Biomedical subjects

Pavel Pevzner

Publications and source records attributed to Pavel Pevzner.

13 recordsLinked to original sources

PubMed2016

Sharing and community curation of mass spectrometry data with Global Natural Products Social Molecular Networking.

The potential of the diverse chemistries present in natural products (NP) for biotechnology and medicine remains untapped because NP databases are not searchable with raw data and the NP community has no way to share data other than in published papers. Although mass spectrometry (MS) techniques are well-suited to high-throughput characterization of NP, there is a pressing need for an infrastructure to enable sharing and curation of data. We present Global Natural Products Social Molecular Networking (GNPS; http://gnps.ucsd.edu), an open-access knowledge base for community-wide organization and sharing of raw, processed or identified tandem mass (MS/MS) spectrometry data. In GNPS, crowdsourced curation of freely available community-wide reference MS libraries will underpin improved annotations. Data-driven social-networking should facilitate identification of spectra and foster collaborations. We also introduce the concept of 'living data' through continuous reanalysis of deposited data.

Biological Products↗

PubMed2006

Representing and comparing protein structures as paths in three-dimensional space.

BACKGROUND: Most existing formulations of protein structure comparison are based on detailed atomic level descriptions of protein structures and bypass potential insights that arise from a higher-level abstraction. RESULTS: We propose a structure comparison approach based on a simplified representation of proteins that describes its three-dimensional path by local curvature along the generalized backbone of the polypeptide. We have implemented a dynamic programming procedure that aligns curvatures of proteins by optimizing a defined sum turning angle deviation measure. CONCLUSION: Although our procedure does not directly optimize global structural similarity as measured by RMSD, our benchmarking results indicate that it can surprisingly well recover the structural similarity defined by structure classification databases and traditional structure alignment programs. In addition, our program can recognize similarities between structures with extensive conformation changes that are beyond the ability of traditional structure alignment programs. We demonstrate the applications of procedure to several contexts of structure comparison. An implementation of our procedure, CURVE, is available as a public webserver.

Algorithms↗

PubMed2006

Decoding the fine-scale structure of a breast cancer genome and transcriptome.

A comprehensive understanding of cancer is predicated upon knowledge of the structure of malignant genomes underlying its many variant forms and the molecular mechanisms giving rise to them. It is well established that solid tumor genomes accumulate a large number of genome rearrangements during tumorigenesis. End Sequence Profiling (ESP) maps and clones genome breakpoints associated with all types of genome rearrangements elucidating the structural organization of tumor genomes. Here we extend the ESP methodology in several directions using the breast cancer cell line MCF-7. First, targeted ESP is applied to multiple amplified loci, revealing a complex process of rearrangement and co-amplification in these regions reminiscent of breakage/fusion/bridge cycles. Second, genome breakpoints identified by ESP are confirmed using a combination of DNA sequencing and PCR. Third, in vitro functional studies assign biological function to a rearranged tumor BAC clone, demonstrating that it encodes anti-apoptotic activity. Finally, ESP is extended to the transcriptome identifying four novel fusion transcripts and providing evidence that expression of fusion genes may be common in tumors. These results demonstrate the distinct advantages of ESP including: (1) the ability to detect all types of rearrangements and copy number changes; (2) straightforward integration of ESP data with the annotated genome sequence; (3) immortalization of the genome; (4) ability to generate tumor-specific reagents for in vitro and in vivo functional studies. Given these properties, ESP could play an important role in a tumor genome project.

Breast Neoplasms↗

PubMed2006

Rapid validation of protein identifications with the borderline statistical confidence via de novo sequencing and MS BLAST searches.

Protein identifications with the borderline statistical confidence are typically produced by matching a few marginal quality MS/MS spectra to database peptide sequences and represent a significant bottleneck in the reliable and reproducible characterization of proteomes. Here, we present a method for rapid validation of borderline hits that circumvents the need in, often biased, manual inspection of raw MS/MS spectra. The approach takes advantage of the independent interpretation of corresponding MS/MS spectra by PepNovo de novo sequencing software followed by mass spectrometry-driven BLAST (MS BLAST) sequence-similarity database searches that utilize all partially inaccurate, degenerate and redundant candidate peptide sequences. In a case study involving the identification of more than 180 Caenorhabditis elegans proteins by nanoLC-MS/MS analysis on a linear ion trap LTQ mass spectrometer, the approach enabled rapid assignment (confirmation or rejection) of more than 70% of Mascot hits of borderline statistical confidence.

Amino Acid Sequence↗

PubMed2005

PepNovo: de novo peptide sequencing via probabilistic network modeling.

We present a novel scoring method for de novo interpretation of peptides from tandem mass spectrometry data. Our scoring method uses a probabilistic network whose structure reflects the chemical and physical rules that govern the peptide fragmentation. We use a likelihood ratio hypothesis test to determine whether the peaks observed in the mass spectrum are more likely to have been produced under our fragmentation model than under a model that treats peaks as random events. We tested our de novo algorithm PepNovo on ion trap data and achieved results that are superior to popular de novo peptide sequencing algorithms. PepNovo can be accessed via the URL http://www-cse.ucsd.edu/groups/bioinformatics/software.html.

Algorithms↗

PubMed2004

Shotgun protein sequencing by tandem mass spectra assembly.

The analysis of mass spectrometry data is still largely based on identification of single MS/MS spectra and does not attempt to make use of the extra information available in multiple MS/MS spectra from partially or completely overlapping peptides. Analysis of MS/MS spectra from multiple overlapping peptides opens up the possibility of assembling MS/MS spectra into entire proteins, similarly to the assembly of overlapping DNA reads into entire genomes. In this paper, we present for the first time a way to detect, score, and interpret overlaps between uninterpreted MS/MS spectra in an attempt to sequence entire proteins rather than individual peptides. We show that this approach not only extends the length of reconstructed amino acid sequences but also dramatically improves the quality of de novo peptide sequencing, even for low mass accuracy MS/MS data.

Amino Acid Sequence↗

PubMed2004

The Alternative Splicing Gallery (ASG): bridging the gap between genome and transcriptome.

Alternative splicing essentially increases the diversity of the transcriptome and has important implications for physiology, development and the genesis of diseases. Conventionally, alternative splicing is investigated in a case-by-case fashion, but this becomes cumbersome and error prone if genes show a huge abundance of different splice variants. We use a different approach and integrate all transcripts derived from a gene into a single splicing graph. Each transcript corresponds to a path in the graph, and alternative splicing is displayed by bifurcations. This representation preserves the relationships between different splicing variants and allows us to investigate systematically all possible putative transcripts. We built a database of splicing graphs for human genes, using transcript information from various major sources (Ensembl, RefSeq, STACK, TIGR and UniGene). A Web interface allows users to display the splicing graphs, to interactively assemble transcripts and to access their sequences as well as neighboring genomic regions. We also provide for each gene an exhaustive pre-computed catalog of putative transcripts--in total more than 1.2 million sequences. We found that approximately 65% of the investigated genes show evidence for alternative splicing, and in 5% of the cases, a single gene might produce over 100 transcripts.

Alternative Splicing↗

PubMed2004

Fragment assembly with short reads.

MOTIVATION: Current DNA sequencing technology produces reads of about 500-750 bp, with typical coverage under 10x. New sequencing technologies are emerging that produce shorter reads (length 80-200 bp) but allow one to generate significantly higher coverage (30x and higher) at low cost. Modern assembly programs and error correction routines have been tuned to work well with current read technology but were not designed for assembly of short reads. RESULTS: We analyze the limitations of assembling reads generated by these new technologies and present a routine for base-calling in reads prior to their assembly. We demonstrate that while it is feasible to assemble such short reads, the resulting contigs will require significant (if not prohibitive) finishing efforts. AVAILABILITY: Available from the web at http://www.cse.ucsd.edu/groups/bioinformatics/software.html

Algorithms↗

PubMed2004

A novel method for multiple alignment of sequences with repeated and shuffled elements.

We describe ABA (A-Bruijn alignment), a new method for multiple alignment of biological sequences. The major difference between ABA and existing multiple alignment methods is that ABA represents an alignment as a directed graph, possibly containing cycles. This representation provides more flexibility than does a traditional alignment matrix or the recently introduced partial order alignment (POA) graph by allowing a larger class of evolutionary relationships between the aligned sequences. Our graph representation is particularly well-suited to the alignment of protein sequences with shuffled and/or repeated domain structure, and allows one to construct multiple alignments of proteins containing (1) domains that are not present in all proteins, (2) domains that are present in different orders in different proteins, and (3) domains that are present in multiple copies in some proteins. In addition, ABA is useful in the alignment of genomic sequences that contain duplications and inversions. We provide several examples illustrating the applications of ABA.

Algorithms↗

PubMed2003

Human and mouse genomic sequences reveal extensive breakpoint reuse in mammalian evolution.

The human and mouse genomic sequences provide evidence for a larger number of rearrangements than previously thought and reveal extensive reuse of breakpoints from the same short fragile regions. Breakpoint clustering in regions implicated in cancer and infertility have been reported in previous studies; we report here on breakpoint clustering in chromosome evolution. This clustering reveals limitations of the widely accepted random breakage theory that has remained unchallenged since the mid-1980s. The genome rearrangement analysis of the human and mouse genomes implies the existence of a large number of very short "hidden" synteny blocks that were invisible in the comparative mapping data and ignored in the random breakage model. These blocks are defined by closely located breakpoints and are often hard to detect. Our results suggest a model of chromosome evolution that postulates that mammalian genomes are mosaics of fragile regions with high propensity for rearrangements and solid regions with low propensity for rearrangements.

Animals↗

PubMed2003

Genome rearrangements in mammalian evolution: lessons from human and mouse genomes.

Although analysis of genome rearrangements was pioneered by Dobzhansky and Sturtevant 65 years ago, we still know very little about the rearrangement events that produced the existing varieties of genomic architectures. The genomic sequences of human and mouse provide evidence for a larger number of rearrangements than previously thought and shed some light on previously unknown features of mammalian evolution. In particular, they reveal that a large number of microrearrangements is required to explain the differences in draft human and mouse sequences. Here we describe a new algorithm for constructing synteny blocks, study arrangements of synteny blocks in human and mouse, derive a most parsimonious human-mouse rearrangement scenario, and provide evidence that intrachromosomal rearrangements are more frequent than interchromosomal rearrangements. Our analysis is based on the human-mouse breakpoint graph, which reveals related breakpoints and allows one to find a most parsimonious scenario. Because these graphs provide important insights into rearrangement scenarios, we introduce a new visualization tool that allows one to view breakpoint graphs superimposed with genomic dot-plots.

Algorithms↗

PubMed2003

Reconstructing the genomic architecture of mammalian ancestors using multispecies comparative maps.

Rapidly developing comparative gene maps in selected mammal species are providing an opportunity to reconstruct the genomic architecture of mammalian ancestors and study rearrangements that transformed this ancestral genome into existing mammalian genomes. Here, the recently developed Multiple Genome Rearrangement (MGR) algorithm is applied to human, mouse, cat and cattle comparative maps (with 311-470 shared markers) to impute the ancestral mammalian genome. Reconstructed ancestors consist of 70-100 conserved segments shared across the genomes that have been exchanged by rearrangement events along the ordinal lineages leading to modern species genomes. Genomic distances between species, dominated by inversions (reversals) and translocations, are presented in a first multispecies attempt using ordered mapping data to reconstruct the evolutionary exchanges that preceded modern placental mammal genomes.

Algorithms↗

PubMedDate not supplied

Peptide sequence tags for fast database search in mass-spectrometry.

Filtration techniques in the form of rapid elimination of candidate sequences while retaining the true one are key ingredients of database searches in genomics. Although SEQUEST and Mascot perform a conceptually similar task to the tool BLAST, the key algorithmic idea of BLAST (filtration) was never implemented in these tools. As a result MS/MS protein identification tools are becoming too time-consuming for many applications including search for post-translationally modified peptides. Moreover, matching millions of spectra against all known proteins will soon make these tools too slow in the same way that "genome vs genome" comparisons instantly made BLAST too slow. We describe the development of filters for MS/MS database searches that dramatically reduce the running time and effectively remove the bottlenecks in searching the huge space of protein modifications. Our approach, based on a probability model for determining the accuracy of sequence tags, achieves superior results compared to GutenTag, a popular tag generation algorithm. Our tag generating algorithm along with our de novo sequencing algorithm PepNovo can be accessed via the URL http://peptide.ucsd.edu/.

Algorithms↗