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Biomedical subjects

Christopher H Woelk

Publications and source records attributed to Christopher H Woelk.

10 recordsLinked to original sources
PubMed2006

GARD: a genetic algorithm for recombination detection.

MOTIVATION: Phylogenetic and evolutionary inference can be severely misled if recombination is not accounted for, hence screening for it should be an essential component of nearly every comparative study. The evolution of recombinant sequences can not be properly explained by a single phylogenetic tree, but several phylogenies may be used to correctly model the evolution of non-recombinant fragments. RESULTS: We developed a likelihood-based model selection procedure that uses a genetic algorithm to search multiple sequence alignments for evidence of recombination breakpoints and identify putative recombinant sequences. GARD is an extensible and intuitive method that can be run efficiently in parallel. Extensive simulation studies show that the method nearly always outperforms other available tools, both in terms of power and accuracy and that the use of GARD to screen sequences for recombination ensures good statistical properties for methods aimed at detecting positive selection. AVAILABILITY: Freely available http://www.datamonkey.org/GARD/

Algorithms↗
PubMed2006

Automated phylogenetic detection of recombination using a genetic algorithm.

The evolution of homologous sequences affected by recombination or gene conversion cannot be adequately explained by a single phylogenetic tree. Many tree-based methods for sequence analysis, for example, those used for detecting sites evolving nonneutrally, have been shown to fail if such phylogenetic incongruity is ignored. However, it may be possible to propose several phylogenies that can correctly model the evolution of nonrecombinant fragments. We propose a model-based framework that uses a genetic algorithm to search a multiple-sequence alignment for putative recombination break points, quantifies the level of support for their locations, and identifies sequences or clades involved in putative recombination events. The software implementation can be run quickly and efficiently in a distributed computing environment, and various components of the methods can be chosen for computational expediency or statistical rigor. We evaluate the performance of the new method on simulated alignments and on an array of published benchmark data sets. Finally, we demonstrate that prescreening alignments with our method allows one to analyze recombinant sequences for positive selection.

Algorithms↗
PubMed2005

Codon volatility does not reflect selective pressure on the HIV-1 genome.

Codon volatility is defined as the proportion of a codon's point-mutation neighbors that encode different amino acids. The cumulative volatility of a gene in relation to its associated genome was recently reported to be an indicator of selection pressure. We used this approach to measure selection on all available full-length HIV-1 subtype B genomes in the Los Alamos HIV Sequence Database, and compared these estimates against those obtained via established likelihood- and distance-based comparative methods. Volatility failed to correlate with the results of any of the comparative methods demonstrating that it is not a reliable indicator of selection pressure.

Biological Evolution↗
PubMed2004

Interferon gene expression following HIV type 1 infection of monocyte-derived macrophages.

Macrophages represent one of the primary targets of HIV-1 infection. Changes in gene expression in primary human monocyte-derived macrophages following virus exposure were assessed using oligonucleotide arrays. Over a third of the 100 most modulated genes belonged to the interferon system. Upregulated interferon-stimulated genes included those essential for the innate immune response and also those involved in interferon and virus signal transduction from the cell surface. The promoter regions of a cluster of highly upregulated interferon-stimulated genes were analyzed for common regulatory elements. The nuclear factor in activated T cells (NFAT) and members of the interferon family of transcription factors appeared to be responsible for the upregulation of this set of interferon-stimulated genes following HIV-1 exposure.

Cells, Cultured↗
PubMed2004

Comparative study of adaptive molecular evolution in different human immunodeficiency virus groups and subtypes.

Molecular adaptation, as characterized by the detection of positive selection, was quantified in a number of genes from different human immunodeficiency virus type 1 (HIV-1) group M subtypes, group O, and an HIV-2 subtype using the codon-based maximum-likelihood method of Yang and coworkers (Z. H. Yang, R. Nielsen, N. Goldman, and A. M. K. Pedersen, Genetics 155:431-449, 2000). The env gene was investigated further since it exhibited the strongest signal for positive selection compared to those of the other two major HIV genes (gag and pol). In order to investigate the pattern of adaptive evolution across env, the location and strength of positive selection in different HIV-1 sequence alignments was compared. The number of sites having a significant probability of being positively selected varied among these different alignment data sets, ranging from 25 in HIV-1 group M subtype A to 40 in HIV-1 group O. Strikingly, there was a significant tendency for positively selected sites to be located at the same position in different HIV-1 alignments, ranging from 10 to 16 shared sites for the group M intersubtype comparisons and from 6 to 8 for the group O to M comparisons, suggesting that all HIV-1 variants are subject to similar selective forces. As the host immune response is believed to be the dominant driving force of adaptive evolution in HIV, this result would suggest that the same sites are contributing to viral persistence in diverse HIV infections. Thus, the positions of the positively selected sites were investigated in reference to the inferred locations of different epitope types (antibody, T helper, and cytotoxic T lymphocytes) and the positions of N and O glycosylation sites. We found a significant tendency for positively selected sites to fall outside T-helper epitopes and for positively selected sites to be strongly associated with N glycosylation sites.

Adaptation, Physiological↗
PubMed2002

Genetic constraints and the adaptive evolution of rabies virus in nature.

We used a molecular evolutionary approach to investigate the species adaptation of rabies virus in nature. A maximum likelihood analysis of selection pressures revealed that the nucleoprotein (N) and glycoprotein (G) genes of natural viral isolates were highly constrained, especially at nonsynonymous sites, in contrast to the higher rates of nonsynonymous evolution observed in viruses subject to laboratory passage. Positive selection was only found at a single amino acid site--position 183 in the ectodomain of the G gene. The low rate of nonsynonymous evolution in natural isolates of rabies virus may be due to constraints imposed by the need to replicate in multiple cell types within the host, which in turn facilitates cross-species transmission, or because viral proteins are not subject to immune selection. Using known dates in the epidemiologic history of European viral isolates, we estimated that overall rates of nucleotide substitution in rabies virus were similar to those observed in other RNA viruses. Assuming that the average rate of synonymous change does not vary among species, we estimated that the current genetic diversity in lyssavirus genotype 1 may have arisen only during the last 500 years.

Adaptation, Physiological↗
PubMed2002

Increased positive selection pressure in persistent (SSPE) versus acute measles virus infections.

We compared the extent of positive selection acting on acute and persistent strains of measles virus (MV). Far stronger positive selection was found in the fusion (F) and haemagglutinin (H) genes from subacute sclerosing panencephalitis (SSPE) compared to acute MV cases. Most of the positively selected sites identified in these surface glycoprotein genes from SSPE cases correspond to structural, functional or antigenic areas, and could not be explained by the effects of cell passaging. The correlations between selected sites and functional studies of MV are discussed in detail with reference to the maintenance of persistent infection. No positive selection was found in the matrix (M) gene from acute cases of MV and the effects of including hypermutated SSPE M gene sequences in phylogenetic inference were also explored. Finally, using H gene data, we estimated the rate of molecular evolution for SSPE strains as 3.4 x 10(-4) substitutions/site/year, which is similar to previous estimates obtained for acute strains.

Evolution, Molecular↗
PubMed2002

Phylogenetic evidence for adaptive evolution of dengue viruses in nature.

A maximum-likelihood approach was used to analyse selection pressures acting on genes from all four serotypes of dengue virus (DEN). A number of amino acid positions were identified within the envelope (E) glycoprotein that have been subject to relatively weak positive selection in both DEN-3 and DEN-4, as well as in two of the five genotypes of DEN-2. No positive selection was detected in DEN-1. In accordance with the function of the E protein as the major antigenic determinant of DEN, the majority of these sites were located in, or near to, potential T- or B-cell epitopes. A smaller number of selected sites was located in other well-defined functional domains of the E protein, suggesting that cell tropism and virus-mediated membrane fusion may also confer fitness advantages to DEN in nature. Several positively selected amino acid substitutions were also identified in the NS2B and NS5 genes of DEN-2, although the cause of this selection is unclear, whereas the capsid, membrane and non-structural genes NS1, NS2A, NS3 and NS4 were all subject to strong functional constraints. Hence, evidence was found for localized adaptive evolution in natural isolates of DEN, revealing that selection pressures differ among serotypes, genotypes and viral proteins.

Biological Evolution↗
PubMed2001

Immune and artificial selection in the haemagglutinin (H) glycoprotein of measles virus.

We present a maximum likelihood (ML) analysis of the selection pressures that have shaped the evolution of the large (L) protein and the haemagglutinin (H) glycoprotein of measles virus (MV). A number of amino acid sites that have potentially been subject to adaptive evolution were identified in the H protein using sequences from every known genotype of MV. All but one of these putative positively selected sites reside within the ectodomain of the H protein, where they often show an association with positions of potential B-cell epitopes and sites known to interact with the CD46 receptor. This suggests that MV may be under pressure from the immune system, albeit relatively weakly, to alter sites within epitopes and hence evade the humoral immune response. The positive selection identified at amino acid 546 was shown to correlate with the passage history of MV isolates in Vero cells. We reveal that Vero cell passaging has the potential to introduce an artificial signal of adaptive evolution through selection for changes that increase affinity for the CD46 receptor.

Amino Acid Sequence↗