ácidos Teicoicos/química , Temperatura , beta-Lactamas/químicaRESUMO
Modern medicine is founded on the discovery of penicillin and subsequent small molecules that inhibit bacterial peptidoglycan (PG) and cell wall synthesis. However, the discovery of new chemically and mechanistically distinct classes of PG inhibitors has become exceedingly rare, prompting speculation that intracellular enzymes involved in PG precursor synthesis are not 'druggable' targets. Here, we describe a ß-lactam potentiation screen to identify small molecules that augment the activity of ß-lactams against methicillin-resistant Staphylococcus aureus (MRSA) and mechanistically characterize a compound resulting from this screen, which we have named murgocil. We provide extensive genetic, biochemical, and structural modeling data demonstrating both in vitro and in whole cells that murgocil specifically inhibits the intracellular membrane-associated glycosyltransferase, MurG, which synthesizes the lipid II PG substrate that penicillin binding proteins (PBPs) polymerize and cross-link into the cell wall. Further, we demonstrate that the chemical synergy and cidality achieved between murgocil and the ß-lactam imipenem is mediated through MurG dependent localization of PBP2 to the division septum. Collectively, these data validate our approach to rationally identify new target-specific bioactive ß-lactam potentiation agents and demonstrate that murgocil now serves as a highly selective and potent chemical probe to assist our understanding of PG biosynthesis and cell wall biogenesis across Staphylococcal species.
Assuntos
Antibacterianos/farmacologia , Proteínas da Membrana Bacteriana Externa/antagonistas & inibidores , N-Acetilglucosaminiltransferases/antagonistas & inibidores , Peptidoglicano Glicosiltransferase/metabolismo , Pirazóis/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Esteróis/farmacologia , Simulação por Computador , Farmacorresistência Bacteriana , Inibidores Enzimáticos/farmacologia , Humanos , Microscopia de Fluorescência , Modelos Moleculares , Pirazóis/química , Staphylococcus aureus/enzimologia , Esteróis/químicaRESUMO
Vascular-targeting antiangiogenic therapy (VTAT) of cancer can be advantageous over conventional tumor cell targeted cancer therapy if an appropriate target is found. Our hypothesis is that endoglin (ENG; CD105) is an excellent target in VTAT. ENG is selectively expressed on vascular and lymphatic endothelium in tumors. This allows us to target both tumor-associated vasculature and lymphatic vessels to suppress tumor growth and metastasis. ENG is essential for angiogenesis/vascular development and a co-receptor of TGF-ß. Our studies of selected anti-ENG monoclonal antibodies (mAbs) in several animal models and in vitro studies support our hypothesis. These mAbs and/or their immunoconjugates (immunotoxins and radioimmunoconjugates) induced regression of preformed tumors as well as inhibited formation of new tumors. In addition, they suppressed metastasis. Several mechanisms were involved in the suppressive activity of the naked (unconjugated) anti-ENG mAbs. These include direct growth suppression of proliferating endothelial cells, induction of apoptosis, ADCC (antibody-dependent cell-mediated cytotoxicity) and induction of T cell immunity. To facilitate clinical application, we generated a human/mouse chimeric anti-ENG mAb termed c-SN6j and performed studies of pharmacokinetics, toxicology and immunogenicity of c-SN6j in nonhuman primates. No significant toxicity was detected by several criteria and minimal immune response to the murine part of c-SN6j was detected after multiple i.v. injections. The results support our hypothesis that c-SN6j can be safely administered in cancer patients. This hypothesis is supported by the ongoing phase 1 clinical trial of c-SN6j (also known as TRC105) in patients with advanced or metastatic solid cancer in collaboration with Tracon Pharma and several oncologists (NCT00582985).
Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Antígenos CD/metabolismo , Imunoconjugados/farmacologia , Imunotoxinas/farmacologia , Neoplasias/tratamento farmacológico , Receptores de Superfície Celular/metabolismo , Animais , Ensaios Clínicos como Assunto , Endoglina , Humanos , Imunoconjugados/imunologia , Imunotoxinas/imunologia , Metástase Neoplásica , Neoplasias/irrigação sanguínea , Neoplasias/metabolismoRESUMO
Detailed analyses of the clone-based genome assembly reveal that the recent duplication content of mouse (4.94%) is now comparable to that of human (5.5%), in contrast to previous estimates from the whole-genome shotgun sequence assembly. However, the architecture of mouse and human genomes differs markedly: most mouse duplications are organized into discrete clusters of tandem duplications that show depletion of genes and transcripts and enrichment of long interspersed nuclear element (LINE) and long terminal repeat (LTR) retroposons. We assessed copy number variation of the C57BL/6J duplicated regions within 15 mouse strains previously used for genetic association studies, sequencing and the Mouse Phenome Project. We determined that over 60% of these base pairs are polymorphic among the strains (on average, there was 20 Mb of copy-number-variable DNA between different mouse strains). Our data suggest that different mouse strains show comparable, if not greater, copy number polymorphism when compared to human; however, such variation is more locally restricted. We show large and complex patterns of interstrain copy number variation restricted to large gene families associated with spermatogenesis, pregnancy, viviparity, pheromone signaling and immune response.
Assuntos
Dosagem de Genes , Duplicação Gênica , Variação Genética , Camundongos Endogâmicos/genética , Animais , Animais Recém-Nascidos , Perfilação da Expressão Gênica , Genoma , Elementos Nucleotídeos Longos e Dispersos/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sequência com Séries de Oligonucleotídeos , Sequências Repetidas Terminais/genéticaRESUMO
Human segmental duplications are hotspots for nonallelic homologous recombination leading to genomic disorders, copy-number polymorphisms and gene and transcript innovations. The complex structure and history of these regions have precluded a global evolutionary analysis. Combining a modified A-Bruijn graph algorithm with comparative genome sequence data, we identify the origin of 4,692 ancestral duplication loci and use these to cluster 437 complex duplication blocks into 24 distinct groups. The sequence-divergence data between ancestral-derivative pairs and a comparison with the chimpanzee and macaque genome support a 'punctuated' model of evolution. Our analysis reveals that human segmental duplications are frequently organized around 'core' duplicons, which are enriched for transcripts and, in some cases, encode primate-specific genes undergoing positive selection. We hypothesize that the rapid expansion and fixation of some intrachromosomal segmental duplications during great-ape evolution has been due to the selective advantage conferred by these genes and transcripts embedded within these core duplications.
Assuntos
Cromossomos Humanos/genética , Evolução Molecular , Duplicação Gênica , Ligação Genética , Genoma Humano , Modelos Genéticos , Animais , Simulação por Computador , Dosagem de Genes , Variação Genética , Humanos , Hibridização in Situ Fluorescente , Pan troglodytes/genética , Filogenia , Seleção GenéticaRESUMO
The goals of the human genome project did not include sequencing of the heterochromatic regions. We describe here an initial sequence of 1.1 Mb of the short arm of human chromosome 21 (HSA21p), estimated to be 10% of 21p. This region contains extensive euchromatic-like sequence and includes on average one transcript every 100 kb. These transcripts show multiple inter- and intrachromosomal copies, and extensive copy number and sequence variability. The sequencing of the "heterochromatic" regions of the human genome is likely to reveal many additional functional elements and provide important evolutionary information.
Assuntos
Cromossomos Humanos Par 21 , Eucromatina/genética , Polimorfismo Genético , Mapeamento de Sequências Contíguas , Genoma Humano , Humanos , Hibridização in Situ FluorescenteRESUMO
Compared with other sequenced animal genomes, human segmental duplications appear larger, more interspersed, and disproportionately represented as high-sequence identity alignments. Global sequence divergence estimates of human duplications have suggested an expansion relatively recently during hominoid evolution. Based on primate comparative sequence analysis of 37 unique duplication-transition regions, we establish a molecular clock for their divergence that shows a significant increase in their effective substitution rate when compared with unique genomic sequence. Fluorescent in situ hybridization (FISH) analyses from 1053 random nonhuman primate BACs indicate that great-ape species have been enriched for interspersed segmental duplications compared with representative Old World and New World monkeys. These findings support computational analyses that show a 12-fold excess of recent (>98%) intrachromosomal duplications when compared with duplications between nonhomologous chromosomes. These architectural shifts in genomic structure and elevated substitution rates have important implications for the emergence of new genes, gene-expression differences, and structural variation among humans and great apes.
Assuntos
Pareamento Incorreto de Bases , Cromossomos , Duplicação Gênica , Pan troglodytes/genética , Papio/genética , Animais , Pareamento de Bases , Sequência de Bases , Bases de Dados Factuais , Evolução Molecular , Genoma Humano , Hominidae/genética , Humanos , Hibridização in Situ Fluorescente , Dados de Sequência Molecular , Análise de Sequência de DNA , Homologia de Sequência do Ácido NucleicoRESUMO
BACKGROUND: Evolutionary centromere repositioning and human analphoid neocentromeres occurring in clinical cases are, very likely, two stages of the same phenomenon whose properties still remain substantially obscure. Chromosome 13 is the chromosome with the highest number of neocentromeres. We reconstructed the mammalian evolutionary history of this chromosome and characterized two human neocentromeres at 13q21, in search of information that could improve our understanding of the relationship between evolutionarily new centromeres, inactivated centromeres, and clinical neocentromeres. RESULTS: Chromosome 13 evolution was studied, using FISH experiments, across several diverse superordinal phylogenetic clades spanning >100 million years of evolution. The analysis revealed exceptional conservation among primates (hominoids, Old World monkeys, and New World monkeys), Carnivora (cat), Perissodactyla (horse), and Cetartiodactyla (pig). In contrast, the centromeres in both Old World monkeys and pig have apparently repositioned independently to a central location (13q21). We compared these results to the positions of two human 13q21 neocentromeres using chromatin immunoprecipitation and genomic microarrays. CONCLUSION: We show that a gene-desert region at 13q21 of approximately 3.9 Mb in size possesses an inherent potential to form evolutionarily new centromeres over, at least, approximately 95 million years of mammalian evolution. The striking absence of genes may represent an important property, making the region tolerant to the extensive pericentromeric reshuffling during subsequent evolution. Comparison of the pericentromeric organization of chromosome 13 in four Old World monkey species revealed many differences in sequence organization. The region contains clusters of duplicons showing peculiar features.