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At least 19 recordsLinked to original sources

PubMed2025

A General Framework for Branch Length Estimation in Ancestral Recombination Graphs.

Inference of Ancestral Recombination Graphs (ARGs) is of central interest in the analysis of genomic variation. ARGs can be specified in terms of topologies and coalescence times. The coalescence times are usually estimated using an informative prior derived from coalescent theory, but this may generate biased estimates and can also complicate downstream inferences based on ARGs. Here we introduce, POLEGON, a novel approach for estimating branch lengths for ARGs which uses an uninformative prior. Using extensive simulations, we show that this method provides improved estimates of coalescence times and lead to more accurate inferences of effective population sizes under a wide range of demographic assumptions (population expansion, bottleneck, split, etc). It also improves other downstream inferences including estimates of mutation rates. We apply the method to data from the 1000 Genomes Project to investigate population size histories and differential mutation signatures across populations. We also estimate coalescence times in the HLA region, and show that they exceed 30 million years in multiple segments.

Ancestral Recombination Graph↗

PubMed1991

Robustness of maximum likelihood tree estimation against different patterns of base substitutions.

In the maximum likelihood (ML) method for estimating a molecular phylogenetic tree, the pattern of nucleotide substitutions for computing likelihood values is assumed to be simpler than that of the actual evolutionary process, simply because the process, considered to be quite devious, is unknown. The problem, however, is that there has been no guarantee to endorse the simplification. To study this problem, we first evaluated the robustness of the ML method in the estimation of molecular trees against different nucleotide substitution patterns, including Jukes and Cantor's, the simplest ever proposed. Namely, we conducted computer simulations in which we could set up various evolutionary models of a hypothetical gene, and define a true tree to which an estimated tree by the ML method was to be compared. The results show that topology estimation by the ML method is considerably robust against different ratios of transitions to transversions and different GC contents, but branch length estimation is not so. The ML tree estimation based on Jukes and Cantor's model is also revealed to be resistant to GC content, but rather sensitive to the ratio of transitions to transversions. We then applied the ML method with different substitution patterns to nucleotide sequence data on tax gene from T-cell leukemia viruses whose evolutionary process must have been more complicated than that of the hypothetical gene. The results are in accordance with those from the simulation study, showing that Jukes and Cantor's model is as useful as a more complicated one for making inferences about molecular phylogeny of the viruses.

Base Composition↗

PubMed1992

Interpretation of time constant and electrotonic length estimates in multicylinder or branched neuronal structures.

1. We have investigated the theoretical and practical problems associated with the interpretation of time constants and the estimation of electrotonic length with equivalent cylinder formulas for neurons best represented as multiple cylinders or branched structures. Two analytic methods were used to compute the time constants and coefficients of passive voltage transients (and time constants of current transients under voltage clamp). One method, suitable for simple geometries, involves analytic solutions to boundary value problems. The other, suitable for neurons of any geometric complexity, is an algebraic approach based on compartmental models. Neither of these methods requires the simulation of transients. 2. We computed the time constants and coefficients of voltage transients for several hypothetical neurons and also for a spinal motoneuron whose morphology was characterized from serial reconstructions. These time constants and coefficients were used to generate voltage transients. Then exponential peeling, nonlinear regression, and transform methods were applied to these transients to test how well these procedures estimate the underlying time constants and coefficients. 3. For a serially reconstructed motoneuron with 732 compartments, we found that the theoretical and peeled tau 0 values were nearly equal, but the theoretical tau 1 was much larger than the peeled tau 1. The theoretical tau 1 could not be peeled because it was associated with a coefficient, C1, that had a very small value. In fact, there were 156 time constants between 1.0 and 6.0 ms, most of which had very small coefficients; none had a coefficient larger than 2% of the signal. The peeled value of tau 1 (called tau 1 peel) can be viewed as some sort of a weighted average of the time constants having the largest coefficients. 4. We studied simple hypothetical neurons to determine what interpretation could be applied to the multitude of theoretical time constants. We found that after tau 0, there was a group of time constants associated with eigenfunctions that were odd (or approximately odd) functions with respect to the soma. These time constants could be interpreted as "equalizing" time constants along particular paths between different pairs of dendritic terminals in the neuron. After this group of time constants, there was one that we call tau even because it was associated with an eigen-function that was approximately even with respect to the soma. This tau even could be interpreted as an equalizing time constant for charge equalization between proximal membrane (soma and proximal dendrites) and distal membrane (including all distal dendrites).4=

Animals↗

PubMed1992

Statistical method for estimating the standard errors of branch lengths in a phylogenetic tree reconstructed without assuming equal rates of nucleotide substitution among different lineages.

A statistical method is developed for estimating the standard errors of branch lengths in a phylogenetic tree reconstructed without assuming equal rates of nucleotide substitution among different lineages. This method can be easily used for testing whether the length of an interior branch in a reconstructed tree is positive, i.e., whether the topology of the tree is correct. Computer simulations indicate that this method is appropriate for a statistical test. As an example, this method is applied to phylogenetic trees reconstructed for the four hominoid species: human, chimpanzee, gorilla, and orangutan. The results obtained show that the present method provides a powerful statistical test.

Animals↗

PubMed1989

A statistical test of phylogenies estimated from sequence data.

A simple approach to testing the significance of the branching order, estimated from protein or DNA sequence data, of three taxa is proposed. The branching order is inferred by the transformed-distance method, under the assumption that one or two outgroups are available, and the branch lengths are estimated by the least-squares method. The inferred branching order is considered significant if the estimated internodal distance is significantly greater than zero. To test this, a formula for the variance of the internodal distance has been developed. The statistical test proposed has been checked by computer simulation. The same test also applies to the case of four taxa with no outgroup, if one considers an unrooted tree. Formulas for the variances of internodal distances have also been developed for the case of five taxa. Conditions are given under which it is more efficient to add the sequence of a fifth taxon than to do 25% more nucleotide sequencing in each of the original four. A method is presented for combining analyses of disparate data to get a single P value. Finally, the test, applied to the human-chimpanzee-gorilla problem, shows that the issue is not yet resolved.

Animals↗

PubMed1989

Effectiveness of measures requiring and not requiring prior sequence alignment for estimating the dissimilarity of natural sequences.

Various measures of sequence dissimilarity have been evaluated by how well the additive least squares estimation of edges (branch lengths) of an unrooted evolutionary tree fit the observed pairwise dissimilarity measures and by how consistent the trees are for different data sets derived from the same set of sequences. This evaluation provided sensitive discrimination among dissimilarity measures and among possible trees. Dissimilarity measures not requiring prior sequence alignment did about as well as did the traditional mismatch counts requiring prior sequence alignment. Application of Jukes-Cantor correction to singlet mismatch counts worsened the results. Measures not requiring alignment had the advantage of being applicable to sequences too different to be critically alignable. Two different measures of pairwise dissimilarity not requiring alignment have been used: (1) multiplet distribution distance (MDD), the square of the Euclidean distance between vectors of the fractions of base signlets (or doublets, or triplets, or ...) in the respective sequences, and (2) complements of long words (CLW), the count of bases not occurring in significantly long common words. MDD was applicable to sequences more different than was CLW (noncoding), but the latter often gave better results where both measures were available (coding). MDD results were improved by using longer mutliplets and, if the sequences were coding, by using the larger amino acid and codon alphabets rather than the nucleotide alphabet. The additive least squares method could be used to provide a reasonable consensus of different trees for the same set of species (or related genes).

Animals↗

PubMed2026

IQ-NET: fast and accurate quartet phylogenetic inference using deep learning trained on empirical DNA alignments.

Phylogenetic inference is fundamental to modern biology, with many applications including evolutionary biology, epidemiology, and comparative genomics. While maximum likelihood and Bayesian methods remain the gold standard for phylogenetic analysis, they rely on simplifying assumptions and are computationally intensive. Recent machine learning approaches for phylogenetics offer speed advantages, but have several limitations: exclusive reliance on simulated data for training, inadequate handling of gaps, and sensitivity to input sequence order. Here, we introduce IQ-NET (Intelligent Quartet NETwork), a deep learning framework that solves these limitations to infer four-taxon trees. IQ-NET estimates both tree topology and branch lengths directly from gapped alignments. IQ-NET outperforms existing machine learning methods in terms of accuracy, and obtained a 24-fold speedup compared with the widely used maximum likelihood software, IQ-TREE. We finally introduce a pipeline using IQ-NET and the ASTRAL software to reconstruct a larger species tree, i.e., with more than four taxa.

Empirical data training↗

PubMed1992

Estimating neuron dendritic length in 3D from total vertical projections and from vertical slices.

The recently developed method of total vertical projections is illustrated to estimate the total dendritic length of a human Substantia Nigra neuron. Next, the length of the different orders of dendritic branches, and the mean segment length for each order--commonly regarded as important parameters in neuron physiology--are also estimated. Finally, it is shown how to estimate the mean dendritic length in a population of neurons from vertical slices of arbitrary and unknown thickness. Being unbiased and highly efficient, the proposed methods offer interesting alternatives to current procedures used for the metric analysis of neuron arborizations.

Dendritic Cells↗

PubMed1992

Statistical properties of bootstrap estimation of phylogenetic variability from nucleotide sequences: II. Four taxa without a molecular clock.

The statistical properties of sample estimation and bootstrap estimation of phylogenetic variability from a sample of nucleotide sequences were studied by considering model trees of three taxa with an outgroup. The cases of constant and varying rates of nucleotide substitution were compared. From sequences obtained by simulation, phylogenetic trees were constructed by using the maximum parsimony (MP) and neighbor-joining (NJ) methods. The effectiveness and consistency of the MP method were studied in terms of proportions of informative sites. The results of simulation showed that bootstrap estimation of the confidence level for an inferred phylogeny can be used even under unequal rates of evolution if the rate differences are not large so that the MP method is not misleading. The condition under which the MP method becomes misleading (inconsistent) is more stringent for slowly evolving sequences than for rapidly evolving ones, and it also depends on the length of the internal branch. If the rate differences are large so that the MP method becomes consistently misleading, then bootstrap estimation will reinforce an erroneous conclusion on topology. Similar conclusions apply to the NJ method with uncorrected distances. The NJ method with corrected distances performs poorly when the sequence length is short but can avoid the inconsistency problem if the sequence length is long and if the distances can be estimated accurately.

Base Sequence↗

PubMed2026

Phylogenomic subsampling and upsampling for efficient evolutionary analyses of big data.

Long runtimes, high memory demands, and reliance on high-performance computing impede phylogenomic analyses. We review a scalable phylogenomic subsampling with upsampling (PSU) framework, in which small subsamples of sites from a concatenated alignment are expanded by upsampling before inference, and the resulting analyses are then aggregated to obtain evolutionary estimates. PSU harnesses the fact that the computational cost of maximum likelihood analysis is strongly influenced by the number of distinct site patterns in the concatenated alignment, whereas statistical power depends primarily on the amount of evolutionary information represented by the total number of sites and substitutions. By reducing the former while restoring the latter through upsampling, PSU can approximate many full-data analyses at substantially lower computational cost. Analysis of simulated and empirical datasets shows that PSU can accurately estimate bootstrap support values, select the optimal substitution model, test evolutionary hypotheses, and infer branch lengths, divergence times, and associated uncertainty measures, while reducing runtime and memory requirements by orders of magnitude. PSU also provides distributions of inferred clade support across independent subsamples, enabling detection of conflicting phylogenetic signals that may remain hidden in conventional bootstrap analysis. Automated tuning of subsample size, the number of subsamples, and the number of upsampling replicates make PSU practical across diverse datasets. We suggest that PSU is a general strategy for scalable phylogenomic inference using a broad range of statistical methods. By enabling analyses of genome-scale alignments on commodity hardware, PSU broadens research access and reduces environmental and infrastructural costs of big-data phylogenomics.

confidence limits↗

PubMed2026

Phylogenomic subsampling and upsampling for efficient evolutionary analyses of big data.

Long runtimes, high memory demands, and reliance on high-performance computing impede phylogenomic analyses. We review a scalable phylogenomic subsampling with upsampling (PSU) framework to address this challenge, which reduces runtime and memory requirements by orders of magnitude. In PSU, small subsamples of sites from a concatenated alignment are analyzed, which are expanded by upsampling before inference, and the resulting inferences are aggregated to obtain evolutionary estimates. PSU harnesses the fact that the computational cost of maximum likelihood analysis is strongly influenced by the number of distinct site patterns in the concatenated alignment, whereas statistical power depends primarily on the amount of evolutionary information represented by the total number of sites and substitutions. By reducing the former while restoring the latter through upsampling, PSU can approximate many full-alignment analyses at substantially lower computational cost. Analysis of simulated and empirical datasets shows that PSU can accurately estimate bootstrap support values, select the optimal substitution model, test evolutionary hypotheses, and infer branch lengths, divergence times, and associated uncertainty measures. PSU also provides distributions of inferred clade support across independent subsamples, enabling detection of conflicting phylogenetic signals that may remain hidden in conventional bootstrap analysis of concatenated alignments. Automated tuning of subsample size, the number of subsamples, and the number of upsampling replicates make PSU practical. We suggest that PSU is a general approach for scalable phylogenomic inference using a broad range of statistical methods. By enabling analyses of genome-scale alignments on commodity hardware, PSU broadens research access and reduces environmental and infrastructural costs of big-data phylogenomics.

Phylogeny↗

PubMed1992

Rate and mode differences between nuclear and mitochondrial small-subunit rRNA genes in mushrooms.

Sequences from homologous regions of the nuclear and mitochondrial small-subunit rRNA genes from 10 members of the mushroom order Boletales were used to construct evolutionary trees and to compare the rates and modes of evolution. Trees constructed independently for each gene by parsimony and tested by bootstrap analysis have identical topologies in all statistically significant branches. Examination of base substitutions revealed that the nuclear gene is biased toward C-T transitions and that the distribution of transversions in the mitochondrial gene is strongly effected by an A-T bias. When only homologous regions of the two genes were compared, base substitutions per nucleotide were roughly 16-fold greater in the mitochondrial gene. The difference in the frequency of length mutations was at least as great but was impossible to estimate accurately because of their absence in the nuclear gene. Maximum likelihood was used to show that base-substitution rates vary dramatically among the branches. A significant part of the rate inconstancy was caused by an accelerated nuclear rate in one branch and a retarded mitochondrial rate in a different branch. A second part of the rate variability involved a consistent inconstancy: short branches exhibit ratios of mitochondrial to nuclear divergences of less than 1, while longer branches had ratios of approximately 4:1-8:1. This pattern suggests a systematic error in the branch length calculation. The error may be related to the simplicity of the divergence estimates, which assumes that all base positions have an equal probability of change.

Base Composition↗

PubMed1991

Muscle capillary-to-fiber perimeter ratio: morphometry.

It is known that a substantial amount of capillary tortuosity is found in shortened muscles. However, the increased capillary length and surface area contributed by tortuosity and branching are seldom taken into account when capillarity is estimated and/or blood-tissue exchange is modeled in muscles. In this paper, we sought morphometric estimates of capillarity in transverse sections that incorporated data on capillary geometry. We derived equations to estimate capillary perimeter per fiber perimeter (i.e., capillary-to-fiber perimeter ratio) in transverse sections. We show how capillary-to-fiber perimeter ratio is related to capillary surface per fiber surface, i.e., to the amount of capillary surface available for exchange per muscle fiber surface area, and how it can be obtained by morphometry. Because capillary tortuosity and fiber perimeter are both a function of sarcomere length, the degree of extension or shortening of muscle samples obviously needs to be taken into account when capillary-to-fiber perimeter ratio is compared between muscles and/or samples. Using data currently available on capillary length and diameter with fiber shortening and extension, we show that it is a feature of capillary-to-fiber perimeter ratio to change relatively little with sarcomere length. As sarcomere length decreases from 2.80 to 1.58 microns in perfusion-fixed hindlimb muscles of rats, capillary and fiber perimeters in transverse sections increase substantially, whereas the ratio between the two variables, capillary-to-fiber perimeter ratio, changes only less than or equal to 10-15%.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Restorative effects of reinnervation on the size and dendritic arborization patterns of axotomized cat spinal alpha-motoneurons.

In a preceding paper [Brännström, et al. (1992) J. Comp. Neurol. 318:439-451] a marked reduction in dendritic size was observed in cat spinal motoneurons following permanent axotomy. The aim of the present study was to analyse the possible restorative effects of peripheral reinnervation on the size and dendritic branching patterns of cat spinal motoneurons which had been deprived of neuromuscular contact for an extended period of time. In adult cats the medial gastrocnemius (MG) nerve was transected and ligated. After 6 weeks the nerve was allowed to reinnervate its muscle through a nerve graft. With approximately 6 weeks needed for muscle reinnervation [Foehring, et al. (1986) J. Neurophysiol. 55:947-965], the MG motoneurons were devoid of neuromuscular contact for altogether about 12 weeks. Two years later reinnervated MG alpha-motoneurons were intracellularly labelled with horseradish peroxidase to allow quantitative analyses of the cell bodies and dendritic trees. Comparisons were made with previous data from normal and permanently axotomized MG motoneurons. The reinnervated motoneurons exhibited positive correlations between dendritic stem diameter, on one hand, and combined length, volume, membrane area, and number of end branches of the whole dendrite, on the other. By using the regression equations for these correlations, the total dendritic size of whole reinnervated motoneurons could be estimated. Such calculations showed that in comparison with the reduction in dendritic size found at 12 weeks after permanent axotomy (Brännström et al., see above), peripheral reinnervation caused the dendritic volume and membrane area to return to normal values. However, the values for combined dendritic length and number of dendritic end branches were still reduced by more than 25% as compared to the normal situation. The results indicate that following reinnervation of the target muscle, the axotomized motoneurons did not recover their original number of dendritic branches. The normalization of dendritic membrane area and volume was instead accomplished by two other mechanisms, namely an increase in dendritic diameters and an increased number of dendrites per neuron.

Animals↗

PubMed1992

Measurement of myocardium at risk by technetium-99m sestamibi: correlation with coronary angiography.

Previous studies have shown that tomographic perfusion imaging with technetium-99m sestamibi (RP-30A) can accurately measure the myocardium at risk during acute myocardial infarction. The ability of coronary angiography to predict the wide variability in myocardium at risk was studied in 21 patients with their first acute myocardial infarction. In blinded fashion, two experienced angiographers provided an overall "best estimate" of the percent of left ventricular myocardium at risk considering multiple angiographic variables--infarct-related artery, location of stenosis (proximal or nonproximal), vessel diameter, length, territory and the number and size of proximal branches and collateral vessels. Many of these individual variables showed a significant association with myocardium at risk. The most important angiographic variable was the mean best estimate of the two angiographers (r = 0.89, p less than 0.0001). However, the SEE was large (8.6% of the left ventricle) and angiography significantly (p less than 0.002) overestimated myocardium at risk. When patients with an anterior or an inferior infarct were considered separately, the angiographic best estimate had a weaker correlation with myocardium at risk measured by technetium-99m sestamibi in patients in both groups (anterior infarction r = 0.65, p = 0.04; inferior infarction r = 0.65, p = 0.04. Seven patients with an inferior infarct and myocardium at risk ranging from 7% to 32% of the left ventricle had identical angiographic best estimates. Although angiographic estimates correlate closely with measurements of myocardium at risk in groups of patients, their ability to predict the myocardium at risk in individual patients is limited.

Adult↗

PubMedDate not supplied

[Study of cooperative transitions in DNA using phase diagrams].

The study of the triple equilibria (A, B, Coil) and (A, B, Z) makes it possible to obtain interconnection between thermodynamic parameters of different co-operative transitions in DNA. Melting of DNA of poly[d(A--T)] was performed in a broad interval of trifluoroethanol (TFE) concentrations including those of the B to A transition range. A branch, which characterizes the helix-coil equilibrium, has a universal shape for different DNAs and the polynucleotide: melting temperature is minimum near 30% TFE and increases sharply within the region of the A form stability (greater than 65% TFE). The B-A equilibrium depends on temperature only slightly. The slope angles of the branches in the vicinity of the triple point (A, B, Coil) allow to estimate the co-operativity length of the B-A transition: it proves to be of the order of 20 base pairs for DNA and the polynucleotides. Due to the finite transition widths a peculiar situation, not studied up to now, is realized in our cases, at which three different conformations may be present in one polymeric molecule. This results in some new effects, predicted by a theory, such as stabilization by the B/A junctions of the helical state and the increase in width of the melting curves within the B-A transition interval. It thus appears that the phase diagram method may become a very informative approach to the studies of DNA metamorphosis in solution.

Animals↗

PubMed1989

Resonance mode analysis for volume estimation of asymmetric branching structures.

The resonance conditions associated with the propagation of a harmonic wave within a rigid, lossless branching structure can be explicitly derived. In this study, exact resonance conditions are derived for multi-order, rigid, asymmetric branching structures. These are compared with resonance conditions for rigid, multi-order, symmetric branching structures which we reported previously. The effect of asymmetry on the form of the higher-order resonance condition is discussed. In the low-frequency range, the resonance condition can be modified into simpler forms which facilitate volume estimation of the branching structure. Two such volume approximation techniques are presented: (a) a fundamental frequency method, in which the lowest resonance frequency is inversely proportional to the structure volume, and (b) an effective-length method, in which an effective length is calculated for all branches distal to the first bifurcation. Equivalence of the two methods is demonstrated. An experimental study was performed to measure the resonance modes of several second-order glass models with asymmetric branching structures similar to those of mammalian lungs. The resulting volume estimates were in close agreement with the true volumes.

Acoustics↗

PubMed1992

A novel structure associated with a lampbrush chromosome in the chicken, Gallus domesticus.

At a site near the end of the short arms of lampbrush bivalent 2 in the chicken (Gallus domesticus) there is always a marker structure that appears in the phase-contrast light microscope as a solid object with diffuse edges measuring about 4 microns across. When examined by transmission electron microscopy in thin section, this object appears as a loose bundle of fibres. In some preparations individual fibres appear 15-16 nm thick, smooth in outline and solid in cross-section. In other preparations they are 32-38 nm thick, rougher in outline and ring-like in cross-section. High-resolution scanning electron micrographs of the chromosome 2 marker show it to be a loose bundle of spaghetti-like fibres that is quite unlike anything previously seen on a lampbrush chromosome of any organism. As with the sectioned material, fibres in some preparations were smooth and 15-16 nm in diameter, whereas those in others were more knobbly and about 35 nm thick. The fibres appear to branch and in some cases it is clear that the daughter strands of a branch have the same dimensions as the parent strand. Free ends are rare. Total length of fibre material present at one marker locus is estimated to be between 500 and 2000 microns. Similar structures are not present on the lampbrush chromosomes of quail, wood pigeon or chaffinch. The nature of this fibrous marker, referred to in this paper as the "spaghetti marker", is discussed in relation to lampbrush chromosome function and to events that take place during the lampbrush phase of oogenesis in chicken. Evidence is discussed in relation to the possibility that the chromosome 2 marker represents a novel form of nuclear RNP or the specific association of some structural protein with one chromosome locus.

Animals↗