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PubMed1997

Hidden Markov model analysis of motifs in steroid dehydrogenases and their homologs.

The increasing size of protein sequence databases is straining methods of sequence analysis, even as the increased information offers opportunities for sophisticated analyses of protein structure, function, and evolution. Here we describe a method that uses artificial intelligence-based algorithms to build models of families of protein sequences. These models can be used to search protein sequence databases for remote homologs. The MEME (Multiple Expectation-maximization for Motif Elicitation) software package identifies motif patterns in a protein family, and these motifs are combined into a hidden Markvov model (HMM) for use as a database searching tool. Meta-MEME is sensitive and accurate, as well as automated and unbiased, making it suitable for the analysis of large datasets. We demonstrate Meta-MEME on a family of dehydrogenases that includes mammalian 11 beta-hydroxysteroid and 17 beta-hydroxysteroid dehydrogenase and their homologs in the short chain alcohol dehydrogenase family. We chose this dataset because it is large and phylogenetically diverse, providing a good test of the sensitivity and selectivity of Meta-MEME on a protein family of biological interest. Indeed, Meta-MEME identifies at least 350 members of this family in Genpept96 and clearly separates these sequences from non-homologous proteins. We also show how the MEME motif output can be used for phylogenetic analysis.

Algorithms↗
PubMed1997

The assessment of biomarkers to detect nephrotoxicity using an integrated database.

Groups of industrial workers exposed to heavy metals (cadmium, mercury, and lead) or solvents were studied together with corresponding control groups. The cohorts were collected from several European centers (countries). Eighty-one measurements were carried out on urine, blood, and serum samples and the results of these analyses together with questionnaire information on each individual were entered into a central database using the relational database package Rbase. After the completion of the database construction phase, the data were exported in a format suitable for analysis by the statistical package SAS. The potential value of each test as an indicator of nephrotoxicity was then assessed. Rigorous exclusion criteria were applied which resulted in the elimination of some tests and samples from the dataset. The measurable contributions of smoking, gender, metal exposure, and site were either singly or in combination assessed by biomarkers for nephrotoxicity. The parameters measured included three urinary enzymes, six specific proteins, total protein, two extracellular matrix markers, four prostaglandins and anti-GBM antibodies, and beta 2-microglobulin in serum. The most sensitive renal tests included the urinary enzymes N-acetyl-beta-D-glucosaminidase (NAG) and intestinal alkaline phosphatase (IAP), brush border antigens, and urinary low-molecular-weight proteins. Of the newer tests investigated the prostaglandins were the most promising. Different patterns of biomarker excretion were observed following exposure to lead, cadmium, or mercury. The dataset provides a unique repository of data which could provide the basis of an enlarging source of information on normal human reference ranges and on the effects of exposure to toxins and the use of biomarkers for monitoring nephrotoxicity.

Biomarkers↗
PubMed2000

Estimating missing data: an iterative regression approach.

The problem of missing data is common in all fields of science. Various methods of estimating missing values in a dataset exist, such as deletion of cases, insertion of sample mean, and linear regression. Each approach presents problems inherent in the method itself or in the nature of the pattern of missing data. We report a method that (1) is more general in application and (2) provides better estimates than traditional approaches, such as one-step regression. The model is general in that it may be applied to singular matrices, such as small datasets or those that contain dummy or index variables. The strength of the model is that it builds a regression equation iteratively, using a bootstrap method. The precision of the regressed estimates of a variable increases as regressed estimates of the predictor variables improve. We illustrate this method with a set of measurements of European Upper Paleolithic and Mesolithic human postcranial remains, as well as a set of primate anthropometric data. First, simulation tests using the primate data set involved randomly turning 20% of the values to "missing". In each case, the first iteration produced significantly better estimates than other estimating techniques. Second, we applied our method to the incomplete set of human postcranial measurements. MISDAT estimates always perform better than replacement of missing data by means and better than classical multiple regression. As with classical multiple regression, MISDAT performs when squared multiple correlation values approach the reliability of the measurement to be estimated, e.g., above about 0. 8.

Animals↗
PubMed2001

Homoplasy and the early hominid masticatory system: inferences from analyses of extant hominoids and papionins.

Early hominid masticatory characters are widely considered to be more prone to homoplasy than characters from other regions of the early hominid skull and therefore less reliable for phylogenetic reconstruction. This hypothesis has important implications for current reconstructions of early hominid phylogeny, but it has never been tested. In this paper we evaluate the likely veracity of the hypothesis using craniometric data from extant primate groups for which reliable consensus molecular phylogenies are available. Datasets representing the extant large-bodied hominoid genera and the extant papionin genera were compiled from standard measurements. The data were adjusted to minimise the confounding effects of body size, and then converted into discrete character states using divergence coding. Each dataset was divided into four regional character groups: (1) palate and upper dentition, (2) mandible and lower dentition, (3) face and (4) cranial vault and base. Thereafter, the regional character groups were analysed using cladistic methods and the resulting phylogenetic hypotheses judged against the consensus molecular phylogenies for the hominoids and papionins. The analyses indicated that the regions dominated by masticatory characters-the palate and upper dentition, and the mandible and lower dentition-are no less reliable for phylogenetic reconstruction than the other regions of the skull. The four regions were equally affected by homoplasy and were, therefore, equally unreliable for phylogenetic reconstruction. This finding challenges the recent suggestion that Paranthropus is polyphyletic, which is based on the assumption that masticatory characters are especially prone to homoplasy. Our finding also suggests that, contrary to current practice, there is no a priori reason to de-emphasise the phylogenetic significance of the masticatory similarities between Homo rudolfensis and the australopiths. The corollary of this is that H. rudolfensis is unlikely to be a member of the Homo clade and should therefore be allocated to another genus.

Animals↗
PubMed1994

Factors influencing the ability of knowledge-based potentials to identify native sequence-structure matches.

Several types of potentials are derived from a dataset of known protein structures by computing statistical relations between amino acid sequence and different descriptions of the protein conformation. These potentials formulate in different ways backbone dihedral angle preferences, pairwise distance-dependent interactions between amino acid residues, and solvation effects based on accessible surface area calculations. Parameters affecting the characteristics and the performance of the potentials are critically assessed by monitoring recognition of the native fold in a strict screening test, where each sequence in the dataset is threaded through a repertoire of motifs, generated from all corresponding structures. Sequence gaps are not allowed, to avoid additional approximations. Results show that residue interaction potentials computed from distances between average side-chain centroids perform significantly better on this test than those computed considering inter-C alpha or inter-C beta distances. Combining potentials that are based on different structural descriptions and different interactions is also beneficial. The performance of some of these potentials is in fact so good that they recognize the correct fold for all the tested proteins, including subunits known to be unstable in the absence of quaternary interactions. Most strikingly, potentials representing backbone dihedral angle preferences recognize as many as 68 protein chains out of a total of 74, even though they consider solely local interactions along the chain, which, being the same as those considered in secondary structure prediction methods, are well known to be incapable of determining the full three-dimensional fold. This leads us to question the ability of procedures that screen a limited repertoire of structures to act as a stringent test for the potentials. We concede, however, that they are useful and fast tests, capable of revealing gross shortcomings of the potentials, or possible biases towards native recognition due, for example, to effects of sequence memory.

Algorithms↗
PubMed1996

Analysis of domain structural class using an automated class assignment protocol.

The extent to which the contemporary dataset of protein structures can be segregated into four structural "classes" as originally defined by Levitt & Chothia in 1976 is examined and a simple method presented for the assignment of protein domains into these classes. Assignments are based on known three-dimensional structures, and for successful assignment it was found that helix/sheet content, contacts between secondary structures and their sequential order had to be used. The procedure attempts to maximise the automatic separation into classes for a dataset of 197 manually classified, non-homologous domains. It was found that approximately 90% of the structures were classified automatically; the remainder were borderline and were left for manual inspection. The method was then applied to a test set of 43 protein domains with similar results. The data support the concept of distinct classes of protein structure, although a few intermediate structures are found, demonstrating that it is possible to define relatively simple parameters complying with commonly accepted nomenclature that automatically define 90% of protein domains with essentially 100% accuracy. However, re-examination of the data also suggested that the previously separate alpha/beta and alpha + beta classes show considerable overlap and are more naturally represented as a single alpha beta class. This large alpha beta class can then be most easily subdivided by consideration of whether the sheets are mainly parallel, antiparallel or mixed. The correlation between structural class and function is discussed, together with the conservation of class within a sequence superfamily. This represents the first step in an automated phenetic description of protein structure complementing the usual phylogenetic approach to protein structure classification.

Algorithms↗
PubMed1996

How to derive a protein folding potential? A new approach to an old problem.

In this paper we introduce a novel method of deriving a pairwise potential for protein folding. The potential is obtained by an optimization procedure that simultaneously maximizes thermodynamic stability for all proteins in the database. When applied to the representative dataset of proteins and with the energy function taken in pairwise contact approximation, our potential scored somewhat better than existing ones. However, the discrimination of the native structure from decoys is still not strong enough to make the potential useful for ab initio folding. Our results suggest that the problem lies with pairwise amino acid contact approximation and/or simplified presentation of proteins rather than with the derivation of potential. We argue that more detail of protein structure and energetics should be taken into account to achieve energy gaps. The suggested method is general enough to allow us to systematically derive parameters for more sophisticated energy functions. The internal control of validity for the potential derived by our method is convergence to a unique solution upon addition of new proteins to the database. The method is tested on simple model systems where sequences are designed, using the preset "true" potential, to have low energy in a dataset of structures. Our procedure is able to recover the potential with correlation r approximately 91% with the true one and we were able to fold all model structures using the recovered potential. Other statistical knowledge-based approaches were tested using this model and the results indicate that they also can recover the true potential with high degree of accuracy.

Databases, Factual↗
PubMed1998

Three-dimensional profiles: a new tool to identify protein surface similarities.

We report a procedure for the description and comparison of protein surfaces, which is based on a three-dimensional (3D) transposition of the profile method for sensitive protein homology sequence searches. Although the principle of the method can be applied to detect similarities to a single protein surface, the possibility of extending this approach to protein families displaying common structural and/or functional properties, makes it a more powerful tool. In analogy to profiles derived from the multiple alignment of protein sequences, we derive a 3D surface profile from a protein structure or from a multiple structure alignment of several proteins. The 3D profile is used to screen the protein structure database, searching for similar protein surfaces. The application of the procedure to SH2 and SH3 binding pockets and to the nucleotide binding pocket associated with the p-loop structural motif is described. The SH2 and SH3 3D profiles can identify all the SH2 and SH3 binding regions present in the test dataset; the p-loop 3D profile is able to recognize all the p-loop-containing proteins present in the test dataset. Analysis of the p-loop 3D profile allowed the identification of a positive charge whose position is conserved in space but not in sequence. The best ranking non-p-loop-containing protein is an ADP-forming succinyl coenzyme A synthetase, whose nucleotide-binding region has not yet been identified.

Amino Acid Sequence↗
PubMed2001

Beyond synexpression relationships: local clustering of time-shifted and inverted gene expression profiles identifies new, biologically relevant interactions.

The complexity of biological systems provides for a great diversity of relationships between genes. The current analysis of whole-genome expression data focuses on relationships based on global correlation over a whole time-course, identifying clusters of genes whose expression levels simultaneously rise and fall. There are, of course, other potential relationships between genes, which are missed by such global clustering. These include activation, where one expects a time-delay between related expression profiles, and inhibition, where one expects an inverted relationship. Here, we propose a new method, which we call local clustering, for identifying these time-delayed and inverted relationships. It is related to conventional gene-expression clustering in a fashion analogous to the way local sequence alignment (the Smith-Waterman algorithm) is derived from global alignment (Needleman-Wunsch). An integral part of our method is the use of random score distributions to assess the statistical significance of each cluster. We applied our method to the yeast cell-cycle expression dataset and were able to detect a considerable number of additional biological relationships between genes, beyond those resulting from conventional correlation. We related these new relationships between genes to their similarity in function (as determined from the MIPS scheme) or their having known protein-protein interactions (as determined from the large-scale two-hybrid experiment); we found that genes strongly related by local clustering were considerably more likely than random to have a known interaction or a similar cellular role. This suggests that local clustering may be useful in functional annotation of uncharacterized genes. We examined many of the new relationships in detail. Some of them were already well-documented examples of inhibition or activation, which provide corroboration for our results. For instance, we found an inverted expression profile relationship between genes YME1 and YNT20, where the latter has been experimentally documented as a bypass suppressor of the former. We also found new relationships involving uncharacterized yeast genes and were able to suggest functions for many of them. In particular, we found a time-delayed expression relationship between J0544 (which has not yet been functionally characterized) and four genes associated with the mitochondria. This suggests that J0544 may be involved in the control or activation of mitochondrial genes. We have also looked at other, less extensive datasets than the yeast cell-cycle and found further interesting relationships. Our clustering program and a detailed website of clustering results is available at http://www.bioinfo.mbb.yale.edu/expression/cluster (or http://www.genecensus.org/expression/cluster).

Algorithms↗
PubMed1999

A new method for spectral decomposition using a bilinear Bayesian approach.

A frequent problem in analysis is the need to find two matrices, closely related to the underlying measurement process, which when multiplied together reproduce the matrix of data points. Such problems arise throughout science, for example, in imaging where both the calibration of the sensor and the true scene may be unknown and in localized spectroscopy where multiple components may be present in varying amounts in any spectrum. Since both matrices are unknown, such a decomposition is a bilinear problem. We report here a solution to this problem for the case in which the decomposition results in matrices with elements drawn from positive additive distributions. We demonstrate the power of the methodology on chemical shift images (CSI). The new method, Bayesian spectral decomposition (BSD), reduces the CSI data to a small number of basis spectra together with their localized amplitudes. We apply this new algorithm to a 19F nonlocalized study of the catabolism of 5-fluorouracil in human liver, 31P CSI studies of a human head and calf muscle, and simulations which show its strengths and limitations. In all cases, the dataset, viewed as a matrix with rows containing the individual NMR spectra, results from the multiplication of a matrix of generally nonorthogonal basis spectra (the spectral matrix) by a matrix of the amplitudes of each basis spectrum in the the individual voxels (the amplitude matrix). The results show that BSD can simultaneously determine both the basis spectra and their distribution. In principle, BSD should solve this bilinear problem for any dataset which results from multiplication of matrices representing positive additive distributions if the data overdetermine the solutions.

Adenosine Triphosphate↗
PubMed1996

The probability of occurrence of oligomer motifs in the human genome and genomic microheterogeneity.

A previously published method for predicting the frequency of random occurrence of a completely specified DNA oligomer in a longer sequence dataset has been generalized to allow degeneracy in the oligomer sequence. With this enhancement, several datasets consisting of sequences from the human genome were searched for the occurrence of consensus binding sites for a set of 13 transcription factors. Although because of the biological significance of these sequences one might predict that they would occur more often than the random frequency, many of the consensus oligomers were found at lower than expected frequencies. Several (G+C)-rich oligomers were found to be moderately over-represented, but this could be accounted for, in part, by the occurrence of (G+C)-rich tracts in the human sequences. Regions very high in (G+C) were found to occur at much higher frequencies than expected in the human genome, and this severely limits the usefulness of this approach for predicting the frequency of (G+C)-rich oligomers. Unexpectedly, more than 1% of the human genome consists of tracts at least 28 bp in length with a (G+C) content greater than 85%.

Base Sequence↗
PubMed2002

Zipf's law in importance of genes for cancer classification using microarray data.

Using a measure of how differentially expressed a gene is in two biochemically/phenotypically different conditions, we can rank all genes in a microarray dataset. We have shown that the falling-off of this measure (normalized maximum likelihood in a classification model such as logistic regression) as a function of the rank is typically a power-law function. This power-law function in other similar ranked plots are known as the Zipf's law, observed in many natural and social phenomena. The presence of this power-law function prevents an intrinsic cutoff point between the "important" genes and "irrelevant" genes. We have shown that similar power-law functions are also present in permuted dataset, and provide an explanation from the well-known chi(2) distribution of likelihood ratios. We discuss the implication of this Zipf's law on gene selection in a microarray data analysis, as well as other characterizations of the ranked likelihood plots such as the rate of fall-off of the likelihood.

Diagnosis, Differential↗
PubMed1996

A new approach to studying modern human origins: hypothesis testing with coalescence time distributions.

A new approach for testing hypotheses about modern human origins using molecular divergence dates is presented. Coalescence times from many unlinked loci are needed to test the alternative models. Hypotheses are evaluated on the basis of their differing predicted distribution patterns of coalescence times from multiple genes. No single coalescence time from one genetic system is sufficient to reject any of the three alternative models. Several nuclear datasets give recent dates for human genetic ancestors, at approximately the mitochondrial coalescence time, while some nuclear datasets support older dates. Given the overall distribution of available mitochondrial and nuclear coalescence times, the rapid replacement hypothesis is the likeliest model for modern human origins. The unusual nature of the human mitochondrial pattern is highlighted by comparative data from nonhuman hominoids. To understand the pattern of modern human genetic variability better, more nuclear data from all hominoid species are needed.

Animals↗
PubMed2000

Molecular phylogenetics of subfamily Calamoideae (Palmae) based on nrDNA ITS and cpDNA rps16 intron sequence data.

Phylogenetic relationships among the 22 genera of the palm subfamily Calamoideae were investigated using DNA sequence data from the nuclear ribosomal internal transcribed spacer (ITS) region and the chloroplast rps16 intron. The rps16 intron displayed low levels of variation, corroborating previous reports that the chloroplast genome of palms is highly conserved. High levels of within-individual polymorphism were identified in the ITS region, indicating that concerted evolution is not effectively homogenizing the ITS repeats. In the majority of cases, multiple clones from individuals resolved as monophyletic. However, the high levels of homoplasy in the ITS dataset, along with generally poor jackknife support for many clades, led to concerns that topologies obtained from these data might be unreliable. Nevertheless, congruence between trees based on ITS data alone and those based on rps16 intron data was high. Simultaneous analyses of both datasets yielded well-resolved topologies with high levels of jackknife support. A number of exciting groups emerged from the analyses: the African rattan clade comprising the endemic African rattan genera Laccosperma, Eremospatha, and Oncocalamus; the Lepidocaryeae-Raphia clade comprising the fan-leaved New World tribe Lepidocaryeae and the African genus Raphia; and the Asian clade comprising all Asian genera except Eugeissona. The position of Eugeissona was variable, although it did not resolve inside any of the three major clades mentioned above.

Chloroplasts↗
PubMed2000

The impact of parsimony weighting schemes on inferred relationships among toucans and neotropical barbets (Aves: piciformes).

The development of new schemes for weighting DNA sequence data for phylogenetic analysis continues to outpace the development of consensus on the most appropriate weights. The present study is an exploration of the similarities and differences between results from 22 character weighting schemes when applied to a study of barbet and toucan (traditional avian families Capitonidae and Ramphastidae) phylogenetic relationships. The dataset comprises cytochrome b sequences for representatives of all toucan and Neotropical barbet genera, as well as for several genera of Paleotropical barbets. The 22 weighting schemes produced conflicting patterns of relationship among taxa, often with conflicting patterns each receiving strong bootstrap support. Use of multiple weighting schemes helped to identify the source within the dataset (codon position, transitions, transversions) of the various putative phylogenetic signals. Importantly, some phylogenetic hypotheses were consistently supported despite the wide range of weights employed. The use of phylogenetic frameworks to summarize the results of these multiple analyses proved very informative. Relationships among barbets and toucans inferred from these data support the paraphyly of the traditional Capitonidae. Additionally, these data support paraphyly of Neotropical barbets, but rather than indicating a relationship between Semnornis and toucans, as previously suggested by morphological data, most analyses indicate a basal position of Semnornis within the Neotropical radiation. The cytochrome b data also allow inference of relationships among toucans. Supported hypotheses include Ramphastos as the sister to all other toucans, a close relationship of Baillonius and Pteroglossus with these two genera as the sister group to an (Andigena, Selenidera) clade, and the latter four genera as a sister group to Aulacorhynchus.

Animals↗
PubMed2000

The evolution of the atpbeta-rbcL intergenic spacer in the epacrids (Ericales) and its systematic and evolutionary implications.

Sequence data from the noncoding region separating the plastid genes atpbeta and rbcL were gathered for 27 epacrid taxa, representing all previously recognized infrafamilial groups, and four outgroup taxa (Ericaceae), to address several persistent phylogenetic questions in the group. Parsimony analyses were conducted on these data, as well as on a complementary rbcL sequence dataset assembled from the literature and the combined dataset. The atpbeta-rbcL spacer was notable for the high frequency of insertion-deletion mutations (indels); their distributions were coded as binary characters and included as a adjunct matrix in some of the analyses. The phylogenetic patterns derived from the spacer and rbcL data and the combined analyses, both including and excluding the indel data, concur in resolving seven major lineages corresponding to the tribes of Crayn et al. (1998, Aust. J. Bot. 46, 187-200), viz. Prionoteae, Archerieae, Oligarrheneae, Cosmelieae, Richeeae, Epacrideae, and Styphelieae. The relationships of the tribes and within Styphelieae, however, are not convincingly resolved. Minor conflicts in the positions of some taxa between the spacer and the rbcL trees are poorly supported. Among epacrids, the spacer region provided more cladistically informative characters than rbcL and resulted in trees with lower homoplasy. Further, the spacer data, when analyzed alone and when combined with rbcL, resolved several clades that could not be retrieved on rbcL data alone and provided increased support for many other relationships. The evolution of a putative three-base inversion associated with a hairpin secondary structure in the spacer region is discussed in the light of the inferred phylogeny.

Classification↗
PubMed2001

A total-evidence phylogeny of ticks provides insights into the evolution of life cycles and biogeography.

We inferred the phylogeny of 33 species of ticks from the subfamilies Rhipicephalinae and Hyalomminae from analyses of nuclear and mitochondrial DNA and morphology. We used nucleotide sequences from 12S rRNA, cytochrome c oxidase I, internal transcribed spacer 2 of the nuclear rRNA, and 18S rRNA. Nucleotide sequences and morphology were analyzed separately and together in a total-evidence analysis. Analyses of the five partitions together (3303 characters) gave the best-resolved and the best-supported hypothesis so far for the phylogeny of ticks in the Rhipicephalinae and Hyalomminae, despite the fact that some partitions did not have data for some taxa. However, most of the hidden conflict (lower support in the total-evidence analyses compared to that in the individual analyses) was found in those partitions that had taxa without data. The partitions with complete taxonomic sampling had more hidden support (higher support in the total-evidence analyses compared to that in the separate-partition analyses) than hidden conflict. Mapping of geographic origins of ticks onto our phylogeny indicates an African origin for the Rhipicephalinae sensu lato (i.e., including Hyalomma spp.), the Rhipicephalus-Boophilus lineage, the Dermacentor-Anocentor lineage, and the Rhipicephalus-Booophilus-Nosomma-Hyalomma-Rhipicentor lineage. The Nosomma-Hyalomma lineage appears to have evolved in Asia. Our total-evidence phylogeny indicates that (i) the genus Rhipicephalus is paraphyletic with respect to the genus Boophilus, (ii) the genus Dermacentor is paraphyletic with respect to the genus Anocentor, and (iii) some subgenera of the genera Hyalomma and Rhipicephalus are paraphyletic with respect to other subgenera in these genera. Study of the Rhipicephalinae and Hyalomminae over the last 7 years has shown that analyses of individual datasets (e.g., one gene or morphology) seldom resolve many phylogenetic relationships, but analyses of more than one dataset can generate well-resolved phylogenies for these ticks.

Animals↗
PubMed1996

Reproducibility of PET activation studies: lessons from a multi-center European experiment. EU concerted action on functional imaging.

PET activation studies are performed widely to study human brain function. The question of reproducibility, reliability, and comparability of the results of such experiments has never been addressed on a large scale. Recently, 12 European PET centers performed the same cognitive activation experiment in a European Union funded concerted action. The experiment involved a standardized and validated cross-lingual experimental and control task involving verbal fluency. Each center contributed at least 6 subjects. In total there were 77 subjects and 247 scans in each of the two conditions, giving 494 scans in total. We have analyzed each center's dataset and pooled datasets using statistical parametric mapping. We present results that address the consistency of these analyses, discuss the factors that influence their sensitivity, and comment on a number of related methodological issues. We used a MANOVA to test for center, condition, and centre by condition effects and found a strong condition and center effect and weaker interactions. The main effect determining reproducibility was the overall sensitivity of the experiment, to which the scanner and number of scans contribute in a major way, with a marked advantage for 3D scanners and a large field of view. An important conclusion is that data from different centers can be pooled to improve the reliability of results, which is of particular importance for studies in patients with rare conditions.

Adult↗