Barbara R Holland

Publications of Barbara R Holland

• Gaps, an Elusive Source of Phylogenetic Information.

  Authors: Kumar Saurabh, Barbara R Holland, Gillian C Gibb, David Penny

  Systematic biology. 03/2012;

• Faster exact maximum parsimony search with XMP.

  Authors: W Timothy J White, Barbara R Holland

  Bioinformatics (Oxford, England). 03/2011; 27(10):1359-67.

  Despite trends towards maximum likelihood and Bayesian criteria, maximum parsimony (MP) remains an important criterion for evaluating phylogenetic trees. Because exact MP search is NP-complete, theDespite trends towards maximum likelihood and Bayesian criteria, maximum parsimony (MP) remains an important criterion for evaluating phylogenetic trees. Because exact MP search is NP-complete, the computational effort needed to find provably optimal trees skyrockets with increasing numbers of taxa, limiting analyses to around 25-30 taxa. This is, in part, because currently available programs fail to take advantage of parallelism. We present XMP, a new program for finding exact MP trees that comes in both serial and parallel versions. The serial version is faster in nearly all tests than existing software. The parallel version uses a work-stealing algorithm to scale to hundreds of CPUs on a distributed-memory multiprocessor with high efficiency. An optimized SSE2 inner loop provides additional speedup for Pentium 4 and later CPUs. C source code and several binary versions are freely available from http://www.massey.ac.nz/~wtwhite/xmp. The parallel version requires an MPI implementation, such as the freely available MPICH2.

• Biogeography of circum-Antarctic springtails.

  Authors: Angela McGaughran, Mark I Stevens, Barbara R Holland

  Molecular phylogenetics and evolution. 10/2010; 57(1):48-58.

  We examine the effects of isolation over both ancient and contemporary timescales on evolutionary diversification and speciation patterns of springtail species in circum-Antarctica, with specialWe examine the effects of isolation over both ancient and contemporary timescales on evolutionary diversification and speciation patterns of springtail species in circum-Antarctica, with special focus on members of the genus Cryptopygus (Collembola, Isotomidae). We employ phylogenetic analysis of mitochondrial DNA (cox1), and ribosomal DNA (18S and 28S) genes in the programmes MrBayes and RAxML. Our aims are twofold: (1) we evaluate existing taxonomy in light of previous work which found dubious taxonomic classification in several taxa based on cox1 analysis; (2) we evaluate the biogeographic origin of our chosen suite of springtail species based on dispersal/vicariance scenarios, the magnitude of genetic divergence among lineages and the age and accessibility of potential habitat. The dubious taxonomic characterisation of Cryptopygus species highlighted previously is confirmed by our multi-gene phylogenetic analyses. Specifically, according to the current taxonomy, Cryptopygus antarcticus subspecies are not completely monophyletic and neither are Cryptopygus species in general. We show that distribution patterns among species/lineages are both dispersal- and vicariance-driven. Episodes of colonisation appear to have occurred frequently, the routes of which may have followed currents in the Southern Ocean. In several cases, the estimated divergence dates among species correspond well with the timing of terrestrial habitat availability. We conclude that these isotomid springtails have a varied and diverse evolutionary history in the circum-Antarctic that consists of both ancient and recent elements and is reflected in a dynamic contemporary fauna.

• Identifying cliques of convergent characters: concerted evolution in the cormorants and shags.

  Authors: Barbara R Holland, Hamish G Spencer, Trevor H Worthy, Martyn Kennedy

  Systematic biology. 07/2010; 59(4):433-45.

  A phylogenetic tree comprising clades with high bootstrap values or other strong measures of statistical support is usually interpreted as providing a good estimate of the true phylogeny. ConvergentA phylogenetic tree comprising clades with high bootstrap values or other strong measures of statistical support is usually interpreted as providing a good estimate of the true phylogeny. Convergent evolution acting on groups of characters in concert, however, can lead to highly supported but erroneous phylogenies. Identifying such groups of phylogenetically misleading characters is obviously desirable. Here we present a procedure that uses an independent data source to identify sets of characters that have undergone concerted convergent evolution. We examine the problematic case of the cormorants and shags, for which trees constructed using osteological and molecular characters both have strong statistical support and yet are fundamentally incongruent. We find that the osteological characters can be separated into those that fit the phylogenetic history implied by the molecular data set and those that do not. Moreover, these latter nonfitting osteological characters are internally consistent and form groups of mutually compatible characters or "cliques," which are significantly larger than cliques of shuffled characters. We suggest, therefore, that these cliques of characters are the result of similar selective pressures and are a signature of concerted convergence.

• Phylogenetic tree reconstruction accuracy and model fit when proportions of variable sites change across the tree.

  Authors: Liat Shavit Grievink, David Penny, Michael D Hendy, Barbara R Holland

  Systematic biology. 05/2010; 59(3):288-97.

  Commonly used phylogenetic models assume a homogeneous process through time in all parts of the tree. However, it is known that these models can be too simplistic as they do not account forCommonly used phylogenetic models assume a homogeneous process through time in all parts of the tree. However, it is known that these models can be too simplistic as they do not account for nonhomogeneous lineage-specific properties. In particular, it is now widely recognized that as constraints on sequences evolve, the proportion and positions of variable sites can vary between lineages causing heterotachy. The extent to which this model misspecification affects tree reconstruction is still unknown. Here, we evaluate the effect of changes in the proportions and positions of variable sites on model fit and tree estimation. We consider 5 current models of nucleotide sequence evolution in a Bayesian Markov chain Monte Carlo framework as well as maximum parsimony (MP). We show that for a tree with 4 lineages where 2 nonsister taxa undergo a change in the proportion of variable sites tree reconstruction under the best-fitting model, which is chosen using a relative test, often results in the wrong tree. In this case, we found that an absolute test of model fit is a better predictor of tree estimation accuracy. We also found further evidence that MP is not immune to heterotachy. In addition, we show that increased sampling of taxa that have undergone a change in proportion and positions of variable sites is critical for accurate tree reconstruction.

• Impact of genetic background on allele selection in a highly mutable Candida albicans gene, PNG2.

  Authors: Ningxin Zhang, Richard D Cannon, Barbara R Holland, Mark L Patchett, Jan Schmid

  PloS one. 01/2010; 5(3):e9614.

  In many microbes rapid mutation of highly mutable contingency genes continually replenishes a pool of variant alleles from which the most suitable are selected, assisting in rapid adaptation andIn many microbes rapid mutation of highly mutable contingency genes continually replenishes a pool of variant alleles from which the most suitable are selected, assisting in rapid adaptation and evasion of the immune response. In some contingency genes mutability is achieved through DNA repeats within the coding region. The fungal human pathogen Candida albicans has 2600 repeat-containing ORFs. For those investigated (ALS genes, HYR1, HYR2, CEK1, RLM1) many protein variants with differing amino acid repeat regions exist, as expected for contingency genes. However, specific alleles dominate in different clades, which is unexpected if allele variation is used for short-term adaptation. Generation of new alleles of repeat-containing C. albicans ORFs has never been observed directly. Here we present evidence for restrictions on the emergence of new alleles in a highly mutable C. albicans repeat-containing ORF, PNG2, encoding a putative secreted or cell surface glycoamidase. In laboratory cultures new PNG2 alleles arose at a rate of 2.8x10(-5) (confidence interval 3.3x10(-6)-9. 9x10(-5)) per cell per division, comparable to rates measured for contingency genes. Among 80 clinical isolates 17 alleles of different length and 23 allele combinations were distinguishable; sequence differences between repeat regions of identical size suggest the existence of 36 protein variants. Specific allele combinations predominated in different genetic backgrounds, as defined by DNA fingerprinting and multilocus sequence typing. Given the PNG2 mutation rate, this is unexpected, unless in different genetic backgrounds selection favors different alleles. Specific alleles or allele combinations were not preferentially associated with C. albicans isolates from particular body sites or geographical regions. Our results suggest that the mutability of PNG2 is not used for short-term adaptation or evasion of the immune system. Nevertheless the large number of alleles observed indicates that mutability of PNG2 may assist C. albicans strains from different genetic backgrounds optimize their interaction with the host in the long term.

• Testing the effect of metabolic rate on DNA variability at the intra-specific level.

  Authors: Angela McGaughran, Barbara R Holland

  PloS one. 01/2010; 5(3):e9686.

  We tested the metabolic rate hypothesis (whereby rates of mtDNA evolution are postulated to be mediated primarily by mutagenic by-products of respiration) by examining whether mass-specific metabolicWe tested the metabolic rate hypothesis (whereby rates of mtDNA evolution are postulated to be mediated primarily by mutagenic by-products of respiration) by examining whether mass-specific metabolic rate was correlated with root-to-tip distance on a set of mtDNA trees for the springtail Cryptopygus antarcticus travei from sub-Antarctic Marion Island.Using Bayesian analyses and a novel application of the comparative phylogenetic method, we did not find significant evidence that contemporary metabolic rates directly correlate with mutation rate (i.e., root-to-tip distance) once the underlying phylogeny is taken into account. However, we did find significant evidence that metabolic rate is dependent on the underlying mtDNA tree, or in other words, lineages with related mtDNA also have similar metabolic rates.We anticipate that future analyses which apply this methodology to datasets with longer sequences, more taxa, or greater variability will have more power to detect a significant direct correlation between metabolic rate and mutation rate. We conclude with suggestions for future analyses that would extend the preliminary approach applied here, in particular highlighting ways to tease apart oxidative stress effects from the effects of population size and/or selection coefficients operating on the molecular evolutionary rate.

• Distribution of mutations distinguishing the most prevalent disease-causing Candida albicans genotype from other genotypes.

  Authors: Ningxin Zhang, Jenine E Upritchard, Barbara R Holland, Lauren E Fenton, Martin M Ferguson, Richard D Cannon, Jan Schmid

  Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases. 08/2009; 9(4):493-500.

  Candida albicans is a major opportunistic pathogen of humans. Previous work has demonstrated the existence of a general-purpose genotype (GPG; equivalent to clade 1 as defined by multi-locus sequenceCandida albicans is a major opportunistic pathogen of humans. Previous work has demonstrated the existence of a general-purpose genotype (GPG; equivalent to clade 1 as defined by multi-locus sequence typing data) that is more frequent than other genotypes as an agent of human disease and commensal colonization. We undertook a genomic screen which indicated that a large number of mutations differentiate GPG strains from other strains and that such mutations are scattered throughout the genome. GPG-specific mutations are non-synonymous more frequently than expected by chance, and are not randomly distributed across functional and structural gene categories. Our analysis has identified three categories of genes in which GPG-specific mutations are over-represented, namely genes for which expression changes during the yeast-hyphal transition, genes for which expression changes as a result of exposure to antifungal agents and repeat-containing ORFs. Although we have no direct evidence that the individual polymorphisms identified confer selective advantages to GPG strains, the results support our contention that the high prevalence of GPG strains is not merely due to genetic drift but that GPG strains have reached a high prevalence because they possess a multitude of fitness-enhancing traits. They also indicate that the distribution of genes marked by GPG-specific mutations across functional and structural categories could identify physiological traits that are of particular importance to the success of GPG strains in their interactions with the human host.

• The emergence of predators in early life: there was no Garden of Eden.

  Authors: Silvester de Nooijer, Barbara R Holland, David Penny

  PloS one. 02/2009; 4(6):e5507.

  BACKGROUND: Eukaryote cells are suggested to arise somewhere between 0.85~2.7 billion years ago. However, in the present world of unicellular organisms, cells that derive their food and metabolicBACKGROUND: Eukaryote cells are suggested to arise somewhere between 0.85~2.7 billion years ago. However, in the present world of unicellular organisms, cells that derive their food and metabolic energy from larger cells engulfing smaller cells (phagocytosis) are almost exclusively eukaryotic. Combining these propositions, that eukaryotes were the first phagocytotic predators and that they arose only 0.85~2.7 billion years ago, leads to an unexpected prediction of a long period (approximately 1-3 billion years) with no phagocytotes -- a veritable Garden of Eden. METHODOLOGY: We test whether such a long period is reasonable by simulating a population of very simple unicellular organisms -- given only basic physical, biological and ecological principles. Under a wide range of initial conditions, cellular specialization occurs early in evolution; we find a range of cell types from small specialized primary producers to larger opportunistic or specialized predators. CONCLUSIONS: Both strategies, specialized smaller cells and phagocytotic larger cells are apparently fundamental biological strategies that are expected to arise early in cellular evolution. Such early predators could have been 'prokaryotes', but if the earliest cells on the eukaryote lineage were predators then this explains most of their characteristic features.

• Optimizing Automated AFLP Scoring Parameters to Improve Phylogenetic Resolution.

  Authors: Barbara R Holland, Andrew C Clarke, Heidi M Meudt

  Systematic biology. 07/2008; 57(3):347-66.

  The amplified fragment length polymorphism (AFLP) technique is an increasingly popular component of the phylogenetic toolbox, particularly for plant species. Technological advances in capillaryThe amplified fragment length polymorphism (AFLP) technique is an increasingly popular component of the phylogenetic toolbox, particularly for plant species. Technological advances in capillary electrophoresis now allow very precise estimates of DNA fragment mobility and amplitude, and current AFLP software allows greater control of data scoring and the production of the binary character matrix. However, for AFLP to become a useful modern tool for large data sets, improvements to automated scoring are required. We design a procedure that can be used to optimize AFLP scoring parameters to improve phylogenetic resolution and demonstrate it for two AFLP scoring programs (GeneMapper and GeneMarker). In general, we found that there was a trade-off between getting more characters of lower quality and fewer characters of high quality. Conservative settings that gave the least error did not give the best phylogenetic resolution, as too many useful characters were discarded. For example, in GeneMapper, we found that bin width was a crucial parameter, and that although reducing bin width from 1.0 to 0.5 base pairs increased the error rate, it nevertheless improved resolution due to the increased number of informative characters. For our 30-taxon data sets, moving from default to optimized parameter settings gave between 3 and 11 extra internal edges with >50% bootstrap support, in the best case increasing the number of resolved edges from 14 to 25 out of a possible 27. Nevertheless, improvements to current AFLP software packages are needed to (1) make use of replicate profiles to calibrate the data and perform error calculations and (2) perform tests to optimize scoring parameters in a rigorous and automated way. This is true not only when AFLP data are used for phylogenetics, but also for other applications, including linkage mapping and population genetics.

• The problem of rooting rapid radiations.

  Authors: Liat Shavit, David Penny, Michael D Hendy, Barbara R Holland

  Molecular biology and evolution. 12/2007; 24(11):2400-11.

  There are many examples of groups (such as birds, bees, mammals, multicellular animals, and flowering plants) that have undergone a rapid radiation. In such cases, where there is a combination ofThere are many examples of groups (such as birds, bees, mammals, multicellular animals, and flowering plants) that have undergone a rapid radiation. In such cases, where there is a combination of short internal and long external branches, correctly estimating and rooting phylogenetic trees is known to be a difficult problem. In this simulation study, we tested the performances of different phylogenetic methods at estimating a tree that models a rapid radiation. We found that maximum likelihood, corrected and uncorrected neighbor-joining, and corrected and uncorrected parsimony, all suffer from biases toward specific tree topologies. In addition, we found that using a single-taxon outgroup to root a tree frequently disrupts an otherwise correct ingroup phylogeny. Moreover, for uncorrected parsimony, we found cases where several individual trees (in which the outgroup was placed incorrectly) were selected more frequently than the correct tree. Even for parameter settings where the correct tree was selected most frequently when using extremely long sequences, for sequences of up to 60,000 nucleotides the incorrectly rooted trees were each selected more frequently than the correct tree. For all the cases tested here, tree estimation using a two taxon outgroup was more accurate than when using a single-taxon outgroup. However, the ingroup was most accurately recovered when no outgroup was used.

• Deciphering past human population movements in Oceania: provably optimal trees of 127 mtDNA genomes.

  Authors: Melanie J Pierson, Rosa Martinez-Arias, Barbara R Holland, Neil J Gemmell, Matthew E Hurles, David Penny

  Molecular biology and evolution. 11/2006; 23(10):1966-75.

  The settlement of the many island groups of Remote Oceania occurred relatively late in prehistory, beginning approximately 3,000 years ago when people sailed eastwards into the Pacific from NearThe settlement of the many island groups of Remote Oceania occurred relatively late in prehistory, beginning approximately 3,000 years ago when people sailed eastwards into the Pacific from Near Oceania, where evidence of human settlement dates from as early as 40,000 years ago. Archeological and linguistic analyses have suggested the settlers of Remote Oceania had ancestry in Taiwan, as descendants of a proposed Neolithic expansion that began approximately 5,500 years ago. Other researchers have suggested that the settlers were descendants of peoples from Island Southeast Asia or the existing inhabitants of Near Oceania alone. To explore patterns of maternal descent in Oceania, we have assembled and analyzed a data set of 137 mitochondrial DNA (mtDNA) genomes from Oceania, Australia, Island Southeast Asia, and Taiwan that includes 19 sequences generated for this project. Using the MinMax Squeeze Approach (MMS), we report the consensus network of 165 most parsimonious trees for the Oceanic data set, increasing by many orders of magnitude the numbers of trees for which a provable minimal solution has been found. The new mtDNA sequences highlight the limitations of partial sequencing for assigning sequences to haplogroups and dating recent divergence events. The provably optimal trees found for the entire mtDNA sequences using the MMS method provide a reliable and robust framework for the interpretation of evolutionary relationships and confirm that the female settlers of Remote Oceania descended from both the existing inhabitants of Near Oceania and more recent migrants into the region.

• Heterozygosity and functional allelic variation in the Candida albicans efflux pump genes CDR1 and CDR2.

  Authors: Ann R Holmes, Sarah Tsao, Soo-Wee Ong, Erwin Lamping, Kyoko Niimi, Brian C Monk, Masakazu Niimi, Aki Kaneko, Barbara R Holland, Jan Schmid, Richard D Cannon

  Molecular microbiology. 10/2006; 62(1):170-86.

  Elevated expression of the plasma membrane drug efflux pump proteins Cdr1p and Cdr2p was shown to accompany decreased azole susceptibility in Candida albicans clinical isolates. DNA sequence analysisElevated expression of the plasma membrane drug efflux pump proteins Cdr1p and Cdr2p was shown to accompany decreased azole susceptibility in Candida albicans clinical isolates. DNA sequence analysis revealed extensive allelic heterozygosity, particularly of CDR2. Cdr2p alleles showed different abilities to transport azoles when individually expressed in Saccharomyces cerevisiae. Loss of heterozygosity, however, did not accompany decreased azole sensitivity in isogenic clinical isolates. Two adjacent non-synonymous single nucleotide polymorphisms (NS-SNPs), G1473A and I1474V in the putative transmembrane (TM) helix 12 of CDR2, were found to be present in six strains including two isogenic pairs. Site-directed mutagenesis showed that the TM-12 NS-SNPs, and principally the G1473A NS-SNP, contributed to functional differences between the proteins encoded by the two Cdr2p alleles in a single strain. Allele-specific PCR revealed that both alleles were equally frequent among 69 clinical isolates and that the majority of isolates (81%) were heterozygous at the G1473A/I1474V locus, a significant (P < 0.001) deviation from the Hardy-Weinberg equilibrium. Phylogenetic analysis by maximum likelihood (Paml) identified 33 codons in CDR2 in which amino acid allelic changes showed a high probability of being selectively advantageous. In contrast, all codons in CDR1 were under purifying selection. Collectively, these results indicate that possession of two functionally different CDR2 alleles in individual strains may confer a selective advantage, but that this is not necessarily due to azole resistance.

• Proceedings of the SMBE Tri-National Young Investigators' Workshop 2005. Improved consensus network techniques for genome-scale phylogeny.

  Authors: Barbara R Holland, Lars S Jermiin, Vincent Moulton

  Molecular biology and evolution. 06/2006; 23(5):848-55.

  Although recent studies indicate that estimating phylogenies from alignments of concatenated genes greatly reduces the stochastic error, the potential for systematic error still remains, heighteningAlthough recent studies indicate that estimating phylogenies from alignments of concatenated genes greatly reduces the stochastic error, the potential for systematic error still remains, heightening the need for reliable methods to analyze multigene data sets. Consensus methods provide an alternative, more inclusive, approach for analyzing collections of trees arising from multiple genes. We extend a previously described consensus network method for genome-scale phylogeny (Holland, B. R., K. T. Huber, V. Moulton, and P. J. Lockhart. 2004. Using consensus networks to visualize contradictory evidence for species phylogeny. Mol. Biol. Evol. 21:1459-1461) to incorporate additional information. This additional information could come from bootstrap analysis, Bayesian analysis, or various methods to find confidence sets of trees. The new methods can be extended to include edge weights representing genetic distance. We use three data sets to illustrate the approach: 61 genes from 14 angiosperm taxa and one gymnosperm, 106 genes from eight yeast taxa, and 46 members of a gene family from 15 vertebrate taxa.

• Untangling long branches: identifying conflicting phylogenetic signals using spectral analysis, neighbor-net, and consensus networks.

  Authors: Martyn Kennedy, Barbara R Holland, Russell D Gray, Hamish G Spencer

  Systematic biology. 09/2005; 54(4):620-33.

  Long-branch attraction is a well-known source of systematic error that can mislead phylogenetic methods; it is frequently invoked post hoc, upon recovering a different tree from the one expectedLong-branch attraction is a well-known source of systematic error that can mislead phylogenetic methods; it is frequently invoked post hoc, upon recovering a different tree from the one expected based on prior evidence. We demonstrate that methods that do not force the data onto a single tree, such as spectral analysis, Neighbor-Net, and consensus networks, can be used to detect conflicting signals within the data, including those caused by long-branch attraction. We illustrate this approach using a set of taxa from three unambiguously monophyletic families within the Pelecaniformes: the darters, the cormorants and shags, and the gannets and boobies. These three families are universally acknowledged as forming a monophyletic group, but the relationship between the families remains contentious. Using sequence data from three mitochondrial genes (12S, ATPase 6, and ATPase 8) we demonstrate that the relationship between these three families is difficult to resolve because they are separated by a short internal branch and there are conflicting signals due to long-branch attraction, which are confounded with nonhomogeneous sequence evolution across the different genes. Spectral analysis, Neighbor-Net, and consensus networks reveal conflicting signals regarding the placement of one of the darters, with support found for darter monophyly, but also support for a conflicting grouping with the outgroup, pelicans. Furthermore, parsimony and maximum-likelihood analyses produced different trees, with one of the two most parsimonious trees not supporting the monophyly of the darters. Monte Carlo simulations, however, were not sensitive enough to reveal long-branch attraction unless the branches are longer than those actually observed. These results indicate that spectral analysis, Neighbor-Net, and consensus networks offer a powerful approach to detecting and understanding the source of conflicting signals within phylogenetic data.

• Using consensus networks to visualize contradictory evidence for species phylogeny.

  Authors: Barbara R Holland, Katharina T Huber, Vincent Moulton, Peter J Lockhart

  Molecular biology and evolution. 08/2004; 21(7):1459-61.

  Building species phylogenies from genome data requires the evaluation of phylogenetic evidence from independent gene loci. We propose an approach to do this using consensus networks. We compare geneBuilding species phylogenies from genome data requires the evaluation of phylogenetic evidence from independent gene loci. We propose an approach to do this using consensus networks. We compare gene trees for eight yeast genomes and show that consensus networks have potential for helping to visualize contradictory evidence for species phylogenies.

• Upper bounds on maximum likelihood for phylogenetic trees.

  Authors: Michael D Hendy, Barbara R Holland

  Bioinformatics (Oxford, England). 11/2003; 19 Suppl 2:ii66-72.

  We introduce a mechanism for analytically deriving upper bounds on the maximum likelihood for genetic sequence data on sets of phylogenies. A simple 'partition' bound is introduced for generalWe introduce a mechanism for analytically deriving upper bounds on the maximum likelihood for genetic sequence data on sets of phylogenies. A simple 'partition' bound is introduced for general models. Tighter bounds are developed for the simplest model of evolution, the two state symmetric model of nucleotide substitution under the molecular clock. This follows earlier theoretical work which has been restricted to this model by analytic complexity. A weakness of current numerical computation is that reported 'maximum likelihood' results cannot be guaranteed, both for a specified tree (because of the possibility of multiple maxima) or over the full tree space (as the computation is intractable for large sets of trees). The bounds we develop here can be used to conclusively eliminate large proportions of tree space in the search for the maximum likelihood tree. This is vital in the development of a branch and bound search strategy for identifying the maximum likelihood tree. We report the results from a simulation study of approximately 10(6) data sets generated on clock-like trees of five leaves. In each trial a likelihood value of one specific instance of a parameterised tree is compared to the bound determined for each of the 105 possible rooted binary trees. The proportion of trees that are eliminated from the search for the maximum likelihood tree ranged from 92% to almost 98%, indicating a computational speed-up factor of between 12 and 44.

• Sixty alleles of the ALS7 open reading frame in Candida albicans: ALS7 is a hypermutable contingency locus.

  Authors: Ningxin Zhang, Annette L Harrex, Barbara R Holland, Lauren E Fenton, Richard D Cannon, Jan Schmid

  Genome research. 10/2003; 13(9):2005-17.

  The ALS (agglutinin-like sequence) gene family encodes proteins that play a role in adherence of the yeast Candida albicans to endothelial and epithelial cells. The proteins are proposed as virulenceThe ALS (agglutinin-like sequence) gene family encodes proteins that play a role in adherence of the yeast Candida albicans to endothelial and epithelial cells. The proteins are proposed as virulence factors for this important fungal pathogen of humans. We analyzed 66 C. albicans strains, representing a worldwide collection of 266 infection-causing isolates, and discovered 60 alleles of the ALS7 open reading frame (ORF). Differences between alleles were largely caused by rearrangements of repeat elements in the so-called tandem repeat domain (21 different types occurred) and the VASES region (19 different types). C. albicans is diploid, and combinations of ALS7 alleles generated 49 different genotypes. ALS7 expression was detected in samples isolated directly from five oral candidosis patients. ORFs in the opposite direction contained within the ALS7 ORF were also transcribed in all strains tested. Isolates representing a more pathogenic general-purpose genotype (GPG) cluster of strains tended to have more tandem repeats than other strains. Two types of VASES regions were largely exclusive to GPG strains; the remaining types were largely exclusive to noncluster strains. Our results provide evidence that ALS7 is a hypermutable contingency locus and important for the success of C. albicans as an opportunistic pathogen of humans.

• Optimal alphabets for an RNA world.

  Authors: Paul P Gardner, Barbara R Holland, Vincent Moulton, Mike Hendy, David Penny

  Proceedings. Biological sciences / The Royal Society. 07/2003; 270(1520):1177-82.

  Experiments have shown that the canonical AUCG genetic alphabet is not the only possible nucleotide alphabet. In this work we address the question 'is the canonical alphabet optimal?' We make theExperiments have shown that the canonical AUCG genetic alphabet is not the only possible nucleotide alphabet. In this work we address the question 'is the canonical alphabet optimal?' We make the assumption that the genetic alphabet was determined in the RNA world. Computational tools are used to infer the RNA secondary structure (shape) from a given RNA sequence, and statistics from RNA shapes are gathered with respect to alphabet size. Then, simulations based upon the replication and selection of fixed-sized RNA populations are used to investigate the effect of alternative alphabets upon RNA's ability to step through a fitness landscape. These results show that for a low copy fidelity the canonical alphabet is fitter than two-, six- and eight-letter alphabets. In higher copy-fidelity experiments, six-letter alphabets outperform the four-letter alphabets, suggesting that the canonical alphabet is indeed a relic of the RNA world.

• Multiple maxima of likelihood in phylogenetic trees: an analytic approach.

  Authors: Benny Chor, Michael D. Hendy, Barbara R. Holland, David Penny

  01/2000