Biomedical subjects

D Kulp

Publications and source records attributed to D Kulp.

8 recordsLinked to original sources

PubMed2004

The effects of alternative splicing on transmembrane proteins in the mouse genome.

Alternative splicing is a major source of variety in mammalian mRNAs, yet many questions remain on its downstream effects on protein function. To this end, we assessed the impact of gene structure and splice variation on signal peptide and transmembrane regions in proteins. Transmembrane proteins perform several key functions in cell signaling and transport, with their function tied closely to their transmembrane architecture. Signal peptides and transmembrane regions both provide key information on protein localization. Thus, any modification to such regions will likely alter protein destination and function. We applied TMHMM and SignalP to a nonredundant set of proteins, and assessed the effects of gene structure and alternative splicing on predicted transmembrane and signal peptide regions. These regions were altered by alternative splicing in roughly half of the cases studied. Transmembrane regions are divided by introns slightly less often than expected given gene structure and transmembrane region size. However, the transmembrane regions in single-pass transmembranes are divided substantially less often than expected. This suggests that intron placement might be subject to some evolutionary pressure to preserve function in these signaling proteins. The data described in this paper is available online at http://www.affymetrix.com/community/publications/affymetrix/tmsplice/.

Alternative Splicing↗

PubMed2000

Half-life measurement for the rp-process waiting point nuclide 80Zr

X-ray bursts have been suggested as a possible site for the astrophysical rp-process. The time scale for the process is governed by beta-decay half-lives of several even-even N = Z waiting point nuclei, in particular, N = Z = 40 80Zr. A 4.1(+0.8/-0.6)-s beta(+)/EC half-life for 80Zr was determined by observing delayed 84-keV gamma rays depopulating a T(1/2) = 4-&mgr;s isomer at 312 keV in the daughter 80Y. As this half-life is lower than many previously predicted values, the calculated excessive production of A = 80 nuclides in astrophysical x-ray burst scenarios is reduced, and less extreme conditions are necessary for the production of heavier nuclides.

Journal Article↗

PubMed2000

Genie--gene finding in Drosophila melanogaster.

A hidden Markov model-based gene-finding system called Genie was applied to the genomic Adh region in Drosophila melanogaster as a part of the Genome Annotation Assessment Project (GASP). Predictions from three versions of the Genie gene-finding system were submitted, one based on statistical properties of coding genes, a second included EST alignment information, and a third that integrated protein sequence homology information. All three programs were trained on the provided Drosophila training data. In addition, promoter assignments from an integrated neural network were submitted. The gene assignments overlapped >90% of the 222 annotated genes and 26 possibly novel genes were predicted, of which some might be overpredictions. The system correctly identified the exon boundaries of 70% of the exons in cDNA-confirmed genes and 77% of the exons with the addition of EST sequence alignments. The best of the three Genie submissions predicted 19 of the annotated 43 gene structures entirely correct (44%). In the promoter category, only 30% of the transcription start sites could be detected, but by integrating this program as a sensor into Genie the false-positive rate could be dropped to 1/16,786 (0.006%). The results of the experiment on the long contiguous genomic sequence revealed some problems concerning gene assembly in Genie. The results were used to improve the system. We show that Genie is a robust hidden Markov model system that allows for a generalized integration of information from different sources such as signal sensors (splice sites, start codon, etc.), content sensors (exons, introns, intergenic) and alignments of mRNA, EST, and peptide sequences. The assessment showed that Genie could effectively be used for the annotation of complete genomes from higher organisms.

Animals↗

PubMed1997

Improved splice site detection in Genie.

We present an improved splice site predictor for the genefinding program Genie. Genie is based on a generalized Hidden Markov Model (GHMM) that describes the grammar of a legal parse of a multi-exon gene in a DNA sequence. In Genie, probabilities are estimated for gene features by using dynamic programming to combine information from multiple content and signal sensors, including sensors that integrate matches to homologous sequences from a database. One of the hardest problems in genefinding is to determine the complete gene structure correctly. The splice site sensors are the key signal sensors that address this problem. We replaced the existing splice site sensors in Genie with two novel neural networks based on dinucleotide frequencies. Using these novel sensors, Genie shows significant improvements in the sensitivity and specificity of gene structure identification. Experimental results in tests using a standard set of annotated genes showed that Genie identified 86% of coding nucleotides correctly with a specificity of 85%, versus 80% and 84% in the older system. In further splice site experiments, we also looked at correlations between splice site scores and intron and exon lengths, as well as at the effect of distance to the nearest splice site on false positive rates.

Animals↗

PubMed1997

Integrating database homology in a probabilistic gene structure model.

We present an improved stochastic model of genes in DNA, and describe a method for integrating database homology into the probabilistic framework. A generalized hidden Markov model (GHMM) describes the grammar of a legal parse of a DNA sequence. Probabilities are estimated for gene features by using dynamic programming to combine information from multiple sensors. We show how matches to homologous sequences from a database can be integrated into the probability estimation by interpreting the likelihood of a sequence in terms of the bit-cost to encode a sequence given a homology match. We also demonstrate how homology matches in protein databases can be exploited to help identify splice sites. Our experiments show significant improvements in the sensitivity and specificity of gene structure identification when these new features are added to our gene-finding system, Genie. Experimental results in tests using a standard set of annotated genes showed that Genie identified 95% of coding nucleotides correctly with a specificity of 91%, and 77% of exons were identified exactly.

Algorithms↗

PubMed1996

A generalized hidden Markov model for the recognition of human genes in DNA.

We present a statistical model of genes in DNA. A Generalized Hidden Markov Model (GHMM) provides the framework for describing the grammar of a legal parse of a DNA sequence (Stormo & Haussler 1994). Probabilities are assigned to transitions between states in the GHMM and to the generation of each nucleotide base given a particular state. Machine learning techniques are applied to optimize these probabilities using a standardized training set. Given a new candidate sequence, the best parse is deduced from the model using a dynamic programming algorithm to identify the path through the model with maximum probability. The GHMM is flexible and modular, so new sensors and additional states can be inserted easily. In addition, it provides simple solutions for integrating cardinality constraints, reading frame constraints, "indels", and homology searching. The description and results of an implementation of such a gene-finding model, called Genie, is presented. The exon sensor is a codon frequency model conditioned on windowed nucleotide frequency and the preceding codon. Two neural networks are used, as in (Brunak, Engelbrecht, & Knudsen 1991), for splice site prediction. We show that this simple model performs quite well. For a cross-validated standard test set of 304 genes [ftp:@www-hgc.lbl.gov/pub/genesets] in human DNA, our gene-finding system identified up to 85% of protein-coding bases correctly with a specificity of 80%. 58% of exons were exactly identified with a specificity of 51%. Genie is shown to perform favorably compared with several other gene-finding systems.

Chromosomes, Human↗

PubMed1994

Objective assessment of spermatogenesis in men with functional and anatomic obstruction of the genital tract.

Experimental rodent models simulating the condition of neurogenic infertility have drawn attention to the role of potential epididymal dysfunction as an underlying cause. This functional obstruction of the genital tract is comparable to the outcome of genital tract obstruction after vasectomy, and may explain the common finding of asthenospermia in both groups following either stimulated semen recovery or vasovasostomy, respectively. Since spermatogenic dysfunction has been reported in spinal cord injury, the relative roles of defective sperm production and sperm transport remain to be determined in men with neurogenic infertility. The objective of this study was to compare the levels of spermatogenesis in groups of vasectomized men and those with spinal cord injury, using objective measurement criteria for spermatogenesis. Groups of 10 spinal cord-injured and six vasectomized men matched for age and duration of disease, underwent incisional testicular biopsy. The specimens were divided equally for parallel quantitation of spermatogenesis by both quantitative cytometry and DNA flow cytometric analysis. Quantitative parameters showed similar values for both groups with reference to mean tubular wall thickness, mean tubular concentration of spermatids and Sertoli cells, as well as the mean spermatid: Sertoli cell ratio per tubule. Additionally, similar percentages of 1N, 2N and 4N cells, were found in both groups. Based on these preliminary findings this study provides a clinical correlation supporting the experimental observation that both anatomical and functional obstruction of the male genital tract exert a similar although minor spermatogenic insult, and that in both the putative cause for neurogenic infertility is more likely to be at the post-testicular level.

Adult↗

PubMed1994

Evolving a legacy system: restructuring the Mendelian Inheritance in Man database.

Mendelian Inheritance in Man (MIM) is an encyclopedia of medical genetics that has been in electronic form for over 30 years. In its lifetime, MIM has undergone many organizational and software changes. In 1994, a major transition was made based on three basic principles: industry standards, open systems architecture, and extensibility. The resulting MIM database allows users to navigate to other genomic databases, permits the delivery of multimedia information, and improves the quality of data. The new MIM database also improved its administration because of 1) an internal format that enforces consistency; 2) a lower maintenance cost of software; and 3) a better ability to migrate MIM content. In addition, the new architecture will allow MIM easily to adopt emergent technologies as they mature.

Computer Systems↗