Biomedical subjects

Melissa S Cline

Publications and source records attributed to Melissa S Cline.

6 recordsLinked to original sources

PubMed2006

Unusual intron conservation near tissue-regulated exons found by splicing microarrays.

Alternative splicing contributes to both gene regulation and protein diversity. To discover broad relationships between regulation of alternative splicing and sequence conservation, we applied a systems approach, using oligonucleotide microarrays designed to capture splicing information across the mouse genome. In a set of 22 adult tissues, we observe differential expression of RNA containing at least two alternative splice junctions for about 40% of the 6,216 alternative events we could detect. Statistical comparisons identify 171 cassette exons whose inclusion or skipping is different in brain relative to other tissues and another 28 exons whose splicing is different in muscle. A subset of these exons is associated with unusual blocks of intron sequence whose conservation in vertebrates rivals that of protein-coding exons. By focusing on sets of exons with similar regulatory patterns, we have identified new sequence motifs implicated in brain and muscle splicing regulation. Of note is a motif that is strikingly similar to the branchpoint consensus but is located downstream of the 5' splice site of exons included in muscle. Analysis of three paralogous membrane-associated guanylate kinase genes reveals that each contains a paralogous tissue-regulated exon with a similar tissue inclusion pattern. While the intron sequences flanking these exons remain highly conserved among mammalian orthologs, the paralogous flanking intron sequences have diverged considerably, suggesting unusually complex evolution of the regulation of alternative splicing in multigene families.

Adaptor Proteins, Signal Transducing↗

PubMed2005

ANOSVA: a statistical method for detecting splice variation from expression data.

MOTIVATION: Many or most mammalian genes undergo alternative splicing, generating a variety of transcripts from a single gene. New information on splice variation is becoming available through technology for measuring expression levels of several exons or splice junctions per gene. We have developed a statistical method, ANalysis Of Splice VAriation (ANOSVA) to detect alternative splicing from expression data. Since ANOSVA requires no transcript information, it can be applied when the level of annotation is poor. When validated against spiked clone data, it generated no false positives and few false negatives. We demonstrated ANOSVA with data from a prototype mouse alternative splicing array, run against normal adult tissues, yielding a set of genes with evidence of tissue-specific splice variation. AVAILABILITY: The results are available at the supplementary information site. SUPPLEMENTARY INFORMATION: The results are available at the supplementary information site https://bioinfo.affymetrix.com/Papers/ANOSVA/

Alternative Splicing↗

PubMed2004

NetAffx Gene Ontology Mining Tool: a visual approach for microarray data analysis.

SUMMARY: The NetAffx Gene Ontology (GO) Mining Tool is a web-based, interactive tool that permits traversal of the GO graph in the context of microarray data. It accepts a list of Affymetrix probe sets and renders a GO graph as a heat map colored according to significance measurements. The rendered graph is interactive, with nodes linked to public web sites and to lists of the relevant probe sets. The GO Mining Tool provides visualization combining biological annotation with expression data, encompassing thousands of genes in one interactive view. AVAILABILITY: GO Mining Tool is freely available at http://www.affymetrix.com/analysis/query/go_analysis.affx

Abstracting and Indexing↗

PubMed2003

Exploring alternative transcript structure in the human genome using blocks and InterPro.

Understanding how alternative splicing affects gene function is an important challenge facing modern-day molecular biology. Using homology-based, protein sequence analysis methods, it should be possible to investigate how transcript diversity impacts protein function. To test this, high-quality exon-intron structures were deduced for over 8000 human genes, including over 1300 (17 percent) that produce multiple transcript variants. A data mining technique (DiffMotif) was developed to identify genes in which transcript variation coincides with changes in conserved motifs between variants. Applying this method, we found that 30 percent of the multi-variant genes in our test set exhibited a differential profile of conserved InterPro and/or BLOCKS motifs across different mRNA variants. To investigate these, a visualization tool (ProtAnnot) that displays amino acid motifs in the context of genomic sequence was developed. Using this tool, genes revealed by the DiffMotif method were analyzed, and when possible, hypotheses regarding the potential role of alternative transcript structure in modulating gene function were developed. Examples of these, including: MEOX1, a homeobox-containing protein; AIRE, involved in auto-immune disease; PLAT, tissue type plasminogen activator; and CD79b, a component of the B-cell receptor complex, are presented. These results demonstrate that amino acid motif databases like BLOCKS and InterPro are useful tools for investigating how alternative transcript structure affects gene function.

Algorithms↗

PubMed2002

Information-theoretic dissection of pairwise contact potentials.

Pairwise contact potentials have a long, successful history in protein structure prediction. They provide an easily-estimated representation of many attributes of protein structures, such as the hydrophobic effect. In order to improve on existing potentials, one should develop a clear understanding of precisely what information they convey. Here, using mutual information, we quantified the information in amino acid potentials, and the importance of hydropathy, charge, disulfide bonding, and burial. Sampling error in mutual information was controlled for by estimating how much information cannot be attributed to sampling bias. We found the information in amino acid contacts to be modest: 0.04 bits per contact. Of that, only 0.01 bits of information could not be attributed to hydropathy, charge, disulfide bonding, or burial.

Amino Acids↗

PubMed2002

Protein-based analysis of alternative splicing in the human genome.

Understanding the functional significance of alternative splicing and other mechanisms that generate RNA transcript diversity is an important challenge facing modern-day molecular biology. Using homology-based, protein sequence analysis methods, it should be possible to investigate how transcript diversity impacts protein structure and function. To test this, a data mining technique ("DiffHit") was developed to identify and catalog genes producing protein isoforms which exhibit distinct profiles of conserved protein motifs. We found that out of a test set of over 1,300 alternatively spliced genes with solved genomic structure, over 30% exhibited a differential profile of conserved InterPro and/or Blocks protein motifs across distinct isoforms. These results suggest that motif databases such as Blocks and InterPro are potentially useful tools for investigating how alternative transcript structure affects gene function.

Algorithms↗