Keio Mutation Database (KMDB) for human disease gene mutations

A database of mutations in human disease-causing genes has been constructed and named as Keio Mutation Database (KMDB). This KMDB utilizes a database software called MutationView which was designed to compile various mutation data and to provide graphical presentation of data analysis. Currently, the KMDB accommodates mutation data of 38 different genes for 35 different diseases which are involved in eye, heart, ear and brain. These KMDBs are accessible through http://mutview.dmb.med.keio.ac.jp with advanced internet browsers.     

Keio Mutation Database for eye disease genes (KMeyeDB).

A database of mutations in human eye disease genes has been constructed. This KMeyeDB employs a database software MutationView which provides graphical data presentation and analysis as a smooth user-interface. Currently, the KMeyeDB contains mutation data of 16 different genes for 18 eye diseases. The KMeyeDB is accessible through http://mutview.dmb.med.keio.ac.jp with advanced internet browsers.     

Highly expressed and alien genes of the Synechocystis genome

Comparisons of codon frequencies of genes to several gene classes are used to characterize highly expressed and alien genes on the SYNECHOCYSTIS: PCC6803 genome. The primary gene classes include the ensemble of all genes (average gene), ribosomal protein (RP) genes, translation processing factors (TF) and genes encoding chaperone/degradation proteins (CH). A gene is predicted highly expressed (PHX) if its codon usage is close to that of the RP/TF/CH standards but strongly deviant from the average gene. Putative alien (PA) genes are those for which codon usage is significantly different from all four classes of gene standards. In SYNECHOCYSTIS:, 380 genes were identified as PHX. The genes with the highest predicted expression levels include many that encode proteins vital for photosynthesis. Nearly all of the genes of the RP/TF/CH gene classes are PHX. The principal glycolysis enzymes, which may also function in CO(2) fixation, are PHX, while none of the genes encoding TCA cycle enzymes are PHX. The PA genes are mostly of unknown function or encode transposases. Several PA genes encode polypeptides that function in lipopolysaccharide biosynthesis. Both PHX and PA genes often form significant clusters (operons). The proteins encoded by PHX and PA genes are described with respect to functional classifications, their organization in the genome and their stoichiometry in multi-subunit complexes.     

Fusion genes in leukemia: an emerging network

The molecular analysis of recurring chromosome rearrangements, especially of translocations and inversions, has provided us with valuable insight into the pathogenesis of hematological malignancies. Many translocations result in the fusion of genes located at the translocation breakpoints. In recent years we have witnessed a rapid rise in the number of chromosome translocations in leukemias being characterized at the molecular level. However, the number of genes being newly identified as translocation fusion genes has not risen at the same pace. This is due to the fact that several genes are involved in more than one translocation forming fusion genes with a number of other partner genes. Not only does one find star-shaped topologies, with one gene forming fusions with several others (e.g. ETV6/PDGFRB, ETV6/JAK2, ETV6/ABL etc.), but also networks connecting several genes with more than one fusion partner (e.g. ETV6/RUNX1 (AML1), RUNX1/CBFA2T1 (ETO), ETV6/EVI1, RUNX1/EVI1, ETV6/ABL, BCR/ABL). The emergence of such networks with the "recycling" of genes in new fusion combinations suggests that there is a rather limited number of genes which can be altered to cause leukemia.     

Patterns of divergence among conifer ESTs and polymorphism in Pinus sylvestris identify putative selective sweeps

Finding genes that are under positive selection is a difficult task, especially in non-model organisms. Here, we have analyzed expressed sequence tag (EST) data from 4 species (Pinus pinaster, Pinus taeda, Picea glauca, and Pseudotsuga menziesii) to investigate selection patterns during their evolution and to identify genes likely to be under positive selection. To confirm selection, population samples of these genes have been sequenced in Pinus sylvestris, a species that was not included in the EST data set. The estimates of branch-specific Ka/Ks (nonsynonymous/synonymous substitution rates) across all genes in the EST data set were similar or smaller than estimates from other higher plant species. There was no evidence for the traditional indication of positive selection, Ka/Ks above 1. However, several lines of evidence based on polymorphism patterns suggest that genes with high Ka/Ks (0.20-0.52) in the EST data set are in fact more affected by positive selection in P. sylvestris than genes with low Ka/Ks (0.01-0.04). The high Ka/Ks genes have a lower level of polymorphism and more negative Tajima's D than the low Ka/Ks genes. Further, in the high Ka/Ks group, the Hudson-Kreitman-Aguade test is significant. This suggests that the EST data set is a good starting point for finding genes under positive selection in conifers and that even moderate Ka/Ks values could be indicative of selection. A group of 5 genes with high Ka/Ks collectively show evidence for positive selection within P. sylvestris.     

网隙裂粉韧革菌不同生长时期转录组分析

网隙裂粉韧革菌Amylostereum areolatum是松树蜂Sirex noctilio携带并传播的共生真菌,与松树蜂之间存在严格的互利共生关系,其正常生长发育是松树蜂完成生活史的关键因子之一。为研究该共生菌生长发育的相关机制,我们对共生菌菌丝最大生长速率前期（7d）和后期（12d）样本进行转录组测序,在转录水平上分析差异表达基因在共生菌生长发育中的功能。结果显示,两个不同生长时期共有差异基因2 425个,其中在共生菌最大生长速率前期样本中上调的基因有946个,下调的有1 479个。Nr注释和GO功能富集分析结果表明,共生菌最大生长速率前期的差异表达基因主要与碳水化合物代谢、蛋白质合成以及水解酶活性相关。Pathway富集分析表明,差异表达基因显著富集在糖酵解/糖异生代谢通路上,并且这些基因在共生菌最大生长速率前期的样本中显著上调,表明其可能在网隙裂粉韧革菌的生长发育中发挥重要作用。通过分析两个不同生长时期共生菌基因的表达情况,挖掘参与共生菌生长发育的关键基因,旨在为探索松树蜂与其共生菌的互利共生机制提供理论基础。     

Molecular characterization and genetic mapping of two clusters of genes encoding chlorophyll a/b-binding proteins in Lycopersicon esculentum (tomato)

We have constructed a tomato genomic library in the λ Charon 4 phage vector. The library was screened with a pea cDNA probe encoding a chlorophyll a/b-binding protein (CAB), and several recombinant phages containing tomato CAB genes were isolated and characterized by restriction mapping, heteroduplex analysis and nucleotide sequencing. Two phages with overlapping segments of the tomato genome contain a total of four CAB genes, all arranged in tandem. A third phage contains three CAB genes, two arranged in tandem and one in opposite orientation, and an additional, truncated CAB gene. Genetic mapping experiments showed that the four CAB genes on the first two phages belong to a locus, previously designated Cab-1, on chromosome 2. The CAB genes from the third phage belong to the Cab-3 locus on chromosome 3. Complete sequence determination of two CAB genes, one from each locus, and additional sequence determination of about 50% of each of the other five CAB genes showed that each gene within a CAB locus is more similar to other CAB genes in the same locus than it is to the CAB genes from the second locus. Furthermore, the polypeptides encoded by Cab-1 genes diverge significantly from those encoded by Cab-3 genes in the domains of transit peptide and the N terminus of the mature polypeptide but are essentially identical in the rest of the sequence.     

药用野生稻GBSS基因的系统发育及组织特异性表达

淀粉作为主要的碳水化合物在储藏能量方面发挥至关重要的作用。颗粒结合型淀粉合酶(GBSS)与直链淀粉的合成息息相关。尽管该酶的编码基因已在许多栽培植物中被分离和确定, 但有关它们在作物野生近缘种中的序列分歧和表达的研究却相对较少。该研究以药用野生稻(Oryza officinalis)为研究对象, 定性和定量地分析了GBSS编码基因的序列特点、与其它植物同源基因的进化关系以及在叶和种子中的表达情况。系统发育分析表明, 该酶在禾本科植物中分别由GBSSI和GBSSII基因编码。在药用野生稻中, 这2种基因所编码蛋白的氨基酸序列一致性为62%, 并且它们在不同器官内呈现时空分化表达, 其中GBSSI在种子中超强表达, GBSSII则主要在叶片表达。     

Isochores,GC3 and mutation biases in the human genome

In this work we re-examined the hypothesis that the variation in GC content in the human genome is due to different regional mutational biases. For this purpose we inferred the mutational pattern by using mutation databases that are available for many genes associated with human genetic diseases. The assumption of this approach is that such mutations reflect the actual frequency distribution of mutations as they arise in the population. Four classes of genes, classified according to their GC₃ level, were included in this study: GC₃-poor genes (GC₃<45%), genes with intermediate GC₃ content (45%3<60%), GC₃-rich genes (60%3<75%) and very GC₃-rich genes (GC₃>75%). Our results show that most genes are under AT mutational biases, with very little variation compared to the expectations of neutral GC level. It is noteworthy that the mutational patterns in the GC₃-rich genes do not appear to account for their GC₃-richness. Instead, GC₃-rich and very GC₃-rich genes exhibit patterns of mutations that yield expectations of neutral GC₃ content that are much lower than their actual GC₃.     

Allelic immunoglobulin VH genes in two mouse strains: possible germline gene recombination.

The nucleotide sequence of two germline immunoglobulin heavy chain variable region (VH) genes of mouse BALB/c origin was determined. These two genes are highly homologous to each other. They both have the unusual codon CCT for proline at position 7, which so far has been found only in a specific set of VH genes, called the NPb family. We show that the two VH genes belong to this set. One of our BALB/c genes, VH124, is more homologous to a C57BL/6 NPb VH gene than to any BALB/c VH gene, and we propose that these two genes are alleles. A comparison of the substitutions between these two genes with published sequences of all other BALB/c and C57BL/6 NPb VH genes reveals evidence for past homologous recombination events between related germline VH genes Homologous recombination may play an important role in the diversification of germline immunoglobulin VH genes.     

The chicken delta-crystallin gene family. Two genes of similar structure in close chromosomal approximation

delta-Crystallin is a major protein product of the differentiated chicken lens. We have isolated two, non-allelic delta-crystallin genes using a recombinant bacteriophage/chicken genomic DNA library. There appear to be only these two delta-crystallin genes in the haploid chicken genome. Southern hybridization and R-loop analyses indicate that the two genes are oriented on the chromosome with similar 5'-3' polarity. delta 1, arbitrarily designated as the directionally 5' of the two genes, is 6.7 kilobases in length, while delta 2 is 9.2 kilobases. The two delta-crystallin genes are about 4.2 kilobases apart. Structurally, both genes are arranged in a similar and characteristic pattern of 17 exons/16 introns, as judged by electron microscopy. The delta-crystallin gene locus represents a simple model for the study of structural co-evolution and/or functional co-expression of two related genes within a developmentally modulated region of the genome.     

药用野生稻GBSS基因的系统发育及组织特异性表达

淀粉作为主要的碳水化合物在储藏能量方面发挥至关重要的作用。颗粒结合型淀粉合酶(GBSS)与直链淀粉的合成息息相关。尽管该酶的编码基因已在许多栽培植物中被分离和确定, 但有关它们在作物野生近缘种中的序列分歧和表达的研究却相对较少。该研究以药用野生稻(Oryza officinalis)为研究对象, 定性和定量地分析了GBSS编码基因的序列特点、与其它植物同源基因的进化关系以及在叶和种子中的表达情况。系统发育分析表明, 该酶在禾本科植物中分别由GBSSI和GBSSII基因编码。在药用野生稻中, 这2种基因所编码蛋白的氨基酸序列一致性为62%, 并且它们在不同器官内呈现时空分化表达, 其中GBSSI在种子中超强表达, GBSSII则主要在叶片表达。     

The unmethylated state of the promoter/leader and 5'-regions of integrated adenovirus genes correlates with gene expression.

An inverse correlation has been established between the levels of DNA methylation at 5'-CCGG-3' (MspI/HpaII) sites in specific genes of integrated viral DNA in adenovirus type 12 (Ad12)-transformed hamster cell lines and the extent to which these genes are expressed ( Sutter and Doerfler , 1979, 1980). In general, early genes are transcribed into mRNA, while late genes are permanently switched off in these cell lines. Adenovirus type 2 genes methylated in vitro at 5'-CCGG-3' sites are not transcribed upon microinjection into nuclei of Xenopus laevis oocytes - unmethylated genes are expressed ( Vardimon et al., 1982a ). The MspI sites in the early and in some of the late Ad12 genes in cell lines HA12 /7, T637 , and A2497 -3 have now been precisely mapped. The data presented here reveal that the promoter/leader and 5'-regions of the early genes are unmethylated both at MspI sites and at 5'-GCGC-3' (HhaI) sites. In some instances, e.g., in the E2a regions in all three lines, the main parts of the early genes are partly methylated, even though the genes are expressed. In cell line HA12 /7, the early region E3 is not expressed, and the promoter/leader and 5'-regions of this segment are fully methylated. All late regions are completely methylated. The results suggest that the state of methylation in the promoter/leader and 5'-regions of integrated adenovirus genes is important in the control of gene expression.     

Conservation analysis of small RNA genes in Escherichia coli

MOTIVATION: Small RNA (sRNA) genes in Escherichia coli have been in focus recently, as 44 out of 55 experimentally confirmed sRNA genes have been precisely located in the genome. The object of this study is to analyze quantitatively the conservation of these sRNA genes and compare it with the conservation of protein-encoding genes, function-unknown regions and tRNA genes. RESULTS: The results show that within an evolutionary distance of 0.26, both sRNA genes and protein-encoding genes display a similar tendency in their degrees of conservation at the nucleotide level. In addition, the conservation of sRNA genes is much stronger than function-unknown regions, but much weaker than tRNA genes. Based on the conservation of studied sRNA genes, we also give clues to estimate the total number of sRNA genes in E.coli. SUPPLEMENTARY INFORMATION: Supplementary information is available at http://www.bioinfo.org.cn/SM/sRNAconservation.htm     

Phthalates: toxicogenomics and inferred human diseases

Phthalates are widely used as plasticizers to soften and increase the flexibility in polyvinyl chloride plastics, but they can leach into the surrounding environment. There is sufficient evidence in rodents that phthalate exposure causes developmental and reproductive toxicity. The curated interactions between 16 phthalates and genes/proteins were obtained from Comparative Toxicogenomics Database (CTD), and a total of 445 interactions between the five most frequently curated phthalates (DEHP/MEHP and DBP/BBP/MBP) and 249 unique genes/proteins were found. The GeneOntology, pathways and networks of these 249 unique genes/proteins were fully analyzed. The pathways and networks of top 34 genes/proteins were found to be very similar to those of the 249 unique genes/proteins. Thus, the top 34 genes/proteins may serve as molecular biomarkers of phthalate toxicity. The top three phthalate toxicity categories were found to be cardiotoxicity, hepatotoxicity and nephrotoxicity, and the top 20 diseases included cardiovascular, liver, urologic, endocrine and genital diseases.