Biomedical subjects
D Penny
Publications and source records attributed to D Penny.
Outgroup misplacement and phylogenetic inaccuracy under a molecular clock--a simulation study.
We conducted a simulation study of the phylogenetic methods UPGMA, neighbor joining, maximum parsimony, and maximum likelihood for a five-taxon tree under a molecular clock. The parameter space included a small region where maximum parsimony is inconsistent, so we tested inconsistency correction for parsimony and distance correction for neighbor joining. As expected, corrected parsimony was consistent. For these data, maximum likelihood with the clock assumption outperformed each of the other methods tested. The distance-based methods performed marginally better than did maximum parsimony and maximum likelihood without the clock assumption. Data correction was generally detrimental to accuracy, especially for short sequence lengths. We identified another region of the parameter space where, although consistent for a given method, some incorrect trees were each selected with up to twice the frequency of the correct (generating) tree for sequences of bounded length. These incorrect trees are those where the outgroup has been incorrectly placed. In addition to this problem, the placement of the outgroup sequence can have a confounding effect on the ingroup tree, whereby the ingroup is correct when using the ingroup sequences alone, but with the inclusion of the outgroup the ingroup tree becomes incorrect.
Mitochondrial genomes of a bandicoot and a brushtail possum confirm the monophyly of australidelphian marsupials.
Recent molecular analyses suggest that the position of bandicoots is the major difficulty in determining the root of the tree of extant marsupials. To resolve this, we analyse mitochondrial genome sequences of a bandicoot (Isoodon macrourus) and a brushtail possum (Trichosurus vulpecula) together with the previously available marsupial mitochondrial genomes, the Virginia opossum (Didelphis virginiana) and the wallaroo (Macropus robustus). Analyses of mitochondrial protein-coding and RNA genes strongly support the bandicoot as sister to the wallaroo and the brushtail possum. This result, combined with other recent molecular analyses, confirms the monophyly of Australidelphia (Australasian marsupials plus Dromiciops from South America). Further, RY coding was found to nullify AGCT coding nucleotide composition bias.
Mathematical elegance with biochemical realism: the covarion model of molecular evolution.
There is an apparent paradox in our understanding of molecular evolution. Current biochemically based models predict that evolutionary trees should not be recoverable for divergences beyond a few hundred million years. In practice, however, trees often appear to be recovered from much older times. Mathematical models, such as those assuming that sites evolve at different rates [including a Gamma distribution of rates across sites (RAS)] may in theory allow the recovery of some ancient divergences. However, such models require that each site maintain its characteristic rate over the whole evolutionary period. This assumption, however, contradicts the knowledge that tertiary structures diverge with time, invalidating the rate-constancy assumption of purely mathematical models. We report here that a hidden Markov version of the covarion model can meet both biochemical and statistical requirements for the analysis of sequence data. The model was proposed on biochemical grounds and can be implemented with only two additional parameters. The two hidden parts of this model are the proportion of sites free to vary (covarions) and the rate of interchange between fixed sites and these variable sites. Simulation results are consistent with this approach, providing a better framework for understanding anciently diverged sequences than the standard RAS models. However, a Gamma distribution of rates may approximate a covarion model and may possibly be justified on these grounds. The accurate reconstruction of older divergences from sequence data is still a major problem, and molecular evolution still requires mathematical models that also have a sound biochemical basis.
Confounded cytosine! Tinkering and the evolution of DNA.
Early in the history of DNA, thymine replaced uracil, thus solving a short-term problem for storing genetic information--mutation of cytosine to uracil through deamination. Any engineer would have replaced cytosine, but evolution is a tinkerer not an engineer. By keeping cytosine and replacing uracil the problem was never eliminated, returning once again with the advent of DNA methylation.
Does endo-symbiosis explain the origin of the nucleus?
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Implications for bat evolution from two new complete mitochondrial genomes.
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Hepatitis B virus genotypes: a South Pacific perspective.
87-91% but still, 0.6% of those that did respond to vaccination became infected. The infection rate of the vaccinated populations in the Pacific Islands ranged between 0.7 and 3.8%, which is comparable to Taiwan. A vigorous polyclonal response This communication discusses the current status of research in the hepatitis B virus in relation to the South Pacific. The hepatitis B virus (HBV) is a small DNA virus--3200 nucleotides. It has a circular genome and replicates through an RNA intermediate giving this DNA virus many characteristics similar to RNA viruses. Viral genomes can be single-stranded (+ or - sense) or double-stranded. If not vaccinated, infants born to HBeAg positive mothers (i.e. with high viral titer) have a 90% chance of being infected and becoming HBV carriers themselves. Mutants that affect the major antigenic determinant in HBV surface antigens are probably responsible for HBV infection despite immunization and mutants in the polymerase protein may render HBV resistant to therapy with nucleoside analogs. Within HBV seven genotypes A-G have been reported that is, HBV genotype A (HBVA), HBV genotype B (HBVB) etc. HBV is endemic worldwide with an estimated that 5% of the worlds population being carriers. Before the introduction of vaccination programs carrier rates varied between 5-30% in communities of these ethnic groups, and in some cases 80-90% of a community tested positive for HBV markers (i.e. were infected or had been infected). In Taiwan, of vaccinated babies born to HBV positive mothers, the proportion of those that responded to vaccination varied between will usually result in an acute infection and viral clearance. An associated problem with HBV, in the South Pacific, is the hepatitis delta virus (HDV). HDV is a satellite viroid-like RNA virus that requires HBV for replication. It can either co-infect with, or super-infect upon HBV infection resulting in acute infection and/or chronic infection respectively.
Proposal for a human genome evolution project.
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Use of RNA secondary structure for studying the evolution of RNase P and RNase MRP.
Secondary structure is evaluated for determining evolutionary relationships between catalytic RNA molecules that are so distantly related they are scarcely alignable. The ribonucleoproteins RNase P (P) and RNase MRP (MRP) have been suggested to be evolutionarily related because of similarities in both function and secondary structure. However, their RNA sequences cannot be aligned with any confidence, and this leads to uncertainty in any trees inferred from sequences. We report several approaches to using secondary structures for inferring evolutionary trees and emphasize quantitative tests to demonstrate that evolutionary information can be recovered. For P and MRP, three hypotheses for the relatedness are considered. The first is that MRP is derived from P in early eukaryotes. The next is that MRP is derived from P from an early endosymbiont. The third is that both P and MRP evolved in the RNA-world (and the need for MRP has since been lost in prokaryotes). Quantitative comparisons of the pRNA and mrpRNA secondary structures have found that the possibility of an organellar origin of MRP is unlikely. In addition, comparison of secondary structures support the identity of an RNase P-like sequence in the maize chloroplast genome. Overall, it is concluded that RNA secondary structure is useful for evaluating evolutionary relatedness, even with sequences that cannot be aligned with confidence.
RNA folding argues against a hot-start origin of life.
Opinion is strongly divided on whether life arose on earth under hot or cold conditions, the hot-start and cold-start scenarios, respectively. The origin of life close to deep thermal vents appears as the majority opinion among biologists, but there is considerable biochemical evidence that high temperatures are incompatible with an RNA world. To be functional, RNA has to fold into a three-dimensional structure. We report both theoretical and experimental results on RNA folding and show that (as expected) hot conditions strongly reduce RNA folding. The theoretical results come from energy-minimization calculations of the average extent of folding of RNA, mainly from 0-90 degrees C, for both random sequences and tRNA sequences. The experimental results are from circular-dichroism measurements of tRNA over a similar range of temperatures. The quantitative agreement between calculations and experiment is remarkable, even to the shape of the curves indicating the cooperative nature of RNA folding and unfolding. These results provide additional evidence for a lower temperature stage being necessary in the origin of life.
The power of relative rates tests depends on the data.
One of the most useful features of molecular phylogenetic analyses is the potential for estimating dates of divergence of evolutionary lineages from the DNA of extant species. But lineage-specific variation in rate of molecular evolution complicates molecular dating, because a calibration rate estimated from one lineage may not be an accurate representation of the rate in other lineages. Many molecular dating studies use a "clock test" to identify and exclude sequences that vary in rate between lineages. However, these clock tests should not be relied upon without a critical examination of their effectiveness at removing rate variable sequences from any given data set, particularly with regard to the sequence length and number of variable sites. As an illustration of this problem we present a power test of a frequently employed triplet relative rates test. We conclude that (1) relative rates tests are unlikely to detect moderate levels of lineage-specific rate variation (where one lineage has a rate of molecular evolution 1.5 to 4.0 times the other) for most commonly used sequences in molecular dating analyses, and (2) this lack of power is likely to result in substantial error in the estimation of dates of divergence. As an example, we show that the well-studied rate difference between murid rodents and great apes will not be detected for many of the sequences used to date the divergence between these two lineages and that this failure to detect rate variation is likely to result in consistent overestimation the date of the rodent-primate split.
Methyl-RNA: an evolutionary bridge between RNA and DNA?
Given the apparent limitation of double-stranded RNA (dsRNA) genomes to about 30 kb, together with the complexity of DNA synthesis, it appears difficult for a dsRNA genome to encode all the information required before the transition from an RNA to a DNA genome. Ribonucleotide reductase itself, which synthesizes deoxyribonucleotides from ribonucleotides, requires complex protein radical chemistry, and RNA world genomes may have reached their limits of coding capacity well before such complex enzymes had evolved. The transition from RNA to DNA thus appears to require intermediate steps, and we suggest that the naturally occurring 2'-O-methylated RNA, with chemical properties intermediate between RNA and DNA, is a suitable candidate.
Multiple maxima of likelihood in phylogenetic trees: an analytic approach.
Maximum likelihood (ML) is a widely used criterion for selecting optimal evolutionary trees. However, the nature of the likelihood surface for trees is still not sufficiently understood, especially with regard to the frequency of multiple optima. Here, we initiate an analytic study for identifying sequences that generate multiple optima. We concentrate on the problem of optimizing edge weights for a given tree or trees (as opposed to searching through the space of all trees). We report a new approach to computing ML directly, which we have used to find large families of sequences that have multiple optima, including sequences with a continuum of optimal points. Such data sets are best supported by different (two or more) phylogenies that vary significantly in their timings of evolutionary events. Some standard biological processes can lead to data with multiple optima, and consequently the field needs further investigation. Our results imply that hill-climbing techniques as currently implemented in various software packages cannot guarantee that one will find the global ML point, even if it is unique.
Parsimony, likelihood, and the role of models in molecular phylogenetics.
Methods such as maximum parsimony (MP) are frequently criticized as being statistically unsound and not being based on any "model." On the other hand, advocates of MP claim that maximum likelihood (ML) has some fundamental problems. Here, we explore the connection between the different versions of MP and ML methods, particularly in light of recent theoretical results. We describe links between the two methods--for example, we describe how MP can be regarded as an ML method when there is no common mechanism between sites (such as might occur with morphological data and certain forms of molecular data). In the process, we clarify certain historical points of disagreement between proponents of the two methodologies, including a discussion of several forms of the ML optimality criterion. We also describe some additional results that shed light on how much needs to be assumed about underlying models of sequence evolution in order to successfully reconstruct evolutionary trees.
Early evolution: prokaryotes, the new kids on the block.
Prokaryotes are generally assumed to be the oldest existing form of life on earth. This assumption, however, makes it difficult to understand certain aspects of the transition from earlier stages in the origin of life to more complex ones, and it does not account for many apparently ancient features in the eukaryotes. From a model of the RNA world, based on relic RNA species in modern organisms, one can infer that there was an absolute requirement for a high-accuracy RNA replicase even before proteins evolved. In addition, we argue here that the ribosome (together with the RNAs involved in its assembly) is so large that it must have had a prior function before protein synthesis. A model that connects and equates these two requirements (high-accuracy RNA replicase and prior function of the ribosome) can explain many steps in the origin of life while accounting for the observation that eukaryotes have retained more vestiges of the RNA world. The later derivation of prokaryote RNA metabolism and genome structure can be accounted for by the two complementary mechanisms of r-selection and thermoreduction.
Growing up with dinosaurs: molecular dates and the mammalian radiation.
Dates of divergence derived from molecular data have been used to place the beginning of the radiation of modern mammalian orders in the Cretaceous, long before the final extinction of the dinosaurs. These molecular dates have been used to challenge the idea that the ordinal diversification of mammals was triggered by the availability of 'empty niches' left vacant by the disappearance of the dinosaurs. However, the broad discrepancies between molecular date estimates from different studies warn that molecular dates should not be accepted uncritically. Consideration of the wide confidence intervals around molecular date estimates, and the potential for geographic bias in the fossil record, could lessen the discrepancy between molecular and palaeontological data but might still prompt a re-evaluation of the timing and causes of the mammalian radiation.
Reply from L. Bromham, D. Penny and M.J. Phillips.
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