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Biomedical subjects

K A Crandall

Publications and source records attributed to K A Crandall.

At least 19 recordsLinked to original sources
PubMed2005

A modified bootscan algorithm for automated identification of recombinant sequences and recombination breakpoints.

We have developed a modified BOOTSCAN algorithm that may be used to screen nucleotide sequence alignments for evidence of recombination without prior identification of nonrecombinant reference sequences. The algorithm is fast and includes a Bonferroni corrected statistical test of recombination to circumvent the multiple testing problems encountered when using the BOOTSCAN method to explore alignments for evidence of recombination. Using both simulated and real datasets we demonstrate that the modified algorithm is more powerful than other phylogenetic recombination detection methods and performs almost as well as one of the best substitution distribution recombination detection methods.

Algorithms↗
PubMed2004

Phylogeography and speciation of colour morphs in the colonial ascidian Pseudodistoma crucigaster.

Variation in pigmentation is common in marine invertebrates, although few studies have shown the existence of genetic differentiation of chromatic forms in these organisms. We studied the genetic structure of a colonial ascidian with populations of different colour morphs in the northwestern Mediterranean. A fragment of the c oxidase subunit 1 (COI) mitochondrial gene was sequenced in seven populations of Pseudodistoma crucigaster belonging to three different colour morphs (orange, yellow and grey). Maximum likelihood analyses showed two well-supported clades separating the orange morph from the yellow-grey morphotypes. Genetic divergence between these clades was 2.12%, and gamma(ST) values between populations of the two clades were high (average 0.936), pointing to genetic isolation. Nested clade and coalescence analyses suggest that a past fragmentation event may explain the phylogeographical origin of these two clades. Non-neutral mtDNA evolution is observed in our data when comparing the two clades, showing a significant excess of nonsynonymous polymorphism within the yellow-grey morphotype using the McDonald-Kreitman test, which is interpreted as further support of reproductive isolation. We conclude that the two clades might represent separate species. We compare the population genetic differentiation found with that estimated for other colonial and solitary ascidian species, and relate it to larval dispersal capabilities and other life-history traits.

Animals↗
PubMed2001

Evaluation of methods for detecting recombination from DNA sequences: computer simulations.

Recombination is a key evolutionary process that shapes the architecture of genomes and the genetic structure of populations. Although many statistical methods are available for the detection of recombination from DNA sequences, their absolute and relative performance is still unknown. Here we evaluated the performance of 14 different recombination detection algorithms. We used the coalescent with recombination to simulate DNA sequences with different levels of recombination, genetic diversity, and rate variation among sites. Recombination detection methods were applied to these data sets, and whether they detected or not recombination was recorded. Different recombination methods showed distinct performance depending on the amount of recombination, genetic diversity, and rate variation among sites. The model of nucleotide substitution under which the data were generated did not seem to have a significant effect. Most methods increase power with more sequence divergence. In general, recombination detection methods seem to capture the presence of recombination, but they are not very powerful. Methods that use substitution patterns or incompatibility among sites were more powerful than methods based on phylogenetic incongruence. Most methods do not seem to infer more false positives than expected by chance. Especially depending on the amount of diversity in the data, different methods could be used to attain maximum power while minimizing false positives. Results shown here will provide some guidance in the selection of the most appropriate method/s for the analysis of the particular data at hand.

Computer Simulation↗
PubMed2001

Selecting models of nucleotide substitution: an application to human immunodeficiency virus 1 (HIV-1).

The blind use of models of nucleotide substitution in evolutionary analyses is a common practice in the viral community. Typically, a simple model of evolution like the Kimura two-parameter model is used for estimating genetic distances and phylogenies, either because other authors have used it or because it is the default in various phylogenetic packages. Using two statistical approaches to model fitting, hierarchical likelihood ratio tests and the Akaike information criterion, we show that different viral data sets are better explained by different models of evolution. We demonstrate our results with the analysis of HIV-1 sequences from a hierarchy of samples; sequences within individuals, individuals within subtypes, and subtypes within groups. We also examine results for three different gene regions: gag, pol, and env. The Kimura two-parameter model was not selected as the best-fit model for any of these data sets, despite its widespread use in phylogenetic analyses of HIV-1 sequences. Furthermore, the model complexity increased with increasing sequence divergence. Finally, the molecular-clock hypothesis was rejected in most of the data sets analyzed, throwing into question clock-based estimates of divergence times for HIV-1. The importance of models in evolutionary analyses and their repercussions on the derived conclusions are discussed.

Databases, Factual↗
PubMed2001

Selecting the best-fit model of nucleotide substitution.

Despite the relevant role of models of nucleotide substitution in phylogenetics, choosing among different models remains a problem. Several statistical methods for selecting the model that best fits the data at hand have been proposed, but their absolute and relative performance has not yet been characterized. In this study, we compare under various conditions the performance of different hierarchical and dynamic likelihood ratio tests, and of Akaike and Bayesian information methods, for selecting best-fit models of nucleotide substitution. We specifically examine the role of the topology used to estimate the likelihood of the different models and the importance of the order in which hypotheses are tested. We do this by simulating DNA sequences under a known model of nucleotide substitution and recording how often this true model is recovered by the different methods. Our results suggest that model selection is reasonably accurate and indicate that some likelihood ratio test methods perform overall better than the Akaike or Bayesian information criteria. The tree used to estimate the likelihood scores does not influence model selection unless it is a randomly chosen tree. The order in which hypotheses are tested, and the complexity of the initial model in the sequence of tests, influence model selection in some cases. Model fitting in phylogenetics has been suggested for many years, yet many authors still arbitrarily choose their models, often using the default models implemented in standard computer programs for phylogenetic estimation. We show here that a best-fit model can be readily identified. Consequently, given the relevance of models, model fitting should be routine in any phylogenetic analysis that uses models of evolution.

Algorithms↗
PubMed2000

Human immunodeficiency virus type 1 quasi species that rebound after discontinuation of highly active antiretroviral therapy are similar to the viral quasi species present before initiation of therapy.

In an effort to identify the sources of the viruses that emerge after discontinuation of therapy, analyses of human immunodeficiency virus (HIV) quasi species were done for 3 patients with sustained levels of HIV RNA of <50 copies/mL for 1-3 years. The sequences found in the rebounding plasma virus were closely related to those of the actively replicating form of viruses present before the initiation of combination therapy. All quasi species found in the rebounding plasma virus were also present in proviral DNA, cell-associated RNA in peripheral blood mononuclear cells (PBMC), and virion RNA derived from PBMC coculture during periods when plasma HIV RNA levels were <50 copies/mL. These findings suggest that the rapid resurgence of plasma viremia observed after discontinuation of therapy and the viruses cocultured from PBMC are derived from a relatively stable pool of the replicating form of virus rather than from activation of a previously latent pool.

Adult↗
PubMed2000

Limited heterogeneity of HIV type 1 in infected mothers correlates with lack of vertical transmission.

The human immunodeficiency virus type 1 (HIV-1) envelope V3 region sequences of peripheral blood mononuclear cell DNA were analyzed from three nontransmitting mothers (infected mothers who failed to transmit HIV-1 to their infants in the absence of antiretroviral therapy), including one mother with two deliveries, and compared with the sequences of seven previously analyzed transmitting mothers. The coding potential of the envelope open reading frame, including several patient-specific amino acid motifs and previously described molecular features across the V3 region, were highly conserved. There was a low degree of heterogeneity within the sequences of each nontransmitting mother compared with the sequences of transmitting mothers. In addition, the estimates of genetic diversity of nontransmitting mother sequences were significantly lower compared with transmitting mother sequences. Phylogenetic analysis showed that the sequences of each nontransmitting mother formed distinct clusters that were well discriminated from each other and the sequences of seven transmitting mothers. In conclusion, a low degree of HIV-1 genetic heterogeneity in these infected mothers correlates with lack of vertical transmission; this finding may be useful in developing strategies for further prevention of maternal-fetal transmission.

Amino Acid Sequence↗
PubMed2000

The monophyletic origin of freshwater crayfish estimated from nuclear and mitochondrial DNA sequences.

Despite their widespread use as model organisms, the phylogenetic status of the around 520 species of freshwater crayfish is still in doubt. One hypothesis suggests two distinct origins of freshwater crayfish as indicated by their geographical distribution, with two centres of origin near the two present centres of diversity; one in south-eastern United States and the other in Victoria, Australia. An alternative theory proposes a single (monophyletic) origin of freshwater crayfish. Here we use over 3000 nucleotides from three different gene regions in estimating phylogenetic relationships among freshwater crayfish and related Crustacea. We show clear evidence for monophyly of freshwater crayfish and for the sister-group relationship between crayfish and clawed lobsters. Monophyly of the superfamilies Astacoidea and Parastacoidea is also supported. However, the monophyly of the family Cambaridae is questioned with the genus Cambaroides being associated with the Astacidae.

Animals↗
PubMed2000

HTLV type I/II in British Columbia Amerindians: a seroprevalence study and sequence characterization of an HTLV type IIa isolate.

It has been established that the human T cell lymphotropic viruses type I and II (HTLV-I and HTLV-II) are both present in some indigenous peoples of the Americas. While HTLV-I has been identified in coastal British Columbia Indians (BCIs), HTLV-II has not been previously reported in the BCIs or other Canadian Amerindians. The prevalence of HTLV-I and HTLV-II in these populations has not been extensively studied. In this article, we examine a group of BCIs from Vancouver Island who belong to the Nuu-Chah-Nulth and are known to have an increased incidence of rheumatic disease. In 494 serum samples from this tribe, the levels of prevalence of HTLV-I and HTLV-II were 2.8 and 1.6%, respectively. No association could be made between arthropathy and HTLV-I infection. In addition, we characterized an HTLV-II isolate of a BCI from the coastal mainland of British Columbia and with a history of intravenous drug abuse. This case represents the first molecular characterization of a Canadian Amerindian HTLV-II isolate: a subtype IIa virus with phylogenetic affinity for intravenous drug user isolates and containing an extended form of the Tax protein. These results are consistent either with this strain having been sampled from a polymorphic ancestral pool of HTLV-II that gave rise to the current epidemic spread of this virus by intravenous drug use and sexual transmission, or with its being "back-transmitted" into the BC Amerindian population in association with intravenous drug use.

Base Sequence↗
PubMed2000

Intragenomic variation within ITS1 and ITS2 of freshwater crayfishes (Decapoda: Cambaridae): implications for phylogenetic and microsatellite studies.

Intragenomic variation in ITS1 and ITS2 is known to exit but is widely ignored in phylogenetic studies using these gene regions. The amount of variation in seven crayfish species, including three populations of Orconectes luteus and two of Procambarus clarkii, was assessed by sequencing 3, 5, or 10 clones from the same individuals, for a total of 77 sequences. The ITS1 and ITS2 sequences reported here are some of the longest known, with aligned lengths of 760 and 1,300 bp, respectively. They contain multiple microsatellite insertions, all of which show considerable intragenomic variation in the number of repeat elements. This variation is enough to obscure phylogenetic relationships at the population level, although relationships between species can be estimated. Given the hybridization techniques used to locate microsatellites, multiple-copy regions like ITS1 and ITS2 will be preferentially found if they contain microsatellites, and in these cases the microsatellites will not behave as typical Mendelian markers and could give spurious results.

Animals↗
PubMed2000

Population genetics of the porB gene of Neisseria gonorrhoeae: different dynamics in different homology groups.

The porB locus codes for the major outer membrane protein of Neisseria gonorrhoeae. Alleles of this locus have been assigned to two homology groups based on close sequence and immunological relationships and are designated as either PIA or PIB. Several population parameters were estimated and compared among these two groups using a data set of 22 PIA sequences and 91 PIB sequences obtained from diverse geographic localities and from time periods spanning approximately 50 years. Recombination appears to be extensive in the porB gene. While the recombination rates are similar for the PIA and PIB sequences, the relative contribution of recombination to genetic diversity is higher for the PIA sequences. Alleles belonging to the PIB group show greater genetic diversity than do those in the PIA group. Although phylogenetic analysis did not reveal temporal or geographic clustering of sequences, estimates of gene flow and the fixation index suggested that PIB sequences exhibit population substructure based on geographic locality. Selection acts in these homology groups in a different way. While positive Darwinian selection is the dominant force driving the evolution of the PIA sequences, purifying selection operates also on the PIB sequences. These differences may be attributable to the greater propensity of PIA strains, as compared with PIB strains, to cause disseminated gonococcal infection, which would expose the former to intense selection pressure from the host immune system. The molecular evolution of Neisseria gonorrhoeae seems to be driven by the simultaneous action of selection and recombination, but under different rates and selection pressures for the PIA and PIB homology groups.

Alleles↗
PubMed2000

PCR detection of host and HIV-1 sequences from archival brain tissue.

Mutations in CCR5 and CCR2b have been recently shown to affect disease progression towards AIDS. A role for these host genotypes in AIDS dementia complex (ADC) has also been postulated but remains unclear. Additionally, brain-derived envelope sequences from HIV-1 have been associated with ADC but their specific contribution to pathogenesis remains uncertain. This study demonstrates the successful use of PCR techniques to isolate host CCR5 and CCR2b, and HIV-1 V3 sequences from paraffin embedded tissues from patients with and without ADC. PCR amplification from archival tissue offers a novel approach for studying the interactions between potential neuroprotective elements in the host and virulence determinants in HIV that may contribute to differences in susceptibility to ADC.

AIDS Dementia Complex↗
PubMed1999

Independent evolution of HIV type 1 in different brain regions.

HIV-1-associated brain pathology exhibits regional variability and we therefore studied the genetic differences in the V1-V5 domains of the HIV env gene in up to four regions of brain (frontal lobe, basal ganglia, medial temporal lobe, and nonmedial temporal lobe) from three patients. We found that in each separate brain region HIV-1 forms different quasispecies and that there is little gene flow among these regions. In further support of brain region-specific evolution of HIV-1, we analyzed amino acid signatures in these clones. In addition to known amino acid signatures associated with macrophage tropism and the lack of syncytium formation, we found 15 majority amino acid signature patterns from the V1-V5 env sequences associated with the neuroanatomical regions analyzed from the three individuals. Furthermore, on average, intrabrain genetic distances for the HIV-1 env were estimated to be much smaller than genetic distances between brain regions. Specific strains of HIV-1 may be neurotropic or neuroinvasive (replication preference in brain tissue) and may contribute to pathology, cognitive loss, and neuropsychiatric disease.

Adult↗
PubMed1999

Different models, different trees: the geographic origin of PTLV-I.

Using nucleotide sequences from three genomic regions of the human and simian T-cell lymphotropic virus type I (HTLV-I/STLV-I)-consisting of 69 sequences from a 140-bp segment of the pol region, 98 sequences from a 503-bp segment of the LTR, and 154 sequences from a 386-bp segment of the env region-we tested two hypotheses concerning the geographic origin and evolution of STLV-I and HTLV-I. First, we tested the assumption of equal rates of evolution along STLV-I and HTLV-I lineages using a likelihood ratio test to ascertain whether current levels of genomic diversity can be used to determine ancestry. We demonstrated that unequal rates of evolution along HTLV-I and STLV-I lineages have occurred throughout evolutionary time, thus calling into question the use of pairwise distances to assign ancestry. Second, we constructed phylogenetic trees using multiple phylogenetic techniques to test for the geographic origin of STLV-I and HTLV-I. Using the principle of likelihood, we chose a statistically justified model of evolution for each data set. We demonstrated the utility of the likelihood ratio test to determine which model of evolution should be chosen for phylogenetic analyses, revealing that using different models of evolution produces conflicting results, and neither the hypothesis of an African origin nor the hypothesis of an Asian origin can be rejected statistically. Our best estimates of phylogenetic relationships, however, support an African origin of PTLV for each gene region.

Animals↗
PubMed1999

Parallel evolution of drug resistance in HIV: failure of nonsynonymous/synonymous substitution rate ratio to detect selection.

Parallel or convergent evolution at the molecular level has been difficult to demonstrate especially when rigorous statistical criteria are applied. We present sequence data from the protease gene from eight patients infected with the human immunodeficiency virus (HIV-1). These patients have been on multiple drug therapies for at least 2 years. We present sequence data from two timepoints: time zero--the initiation of drug therapy--and a subsequent timepoint between 59 and 104 weeks after the initiation of drug therapy. In addition to the sequence data, we present viral load data from both initial and final timepoints. Our phylogenetic analyses indicate significant evolution of virus from initial to final time points, even in three of eight patients who show low viral loads. Of the five patients who escaped drug therapy, identical amino acid replacements were seen in all five patients at two different codon positions, an indication of parallel evolution. We also measured genetic diversity for these patients and found no correlation between genetic diversity and viral load. Finally, we calculated the nonsynonymous and synonymous substitution rates and showed that the ratio of nonsynonymous to synonymous substitution compared to the value of one may be a poor indicator of natural selection.

Anti-HIV Agents↗