Biomedical subjects

Lawrence A Kelley

Publications and source records attributed to Lawrence A Kelley.

3 recordsLinked to original sources

PubMed2006

The proteome: structure, function and evolution.

This paper reports two studies to model the inter-relationships between protein sequence, structure and function. First, an automated pipeline to provide a structural annotation of proteomes in the major genomes is described. The results are stored in a database at Imperial College, London (3D-GENOMICS) that can be accessed at www.sbg.bio.ic.ac.uk. Analysis of the assignments to structural superfamilies provides evolutionary insights. 3D-GENOMICS is being integrated with related proteome annotation data at University College London and the European Bioinformatics Institute in a project known as e-protein (http://www.e-protein.org/). The second topic is motivated by the developments in structural genomics projects in which the structure of a protein is determined prior to knowledge of its function. We have developed a new approach PHUNCTIONER that uses the gene ontology (GO) classification to supervise the extraction of the sequence signal responsible for protein function from a structure-based sequence alignment. Using GO we can obtain profiles for a range of specificities described in the ontology. In the region of low sequence similarity (around 15%), our method is more accurate than assignment from the closest structural homologue. The method is also able to identify the specific residues associated with the function of the protein family.

Computational Biology↗

PubMed2006

Capturing expert knowledge with argumentation: a case study in bioinformatics.

MOTIVATION: The output of a bioinformatic tool such as BLAST must usually be interpreted by an expert before reliable conclusions can be drawn. This may be based upon the expert's experience, additional data and statistical analysis. Often the process is laborious, goes unrecorded and may be biased. Argumentation is an established technique for reasoning about situations where absolute truth or precise probability is impossible to determine. RESULTS: We demonstrate the application of argumentation to 3D-PSSM, a protein structure prediction tool. The expert's interpretation of results is represented as an argumentation framework. Given a 3D-PSSM result, an automated procedure constructs arguments for and against the conclusion that the result is a good predictor of protein structure. In addition to capturing the unique expertise of the author of 3D-PSSM for distribution to users, an improvement in recall of 5-10 percentage points is achieved. This technique can be applied to a wide range of bioinformatic tools. AVAILABILITY: Example public server and benchmarking data are available at http://www.sbg.bio.ic.ac.uk/~brj03/argumentation/paper/. Source code available on request.

Amino Acid Sequence↗

PubMed2004

The extent and importance of intragenic recombination.

We have studied the recombination rate behaviour of a set of 140 genes which were investigated for their potential importance in inflammatory disease. Each gene was extensively sequenced in 24 individuals of African descent and 23 individuals of European descent, and the recombination process was studied separately in the two population samples. The results obtained from the two populations were highly correlated, suggesting that demographic bias does not affect our population genetic estimation procedure. We found evidence that levels of recombination correlate with levels of nucleotide diversity. High marker density allowed us to study recombination rate variation on a very fine spatial scale. We found that about 40 per cent of genes showed evidence of uniform recombination, while approximately 12 per cent of genes carried distinct signatures of recombination hotspots. On studying the locations of these hotspots, we found that they are not always confined to introns but can also stretch across exons. An investigation of the protein products of these genes suggested that recombination hotspots can sometimes separate exons belonging to different protein domains; however, this occurs much less frequently than might be expected based on evolutionary studies into the origins of recombination. This suggests that evolutionary analysis of the recombination process is greatly aided by considering nucleotide sequences and protein products jointly.

Africa↗