Biomedical subjects

Alissa Resch

Publications and source records attributed to Alissa Resch.

3 recordsLinked to original sources

PubMed2004

Evidence for a subpopulation of conserved alternative splicing events under selection pressure for protein reading frame preservation.

Recently there has been much interest in assessing the role of alternative splicing in evolution. We have sought to measure functional selection pressure on alternatively spliced single-exon skips, by calculating the fraction that are an exact multiple of 3 nt in length and therefore preserve protein reading-frame in both the exon-inclusion and exon-skip splice forms. The frame-preservation ratio (defined as the number of exons that are an exact multiple of three in length, divided by the number of exons that are not) was slightly above random for both constitutive exons and alternatively spliced exons as a whole in human and mouse. However, orthologous exons that were observed to be alternatively spliced in the expressed sequence tag data from two or more organisms showed a substantially increased bias to be frame-preserving. This effect held true only for exons within the protein coding region, and not the untranslated region. In five animal genomes (human, mouse, rat, zebrafish, Drosophila), we observed an association between these conserved alternative splicing events and increased selection pressure for frame-preservation. Surprisingly, this effect became stronger as a function of decreasing exon inclusion level: for alternatively spliced exons that were included in a majority of the gene's transcripts, the frame-preservation bias was no higher than that of constitutive exons, whereas for alternatively spliced exons that were included in only a minority of the gene's transcripts, the frame-preservation bias increased nearly 20-fold. These data indicate that a subpopulation of modern alternative splicing events was present in the common ancestors of these genomes, and was under functional selection pressure to preserve the protein reading frame.

Alternative Splicing↗

PubMed2004

The multiassembly problem: reconstructing multiple transcript isoforms from EST fragment mixtures.

Recent evidence of abundant transcript variation (e.g., alternative splicing, alternative initiation, alternative polyadenylation) in complex genomes indicates that cataloging the complete set of transcripts from an organism is an important project. One challenge is the fact that most high-throughput experimental methods for characterizing transcripts (such as EST sequencing) give highly detailed information about short fragments of transcripts or protein products, instead of a complete characterization of a full-length form. We analyze this "multiassembly problem"-reconstructing the most likely set of full-length isoform sequences from a mixture of EST fragment data-and present a graph-based algorithm for solving it. In a variety of tests, we demonstrate that this algorithm deals appropriately with coupling of distinct alternative splicing events, increasing fragmentation of the input data and different types of transcript variation (such as alternative splicing, initiation, polyadenylation, and intron retention). To test the method's performance on pure fragment (EST) data, we removed all mRNA sequences, and found it produced no errors in 40 cases tested. Using this algorithm, we have constructed an Alternatively Spliced Proteins database (ASP) from analysis of human expressed and genomic sequences, consisting of 13,384 protein isoforms of 4422 genes, yielding an average of 3.0 protein isoforms per gene.

Algorithms↗

PubMedDate not supplied

Assessing the impact of alternative splicing on domain interactions in the human proteome.

We have constructed a database of alternatively spliced protein forms (ASP), consisting of 13,384 protein isoform sequences of 4422 human genes (www.bioinformatics.ucla.edu/ASP). We identified fifty protein domain types that were selectively removed by alternative splicing at much higher frequencies than average (p-value < 0.01). These include many well-known protein-interaction domains (e.g., KRAB; ankyrin repeats; Kelch) including some that have been previously shown to be regulated functionally by alternative splicing (e.g., collagen domain). We present a number of novel examples (Kruppel transcription factors; Pbx2; Enc1) from the ASP database, illustrating how this pattern of alternative splicing changes the structure of a biological pathway, by redirecting protein interaction networks at key switch points. Our bioinformatics analysis indicates that a major impact of alternative splicing is removal of protein-protein interaction domains that mediate key linkages in protein interaction networks. ASP expands the available dataset of human alternatively spliced protein forms from 1989 human genes (SwissProt release 42) to 5413 (nonredundant set, ASP + SwissProt), a nearly 3-fold increase. ASP will enhance the existing pool of protein sequences that are searched by mass spectroscopy software during the identification of peptide fragments.

Alternative Splicing↗