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The exhaustive matching of the protein sequence database makes possible a broadly based study of insertions and deletions (indels) during divergent evolution. In this study, the probability of a gap in an alignment of a pair of homologous protein sequences was found to increase with the evolutionary distance measured in PAM units (number of accepted point mutations per 100 amino acid residues). A relationship between the average number of amino acid residues between indels and evolutionary distance suggests that a unit 30 to 40 amino acid residues in length remains, on average, undisrupted by indels during divergent evolution. Further, the probability of a gap was found to be inversely proportional to gap length raised to the 1.7 power. This empirical law fits closely over the entire range of gap lengths examined. Gap length distribution is largely independent of evolutionary distance. These results rule out the widely used linear gap penalty as a satisfactory formula for scoring gaps when constructing alignments. Further, the observed gap length distribution can be explained by a simple model of selective pressures governing the acceptance of indels during divergent evolution. Finally, this model provides theoretical support for using indels as part of "parsing algorithms", important in the de novo prediction of the folded structure of proteins from the sequence data.
J Mol Biol 1993 Feb 20
PMID:Empirical and structural models for insertions and deletions in the divergent evolution of proteins. 844 36

Sequences of 1,862 chromosomally encoded Escherichia coli K12 proteins were examined to identify genes likely to have arisen by duplication of genes in an ancestral chromosome. The criteria for sequence relatedness were an alignment of at least 100 amino acid residues and a PAM distance (number of accepted point mutations per 100 residues separating two sequences) below 250. A total of 971 of the 1,862 proteins examined were found in 2,329 sequence-related pairs that met these criteria. Most proteins of the sequence-related pairs were related in cellular function, as judged by biochemical and/or physiological features. Many of the pairs of proteins could be grouped into sequence-related families. If such groupings were generated from ancestral genes by duplication and divergence events, through these sequence comparisons we can identify putative ancestral sequences of the present-day genes of E. coli and other organisms. The results suggest that the 971 paralogous genes could have been derived from only 204 ancestral genes. We have also shown that the process of duplication and divergence is not the exclusive mechanism of evolution of all E. coli genes. Indeed, the relationships among the sequences of multiple (in the sense of redundant) enzymes indicate that nearly half could have arisen either by convergent evolution or by lateral transfer. Therefore, not all functionally related genes need arise by duplication and divergence.
Mol Biol Evol 1995 Nov
PMID:Gene products of Escherichia coli: sequence comparisons and common ancestries. 852 50

We have tried to approach the nature of the last common ancestor to Haemophilus influenzae and Escherichia coli and to determine how each bacterium could have diverged from this putative organism. The approach used was exhaustive analysis of the homologous proteins coded by genes present in these bacteria, using as criteria for sequence relatedness an alignment of at least 80 amino acid residues and a PAM distance (number of accepted point mutations per 100 residues separating two sequences) below 250. Evolutionarily significant similarities were found between 1,345 H. influenzae proteins (85% of the total genome) and 3,058 E. coli. proteins (75% of the total genome), many of them belonging to families of various sizes (from 666 doublets to 35 large groups of more than 10 members). Nearly all the genes found by this approach to be duplicated in both bacteria were already duplicated in their last common ancestor. This was deduced from (1) the comparison of the respective distributions of evolutionary distances between orthologs (genes separated only by speciation events) and paralogs (genes duplicated in the same genome) and (2) the analysis of the phylogenetic trees reconstructed for each family of paralogs containing at least two members belonging to each bacterium. The distributions of the different categories of homologs show a significant loss of paralogous genes in H. influenzae (reduction proportional to the genome size), of many sequences which are still present in one copy in E. coli, and of some entire gene families. Phylogenetic trees also confirmed this recent loss of paralogous genes in H. influenzae. Thus, the genome size of the last common ancestor of these two bacteria would have been close to that of present-day E. coli, and the evolution of H. influenzae toward a parasitic life led to an important decrease in its genome size by some mechanism of streamlining. During this recent evolution, the memory of the gene order present in the last common ancestor has been blurred, but a few short conserved chromosomal fragments can still be detected in present-day E. coli and H. influenzae.
Mol Biol Evol 1998 Jan
PMID:The evolutionary relationships between the two bacteria Escherichia coli and Haemophilus influenzae and their putative last common ancestor. 949 1

Distances between amino acids were derived from the polar requirement measure of amino acid polarity and Benner and co-workers' (1994) 74-100 PAM matrix. These distances were used to examine the average effects of amino acid substitutions due to single-base errors in the standard genetic code and equally degenerate randomized variants of the standard code. Second-position transitions conserved all distances on average, an order of magnitude more than did second-position transversions. In contrast, first-position transitions and transversions were about equally conservative. In comparison with randomized codes, second-position transitions in the standard code significantly conserved mean square differences in polar requirement and mean Benner matrix-based distances, but mean absolute value differences in polar requirement were not significantly conserved. The discrepancy suggests that these commonly used distance measures may be insufficient for strict hypothesis testing without more information. The translational consequences of single-base errors were then examined in different codon contexts, and similarities between these contexts explored with a hierarchical cluster analysis. In one cluster of codon contexts corresponding to the RNY and GNR codons, second-position transversions between C and G and transitions between C and U were most conservative of both polar requirement and the matrix-based distance. In another cluster of codon contexts, second-position transitions between A and G were most conservative. Despite the claims of previous authors to the contrary, it is shown theoretically that the standard code may have been shaped by position-invariant forces such as mutation and base content. These forces may have left heterogeneous signatures in the code because of differences in translational fidelity by codon position. A scenario for the origin of the code is presented wherein selection for error minimization could have occurred multiple times in disjoint parts of the code through a phyletic process of competition between lineages. This process permits error minimization without the disruption of previously useful messages, and does not predict that the code is optimally error-minimizing with respect to modern error. Instead, the code may be a record of genetic process and patterns of mutation before the radiation of modern organisms and organelles.
J Mol Evol 1998 Jul
PMID:On error minimization in a sequential origin of the standard genetic code. 966 91

Phylogenetic relationships among reptiles were examined using previously published and newly determined hemoglobin sequences. Trees reconstructed from these sequences using maximum-parsimony, neighbor-joining, and maximum-likelihood algorithms were compared with a phylogenetic tree of Amniota, which was assembled on the basis of published morphological data. All analyses differentiated alpha chains into alphaA and alphaD types, which are present in all reptiles except crocodiles, where only alphaA chains are expressed. The occurrence of the alphaD chain in squamates (lizards and snakes only in this study) appears to be a general characteristic of these species. Lizards and snakes also express two types of beta chains (betaI and betaII), while only one type of beta chain is present in birds and crocodiles. Reconstructed hemoglobin trees for both alpha and beta sequences did not yield the monophyletic Archosauria (i.e., crocodilians + birds) and Lepidosauria (i.e., Sphenodon + squamates) groups defined by the morphology tree. This discrepancy, as well as some other poorly resolved nodes, might be due to substantial heterogeneity in evolutionary rates among single hemoglobin lineages. Estimation of branch lengths based on uncorrected amino acid substitutions and on distances corrected for multiple substitutions (PAM distances) revealed that relative rates for squamate alphaA and alphaD chains and crocodilian beta chains are at least twice as high as those of the rest of the chains considered. In contrast to these rate inequalities between reptilian orders, little variation was found within squamates, which allowed determination of absolute evolutionary rates for this subset of hemoglobins. Rate estimates for hemoglobins of lizards and snakes yielded 1.7 (alphaA) and 3.3 (beta) million years/PAM when calibrated with published divergence time vs. PAM distance correlates for several speciation events within snakes and for the squamate left and right arrow sphenodontid split. This suggests that hemoglobin chains of squamate reptiles evolved approximately 3.5 (alphaA) or approximately 1.7 times (beta) faster than their mammalian equivalents. These data also were used to obtain a first estimate of some intrasquamate divergence times.
J Mol Evol 1998 Oct
PMID:Phylogenetic analysis of reptilian hemoglobins: trees, rates, and divergences. 976 92

Peptidylglycine alpha-amidating monooxygenase (PAM; EC 1.14.17.3) is a bifunctional protein containing two enzymes that act sequentially to catalyse the alpha-amidation of neuroendocrine peptides. Previous studies have demonstrated that alpha-adrenergic stimulation results in an increase in intracellular volume and protein content of cultured neonatal rat myocardial cells. The present study examined the regulated expression of PAM during alpha-adrenergic stimulation. Alpha1-adrenergic stimulation activates the expression and release of PAM from myocytes. Following phenylephrine treatment, myocardial cells displayed a several fold increase in PAM activity, and a 2-4-fold increase in the steady state levels of PAM mRNA. This effect of alpha-adrenergic stimulation was dependent on the concentration and duration of exposure to the agonist, and displayed alpha1-adrenergic receptor specificity. The transcription rate experiments indicated that these alpha-adrenergic effects were not due to increased PAM gene activity, suggesting that a post-transcriptional mechanism was involved. The most common mechanism of post-transcriptional regulation affects cytoplasmic mRNA stability. Cardiomyocytes cultures from atria and ventricles in the presence of 5,6 dichloro-1-beta ribofuranosyl benzamidazole (DRB) showed that phenylephrine treatment increased the half-life of PAM mRNA from 13 +/- 1 to 21 +/- 1 h in atrial cells and from 8 +/- 1 to 12 +/- 1 h in ventricle cells. Analysis of nuclear RNA with probes specific for PAM intron sequences shows that increased PAM expression after phenylephrine treatment was not due to intranuclear stabilisation of the primary transcript. Protein kinase C inhibitors H7 and GF109203x, completely blocked the phenylephrine stimulated PAM expression. These results suggest that alpha-adrenergic agonist induces PAM mRNA levels by increasing its stability in the cytoplasm. They indicate that PAM gene expression augments through a H7 and GF109203x sensitive pathway, involving the activation of protein kinase C.
Mol Cell Endocrinol 1999 Aug 20
PMID:Alpha1-adrenergic regulation of peptidylglycine alpha-amidating monooxygenase gene expression in cultured rat cardiac myocytes: transcriptional studies and messenger ribonucleic acid stability. 1050 4

The process by which analogs in peptide chemistry are currently designed does not include any quantitative basis for amino acid substitutions from pharmacological leads. Here, we show that substitution matrices such as PAM 250 can provide quantitative constraints compatible with biological activity. This article describes its use in a strategy of rational amino acid substitution in peptides and proteins: we have computed a chemically derived matrix equivalent to the well-known PAM 250 matrix, reflecting the natural mutability rates of amino acids in protein evolutions but that can be extended to all the noncoded amino acids. Some of these noncoded amino acids are widely used to mimic secondary structure, to constrain backbone conformation, or to evade protease degradation. An automated sequence mutation (ASM) strategy has been defined to generate mutations within constraints. Application of such a substitution matrix to quantitative structure-function relationship studies will be of use in the design of proteins and peptides destined to become pharmaceutical drugs. In particular, issues such as which functionally conserved substitutions are able to satisfy conformational restrictions, oral bioavailability, or formulation demands can be quantitatively addressed.
J Mol Graph Model
PMID:Peptides quantitative structure-function relationships: an automated mutation strategy to design peptides and pseudopeptides from substitution matrices. 1084 Jun 89

Freeland et al. (Mol. Biol. Evol. 2000 a, 17, 511--518) have recently used a transformation of the PAM 74-100 matrix to study the level of optimization reached during genetic code origin. Since the PAM matrix counts the amino acid substitutions that occurred in families of homologous proteins during molecular evolution and as this process is mediated by the genetic code structure itself, it could be that the influence of the code on this matrix is such as to make any conclusion insignificant. As will be shown in the present paper, the transformation of the PAM matrix is affected in a non-marginal way by the organization of the genetic code and, thus, renders the analysis of Freeland et al. tautologous. Although, under the hypothesis of a highly optimized genetic code, some correlations may be expected between a measurement of similarity between amino acids and the genetic code structure, no certain conclusions can be drawn for the measurement used by Freeland et al.
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PMID:The origin of the genetic code cannot be studied using measurements based on the PAM matrix because this matrix reflects the code itself, making any such analyses tautologous. 1116 59

We derive an expectation maximization algorithm for maximum-likelihood training of substitution rate matrices from multiple sequence alignments. The algorithm can be used to train hidden substitution models, where the structural context of a residue is treated as a hidden variable that can evolve over time. We used the algorithm to train hidden substitution matrices on protein alignments in the Pfam database. Measuring the accuracy of multiple alignment algorithms with reference to BAliBASE (a database of structural reference alignments) our substitution matrices consistently outperform the PAM series, with the improvement steadily increasing as up to four hidden site classes are added. We discuss several applications of this algorithm in bioinformatics.
J Mol Biol 2002 Apr 12
PMID:An expectation maximization algorithm for training hidden substitution models. 1195 22

Phylogenetic relationships among the NBS-LRR (nucleotide binding site-leucine-rich repeat) resistance gene homologues (RGHs) from 30 genera and nine families were evaluated relative to phylogenies for these taxa. More than 800 NBS-LRR RGHs were analyzed, primarily from Fabaceae, Brassicaceae, Poaceae, and Solanaceae species, but also from representatives of other angiosperm and gymnosperm families. Parsimony, maximum likelihood, and distance methods were used to classify these RGHs relative to previously observed gene subfamilies as well as within more closely related sequence clades. Grouping sequences using a distance cutoff of 250 PAM units (point accepted mutations per 100 residues) identified at least five ancient sequence clades with representatives from several plant families: the previously observed TIR gene subfamily and a minimum of four deep splits within the non-TIR gene subfamily. The deep splits in the non-TIR subfamily are also reflected in comparisons of amino acid substitution rates in various species and in ratios of nonsynonymous-to-synonymous nucleotide substitution rates ( K(A)/ K(S) values) in Arabidopsis thaliana. Lower K(A)/ K(S) values in the TIR than the non-TIR sequences suggest greater functional constraints in the TIR subfamily. At least three of the five identified ancient clades appear to predate the angiosperm-gymnosperm radiation. Monocot sequences are absent from the TIR subfamily, as observed in previous studies. In both subfamilies, clades with sequences separated by approximately 150 PAM units are family but not genus specific, providing a rough measure of minimum dates for the first diversification event within these clades. Within any one clade, particular taxa may be dramatically over- or underrepresented, suggesting preferential expansions or losses of certain RGH types within particular taxa and suggesting that no one species will provide models for all major sequence types in other taxa.
J Mol Evol 2002 Apr
PMID:Diversity, distribution, and ancient taxonomic relationships within the TIR and non-TIR NBS-LRR resistance gene subfamilies. 1195 93


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