Phylogenetic diversification of immunoglobulin genes and the antibody repertoire

Immunoglobulins are encoded by a large multigene system that undergoes somatic rearrangement and additional genetic change during the development of immunoglobulin-producing cells. Inducible antibody and antibody-like responses are found in all vertebrates. However, immunoglobulin possessing disulfide-bonded heavy and light chains and domain-type organization has been described only in representatives of the jawed vertebrates. High degrees of nucleotide and predicted amino acid sequence identity are evident when the segmental elements that constitute the immunoglobulin gene loci in phylogenetically divergent vertebrates are compared. However, the organization of gene loci and the manner in which the independent elements recombine (and diversify) vary markedly among different taxa. One striking pattern of gene organization is the "cluster type" that appears to be restricted to the chondrichthyes (cartilaginous fishes) and limits segmental rearrangement to closely linked elements. This type of gene organization is associated with both heavy- and light-chain gene loci. In some cases, the clusters are "joined" or "partially joined" in the germ line, in effect predetermining or partially predetermining, respectively, the encoded specificities (the assumption being that these are expressed) of the individual loci. By relating the sequences of transcribed gene products to their respective germ-line genes, it is evident that, in some cases, joined-type genes are expressed. This raises a question about the existence and/or nature of allelic exclusion in these species. The extensive variation in gene organization found throughout the vertebrate species may relate directly to the role of intersegmental (V<==>D<==>J) distances in the commitment of the individual antibody-producing cell to a particular genetic specificity. Thus, the evolution of this locus, perhaps more so than that of others, may reflect the interrelationships between genetic organization and function.      

Association of vitamin D binding protein polymorphism with long-term kidney allograft survival in Hispanic kidney transplant recipients

Polymorphism of genes encoding components of the vitamin D pathway including vitamin D receptor (VDR) and vitamin D binding protein (VDBP), have been widely explored due to the complex role played by vitamin D in renal transplant outcomes. In this study, we investigated whether polymorphisms of genes encoding VDR and VDBP were associated with allograft survival or acute rejection (AR) among a Hispanic kidney transplant population. A total of 502 Hispanic renal allograft recipients at the St. Vincent Medical Center between 2001 and 2010 were genotyped for four different single nucleotide polymorphisms of VDR: FokI C>T (rs2228570), BsmI G>A (rs1544410), ApaI T>G (rs7975232), and TaqI T>C (rs731236). We also performed genotyping for one common polymorphism in the VDBP gene (rs4588). Survival was significantly improved for patients who were homozygous GG for the rs4588 G>T allele in the VDBP gene (GG vs. GT + TT, OR = 0.63, p = 0.02) while GT genotype was associated with a higher risk of graft loss (GT vs. GG + TT, OR = 1.67, p = 0.01). We found no association for polymorphic markers in VDR with allograft survival and AR. The frequency of the haplotype GTCG (in the order of VDR FokI C>T, BsmI G>A, ApaI T>G, and TaqI T>C), was significantly different in the patients with graft rejection compared to the control (p = 0.007) while ACCA haplotype was found to be associated with graft loss (p = 0.02). Hence, the VDBP G>T polymorphism (rs4588) and two haplotypes (GTCG and ACCA) of VDR appear to be associated with renal allograft outcomes among Hispanic allograft recipients.     

Cellware--a multi-algorithmic software for computational systems biology

The intracellular environment of a cell hosts a wide variety of enzymatic reactions, diffusion events, molecular binding, polymerization and metabolic channeling. To transform these biological events into a computational framework, distinct modeling strategies are required. While currently no tool is capable of capturing all these events, progress is being made to create an integrated environment for the modeling community. To address this niche requirement, Cellware has been developed to offer a multi-algorithmic environment for modeling and simulating both deterministic and stochastic events in the cell. AVAILABILITY: The software is available for free and can be downloaded from http://www.bii.a-star.edu.sg/sbg/cellware     

PPD - Proteome Profile Database

With the complete sequencing of multiple genomes, there have been extensions in the methods of sequence analysis from single gene/protein-based to analyzing multiple genes and proteins simultaneously. Therefore, there is a demand of user-friendly software tools that will allow mining of these enormous datasets. PPD is a WWW-based database for comparative analysis of protein lengths in completely sequenced prokaryotic and eukaryotic genomes. PPD's core objective is to create protein classification tables based on the lengths of proteins by specifying a set of organisms and parameters. The interface can also generate information on changes in proteins of specific length distributions. This feature is of importance when the user's interest is focused on some evolutionarily related organisms or on organisms with similar or related tissue specificity or life-style. PPD is available at: PPD Home.     

Distributions of exons and introns in the human genome

The human genome is revisited using exon and intron distribution profiles. The 26,564 annotated genes in the human genome (build October, 2003) contain 233,785 exons and 207,344 introns. On average, there are 8.8 exons and 7.8 introns per gene. About 80% of the exons on each chromosome are < 200 bp in length. < 0.01% of the introns are < 20 bp in length and < 10% of introns are more than 11,000 bp in length. These results suggest constraints on the splicing machinery to splice out very long or very short introns and provide insight to optimal intron length selection. Interestingly, the total length in introns and intergenic DNA on each chromosome is significantly correlated to the determined chromosome size with a coefficient of correlation r = 0.95 and r = 0.97, respectively. These results suggest their implication in genome design.     

A novel genomics approach for the identification of drug targets in pathogens, with special reference to Pseudomonas aeruginosa

Complete genome sequences of several pathogenic bacteria have been determined, and many more such projects are currently under way. While these data potentially contain all the determinants of host-pathogen interactions and possible drug targets, computational tools for selecting suitable candidates for further experimental analyses are currently limited. Detection of bacterial genes that are non-homologous to human genes, and are essential for the survival of the pathogen represents a promising means of identifying novel drug targets. We have used three-way genome comparisons to identify essential genes from Pseudomonas aeruginosa. Our approach identified 306 essential genes that may be considered as potential drug targets. The resultant analyses are in good agreement with the results of systematic gene deletion experiments. This approach enables rapid potential drug target identification, thereby greatly facilitating the search for new antibiotics. These results underscore the utility of large genomic databases for in silico systematic drug target identification in the post-genomic era.     

IE-Kb: intron exon knowledge base

SUMMARY: IE-Kb (Intron Exon-Knowledge base) illustrates the intron-exon dynamics in eukaryotic genes. We have developed three different knowledge sets, namely 'Non-redundant ExInt', 'Non-redundant Pfam-ExInt complement' and 'Non-redundant GenBank eukaryotic subdivisional sets' to understand this phenomenon. Statistical analysis is performed on each knowledge set and the results are made available online. The entries in knowledge sets are ranked based on their intron length, exon length and protein length with relational hyper-links to the corresponding intron phase, intron position, intron sequence, gene definition and parent GenBank entry.     

ExInt: an Exon/Intron database

The Exon/Intron (ExInt) database incorporates information on the exon/intron structure of eukaryotic genes. Features in the database include: intron nucleotide sequence, amino acid sequence of the corresponding protein, position of the introns at the amino acid level and intron phase. From ExInt, we have also generated four additional databases each with ExInt entries containing predicted introns, introns experimentally defined, organelle introns or nuclear introns. ExInt is accessible through a retrieval system with pointers to GenBank. The database can be searched by keywords, locus name, NID, accession number or length of the protein. ExInt is freely accessible at http://intron.bic.nus.edu.sg/exint/exint.html     

Protein subunit interfaces: heterodimers versus homodimers

Protein dimers are either homodimers (complexation of identical monomers) or heterodimers (complexation of non-identical monomers). These dimers are common in catalysis and regulation. However, the molecular principles of protein dimer interactions are difficult to understand mainly due to the geometrical and chemical characteristics of proteins. Nonetheless, the principles of protein dimer interactions are often studied using a dataset of 3D structural complexes determined by X-ray crystallography. A number of physical and chemical properties govern protein dimer interactions. Yet, a handful of such properties are known to dominate protein dimer interfaces. Here, we discuss the differences between homodimer and heterodimer interfaces using a selected set of interface properties.     

Alternatively spliced human genes by exon skipping--a database (ASHESdb)

Alternative splicing of mRNA allows many gene products with different functions to be produced from a single coding sequence. Exon skipping is the most commonly known alternative splicing mechanism. A comprehensive database of alternative splicing by exon skipping is made available for the human genome data. 1,229 human genes are identified to exhibit alternative splicing by exon skipping. Availability: http://sege.ntu.edu.sg/wester/ashes/.