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Letter↗
Biomedical subjects
Cathal Seoighe
Publications and source records attributed to Cathal Seoighe.
Allele-specific transcript isoforms in human.
Estimates of the number of human genes that produce more than one transcript isoform through alternative mRNA splicing depend on the assumption that the observation of multiple transcripts from a gene can be attributed entirely to alternative splicing. It is possible, however, that a substantial proportion of cases where multiple transcripts have been observed for a gene result from differences between alleles. Many examples of genes that are spliced differently from different alleles have been reported but no systematic estimate of the proportion of alternatively spliced genes that are affected by such polymorphisms has been carried out. We find that alternative transcript isoforms are non-randomly associated with closely linked nucleotide polymorphisms, based on an integrated analysis of the dbSNP, dbEST and ASAP databases. From the observed level of association between transcript isoforms and polymorphisms, we estimate that 21% of alternatively spliced genes are affected by polymorphisms that either completely determine which form of the transcript is observed or alter the relative abundances of some of the alternative isoforms. We provide a conservative lower bound of 6% on this estimate and point out that alternative splicing cannot be confirmed absolutely unless more than one transcript is observed from the same allele.
Alleles↗
Incidence of HIV-1 dual infection and its association with increased viral load set point in a cohort of HIV-1 subtype C-infected female sex workers.
This longitudinal study aimed to determine the incidence and pathogenic implications of dual human immunodeficiency virus type 1 (HIV-1) infection in a cohort of female sex workers. Blood samples from 31 recently infected women were screened by use of a heteroduplex mobility assay and sequencing. The median viral load set point was 5404 copies/mL (n=22), which was measured by use of the bDNA assay. Within 3 months of infection, 19% (6/31) of the women were dually infected with 2 distinct HIV-1 subtype C viruses. No evidence of superinfection was detected over the course of 24 months of follow-up, indicating that the risk of dual infection is highest around the time of the initial infection. There was a significant association between dual infection and elevated viral load set point.
Acquired Immunodeficiency Syndrome↗
A plant natriuretic peptide-like gene in the bacterial pathogen Xanthomonas axonopodis may induce hyper-hydration in the plant host: a hypothesis of molecular mimicry.
BACKGROUND: Plant natriuretic peptides (PNPs) are systemically mobile molecules that regulate homeostasis at nanomolar concentrations. PNPs are up-regulated under conditions of osmotic stress and PNP-dependent processes include changes in ion transport and increases of H2O uptake into protoplasts and whole tissue. PRESENTATION OF THE HYPOTHESIS: The bacterial citrus pathogen Xanthomonas axonopodis pv. Citri str. 306 contains a gene encoding a PNP-like protein. We hypothesise that this bacterial protein can alter plant cell homeostasis and thus is likely to represent an example of molecular mimicry that enables the pathogen to manipulate plant responses in order to bring about conditions favourable to the pathogen such as the induced plant tissue hyper-hydration seen in the wet edged lesions associated with Xanthomonas axonopodis infection. TESTING THE HYPOTHESIS: We found a Xanthomonas axonopodis PNP-like protein that shares significant sequence similarity and identical domain organisation with PNPs. We also observed a significant excess of conserved residues between the two proteins within the domain previously identified as being sufficient to induce biological activity. Structural modelling predicts identical six stranded double-psi beta barrel folds for both proteins thus supporting the hypothesis of similar modes of action. No significant similarity between the Xanthomonas axonopodis protein and other bacterial proteins from GenBank was found. Sequence similarity of the Xanthomonas axonopodis PNP-like protein with the Arabidopsis thaliana PNP (AtPNP-A), shared domain organisation and incongruent phylogeny suggest that the PNP-gene may have been acquired by the bacteria in an ancient lateral gene transfer event. Finally, activity of a recombinant Xanthomonas axonopodis protein in plant tissue and changes in symptoms induced by a Xanthomonas axonopodis mutant with a knocked-out PNP-like gene will be experimental proof of molecular mimicry. IMPLICATION OF THE HYPOTHESIS: If the hypothesis is true, it could at least in part explain why the citrus pathogen Xanthomonas campestris that does not contain a PNP-like gene produces dry corky lesions while the closely related Xanthomonas axonopodis forms lesions with wet edges. It also suggests that genes typically found in the host, horizontally transferred or heterologous, can help to explain aspects of the physiology of the host-pathogen interactions.
Amino Acid Sequence↗
FRAGS: estimation of coding sequence substitution rates from fragmentary data.
BACKGROUND: Rates of substitution in protein-coding sequences can provide important insights into evolutionary processes that are of biomedical and theoretical interest. Increased availability of coding sequence data has enabled researchers to estimate more accurately the coding sequence divergence of pairs of organisms. However the use of different data sources, alignment protocols and methods to estimate substitution rates leads to widely varying estimates of key parameters that define the coding sequence divergence of orthologous genes. Although complete genome sequence data are not available for all organisms, fragmentary sequence data can provide accurate estimates of substitution rates provided that an appropriate and consistent methodology is used and that differences in the estimates obtainable from different data sources are taken into account. RESULTS: We have developed FRAGS, an application framework that uses existing, freely available software components to construct in-frame alignments and estimate coding substitution rates from fragmentary sequence data. Coding sequence substitution estimates for human and chimpanzee sequences, generated by FRAGS, reveal that methodological differences can give rise to significantly different estimates of important substitution parameters. The estimated substitution rates were also used to infer upper-bounds on the amount of sequencing error in the datasets that we have analysed. CONCLUSION: We have developed a system that performs robust estimation of substitution rates for orthologous sequences from a pair of organisms. Our system can be used when fragmentary genomic or transcript data is available from one of the organisms and the other is a completely sequenced genome within the Ensembl database. As well as estimating substitution statistics our system enables the user to manage and query alignment and substitution data.
Animals↗
Genome duplication led to highly selective expansion of the Arabidopsis thaliana proteome.
Multiple ancient genome duplications in Arabidopsis thaliana provide unique opportunities to assess factors that influence the fates of duplicated genes. We have found that genes retained in duplicate following one round of genome duplication are significantly more likely to be retained in duplicate again after a subsequent genome duplication. Genes retained in duplicate form a functionally biased set and include a significant over-representation of genes involved in the regulation of transcription.
Arabidopsis↗
Significantly different patterns of amino acid replacement after gene duplication as compared to after speciation.
We have performed a large-scale analysis of amino acid sequence evolution after gene duplication by comparing evolution after gene duplication with evolution after speciation in over 1,800 phylogenetic trees constructed from manually curated alignments of protein domains downloaded from the PFAM database. The site-specific rate of evolution is significantly altered by gene duplication. A significant increase in the proportion of amino acid substitutions at constrained (slowly evolving) sites after duplication was observed. An increase in the proportion of replacements at normally constrained amino acid sites could result from relaxation of purifying selective pressure. However, the proportion of amino acid replacements involving radical changes in amino acid properties after duplication does not appear to be significantly increased by relaxed selective pressure. The increased proportion of replacements at constrained sites was observed over a relatively large range of protein change (up to 25% amino acid replacements per site). These findings have implications for our understanding of the nature of evolution after duplication and may help to shed light on the evolution of novel protein functions through gene duplication.
Algorithms↗
Turning the clock back on ancient genome duplication.
Complete genome sequence data led rapidly to the conclusion that ancient genome duplications had shaped the genomes of the model organisms Saccharomyces cerevisiae and Arabidopsis thaliana. Recent contributions have gone on to refine date estimates for these duplications and, in the case of Arabidopsis, to infer additional, more ancient, rounds of duplication by reconstructing gene order before the most recent duplication event. It is becoming widely accepted that an ancient duplication occurred before the radiation of the ray-finned fish. However, despite methodological advances and the availability of complete genome sequence data the debate over whether very ancient genome duplications have occurred early in the vertebrate lineage has not yet been fully resolved.
Animals↗
Impact of the presence of paralogs on sequence divergence in a set of mouse-human orthologs.
Using a large set of orthologous human and mouse gene pairs, we have characterized genes that have been retained in duplicate in human over timescales comparable to the time of speciation of human and mouse. Orthologous gene pairs for which a paralogous gene has been present for much or all of the time since speciation show an increased rate of nonsynonymous substitution. We have related rate of divergence to functional classification using the Gene Ontology terms. Protein function was found, in some cases, to have a larger impact on rate of evolution than the presence or absence of a paralog. No evidence was found that genes that have been retained in duplicate are weighted toward any functional categories. An increase in the ratio of nonsynonymous to synonymous changes following duplication has previously been reported. However, because amino acid sequences include conservative as well as more freely evolving sites, the ratio of nonsynonymous to synonymous changes tends to be higher for closely related pairs. By measuring the divergence of orthologs only and comparing between genes for which a paralogous gene is either present or absent, we have compared gene pairs that share a common divergence time. We have also found that shorter genes have a higher probability of being found duplicated in the human genome, possibly reflecting a mutational effect.
Alleles↗