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1.
Mol Cell Proteomics ; 9(4): 648-55, 2010 Apr.
Article in English | MEDLINE | ID: mdl-19959820

ABSTRACT

Genes involved in cancer susceptibility and progression can serve as templates for searching protein networks for novel cancer genes. To this end, we introduce a general network searching method, MaxLink, and apply it to find and rank cancer gene candidates by their connectivity to known cancer genes. Using a comprehensive protein interaction network, we searched for genes connected to known cancer genes. First, we compiled a new set of 812 genes involved in cancer, more than twice the number in the Cancer Gene Census. Their network neighbors were then extracted. This candidate list was refined by selecting genes with unexpectedly high levels of connectivity to cancer genes and without previous association to cancer. This produced a list of 1891 new cancer candidates with up to 55 connections to known cancer genes. We validated our method by cross-validation, Gene Ontology term bias, and differential expression in cancer versus normal tissue. An example novel cancer gene candidate is presented with detailed analysis of the local network and neighbor annotation. Our study provides a ranked list of high priority targets for further studies in cancer research. Supplemental material is included.


Subject(s)
Gene Regulatory Networks , Genes, Neoplasm , Genetic Linkage , Neoplasms/genetics , Algorithms , Computational Biology/methods , Female , Gene Expression Profiling/methods , Gene Expression Regulation, Neoplastic , Genetic Association Studies/methods , Humans , Male
2.
Nucleic Acids Res ; 34(6): e49, 2006 Mar 31.
Article in English | MEDLINE | ID: mdl-16582098

ABSTRACT

Efforts to correlate genetic variations with phenotypic differences are intensifying due to the availability of high-density maps of single nucleotide polymorphisms (SNPs) and the development of high throughput scoring methods. These recent advances have led to an increased interest for improved multiplex preparations of genetic material to facilitate such whole genome analyses. Here we propose a strategy for the parallel amplification of polymorphic loci based on a reduced set of nucleotides. The technique denoted Tri-nucleotide Threading (TnT), allows SNPs to be amplified via controlled linear amplification followed by complete removal of the target material and subsequent amplification with a pair of universal primers. A dedicated software tool was developed for this purpose and variable positions in genes associated with different forms of cancer were analyzed using sub-nanogram amounts of starting material. The amplified fragments were then successfully scored using a microarray-based PrASE technique. The results of this study, in which 75 SNPs were analyzed, show that the TnT technique circumvents potential problems associated with multiplex amplification of SNPs from minute amounts of material. The technique is specific, sensitive and can be readily adapted to equipment and genotyping techniques used in other research laboratories without requiring changes to the preferred typing method.


Subject(s)
Genomics/methods , Polymerase Chain Reaction/methods , Polymorphism, Single Nucleotide , Cytidine Triphosphate/chemistry , Genome, Human , Genotype , Guanosine Triphosphate/chemistry , Humans , Oligonucleotide Array Sequence Analysis/methods , Software , Thymine Nucleotides/chemistry
3.
Mol Cell Proteomics ; 4(12): 1920-32, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16127175

ABSTRACT

Antibody-based proteomics provides a powerful approach for the functional study of the human proteome involving the systematic generation of protein-specific affinity reagents. We used this strategy to construct a comprehensive, antibody-based protein atlas for expression and localization profiles in 48 normal human tissues and 20 different cancers. Here we report a new publicly available database containing, in the first version, approximately 400,000 high resolution images corresponding to more than 700 antibodies toward human proteins. Each image has been annotated by a certified pathologist to provide a knowledge base for functional studies and to allow queries about protein profiles in normal and disease tissues. Our results suggest it should be possible to extend this analysis to the majority of all human proteins thus providing a valuable tool for medical and biological research.


Subject(s)
Antibodies, Neoplasm/chemistry , Antibodies/chemistry , Neoplasms/immunology , Proteome/immunology , Antibodies/isolation & purification , Antibodies, Neoplasm/isolation & purification , Blotting, Western , Chromatography, Affinity , Databases, Protein , Epitopes/chemistry , Expressed Sequence Tags , Humans , Neoplasms/genetics , Proteins/immunology , Proteome/isolation & purification , Reference Values
4.
Biotechniques ; 38(5): 723-7, 2005 May.
Article in English | MEDLINE | ID: mdl-15945371

ABSTRACT

Protein functional analysis in the post-genomic era is a huge task that has to be approached by different methods in parallel. The use of protein-specific antibodies in conjunction with tissue microarrays has proven to be one important technology. In this study, we present a strategy for the optimized design of protein subfragments for subsequent antibody production. The fragments are selected based on a principle of lowest sequence similarity to other human proteins, optimally to generate antibodies with high selectivity. Furthermore, the fragments should have properties optimized for efficient protein production in Escherichia coli. The strategy has been implemented in Bishop, which is a Java-based software enabling the high-throughput production of protein fragments. Bishop allows for the avoidance of certain restriction enzyme sites, transmembrane regions, and signal peptides. A Basic Local Alignment Search Tool (BLAST) scanning procedure permits the selection of fragments of a selected size with a minimal sequence similarity to other proteins. The software and the strategy were evaluated on a human test data set and verified to fulfill the requested criteria.


Subject(s)
Algorithms , Antibody Formation , Epitope Mapping/methods , Sequence Alignment/methods , Sequence Analysis, Protein/methods , Software , Amino Acid Sequence , Binding Sites , Molecular Sequence Data , Protein Binding
5.
Planta ; 221(5): 739-46, 2005 Jul.
Article in English | MEDLINE | ID: mdl-15940463

ABSTRACT

The genome sequence of Populus trichocarpa was screened for genes encoding cellulose synthases by using full-length cDNA sequences and ESTs previously identified in the tissue specific cDNA libraries of other poplars. The data obtained revealed 18 distinct CesA gene sequences in P. trichocarpa. The identified genes were grouped in seven gene pairs, one group of three sequences and one single gene. Evidence from gene expression studies of hybrid aspen suggests that both copies of at least one pair, CesA3-1 and CesA3-2, are actively transcribed. No sequences corresponding to the gene pair, CesA6-1 and CesA6-2, were found in Arabidopsis or hybrid aspen, while one homologous gene has been identified in the rice genome and an active transcript in Populus tremuloides. A phylogenetic analysis suggests that the CesA genes previously associated with secondary cell wall synthesis originate from a single ancestor gene and group in three distinct subgroups. The newly identified copies of CesA genes in P. trichocarpa give rise to a number of new questions concerning the mechanism of cellulose synthesis in trees.


Subject(s)
Glucosyltransferases/genetics , Populus/genetics , Chromosome Mapping , Chromosomes, Plant , Conserved Sequence , DNA, Complementary , Expressed Sequence Tags , Genome, Plant , Phylogeny
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