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S Karlin

Publications and source records attributed to S Karlin.

At least 19 recordsLinked to original sources
PubMed1992

Correlation analysis of amino acid usage in protein classes.

We present a comparative study of residue usage correlations of various organism protein sets of diverse phylogenetic species and of open reading frames of several large human viral genomes. Our correlation analysis reveals three major tendencies: (i) charge compensation reflected by the high correlation of basic with acidic residues; (ii) the positive correlations of functionally and structurally similar amino acids including many pairs of hydrophobic amino acids, all pairs of aromatic amino acids, the anionic pair (glutamate and aspartate), but not the cationic pair (lysine and arginine), moderately the hydroxyl pair (serine and threonine), the small amino acids (glycine and alanine), and many (but not all) of those having high values in the Dayhoff substitutability matrix (characteristics such as amino acid polarity or codon usage agreement, except for the wobble position, do not necessarily imply significant positive correlations); (iii) a widespread negative correlation of the aggregate strong codon group amino acids (Ala, Gly, Pro) versus the weak codon group amino acids (Lys, Ile, Tyr, Asn, Phe). Discussion and speculations relate amino acid usage correlations to protein function/structure, cellular localization, proximity in amino acid biosynthetic pathways, amino acid relative abundances, tRNA and aminoacyl synthetase availabilities, and evolutionary processes.

Amino Acids↗
PubMed1992

Chance and statistical significance in protein and DNA sequence analysis.

Statistical approaches help in the determination of significant configurations in protein and nucleic acid sequence data. Three recent statistical methods are discussed: (i) score-based sequence analysis that provides a means for characterizing anomalies in local sequence text and for evaluating sequence comparisons; (ii) quantile distributions of amino acid usage that reveal general compositional biases in proteins and evolutionary relations; and (iii) r-scan statistics that can be applied to the analysis of spacings of sequence markers.

Amino Acid Sequence↗
PubMed1992

Human cytomegalovirus origin of DNA replication (oriLyt) resides within a highly complex repetitive region.

A global analysis of the 230-kilobase-pair (kbp) human cytomegalovirus genome revealed three regions that were very rich in repeated sequences. The region with the highest content of inverted and direct repeats lies between 92,100 and 93,500 bp, upstream of the gene encoding the single-stranded DNA binding protein. Cloned restriction fragments containing this region were able to replicate when trans-acting factors were provided by virus infection in a transient replication assay. With this assay, the region between 92,210 and 93,715 bp on the viral genome was defined as the minimal replication origin, oriLyt. The sequence composition and repeats within oriLyt were used to divide the region into two domains that may be important in origin function. Sequences flanking either the left or right side of the minimal oriLyt contributed to efficient replication; however, these sequences were not essential for origin function. Thus, the region of the viral genome with the most striking concentration of direct and inverted repeats corresponds to the oriLyt of human cytomegalovirus.

Base Sequence↗
PubMed1992

Statistical analyses of counts and distributions of restriction sites in DNA sequences.

Counts and spacings of all 4- and 6-bp palindromes in DNA sequences from a broad range of organisms were investigated. Both 4- and 6-bp average palindrome counts were significantly low in all bacteriophages except one, probably as a means of avoiding restriction enzyme cleavage. The exception, T4 of normal 4- and 6-palindrome counts, putatively derives protection from modification of cytosine to hydroxymethylcytosine plus glycosylation. The counts and distributions of 4-bp and of 6-bp restriction sites in bacterial species are variable. Bacterial cells with multiple restriction systems for 4-bp or 6-bp target specificities are low in aggregate 4- or 6-bp palindrome counts/kb, respectively, but bacterial cells lacking exact 4-cutter enzymes generally show normal or high counts of 4-bp palindromes when compared with random control sequences of comparable nucleotide frequencies. For example, E. coli, apparently without an exact 4-bp target restriction endonuclease (see text), contains normal aggregate 4-palindrome counts/kb, while B. subtilis, which abounds with 4-bp restriction systems, shows a significant under-representation of 4-palindrome counts. Both E. coli and B. subtilis have many 6-bp restriction enzymes and concomitantly diminished aggregate 6-palindrome counts/kb. Eukaryote, viral, and organelle sequences generally have aggregate 4- and 6-palindromic counts/kb in the normal range. Interpretations of these results are given in terms of restriction/methylation regimes, recombination and transcription processes, and possible structural and regulatory roles of 4- and 6-bp palindromes.

Animals↗
PubMed1992

Methods and algorithms for statistical analysis of protein sequences.

We describe several protein sequence statistics designed to evaluate distinctive attributes of residue content and arrangement in primary structure. Considered are global compositional biases, local clustering of different residue types (e.g., charged residues, hydrophobic residues, Ser/Thr), long runs of charged or uncharged residues, periodic patterns, counts and distribution of homooligopeptides, and unusual spacings between particular residue types. The computer program SAPS (statistical analysis of protein sequences) calculates all the statistics for any individual protein sequence input and is available for the UNIX environment through electronic mail on request to V.B. (volker/genomic@stanford.edu).

Algorithms↗
PubMed1992

Over- and under-representation of short oligonucleotides in DNA sequences.

Strand-symmetric relative abundance functionals for di-, tri-, and tetranucleotides are introduced and applied to sequences encompassing a broad phylogenetic range to discern tendencies and anomalies in the occurrences of these short oligonucleotides within and between genomic sequences. For dinucleotides, TA is almost universally under-represented, with the exception of vertebrate mitochondrial genomes, and CG is strongly under-represented in vertebrates and in mitochondrial genomes. The traditional methylation/deamination/mutation hypothesis for the rarity of CG does not adequately account for the observed deficiencies in certain sequences, notably the mitochondrial genomes, yeast, and Neurospora crassa, which lack the standard CpG methylase. Homodinucleotides (AA.TT, CC.GG) and larger homooligonucleotides are over-represented in many organisms, perhaps due to polymerase slippage events. For trinucleotides, GCA.TGC tends to be under-represented in phage, human viral, and eukaryotic sequences, and CTA.TAG is strongly under-represented in many prokaryotic, eukaryotic, and viral sequences. The CCA.TGG triplet is ubiquitously over-represented in human viral and eukaryotic sequences. Among the tetranucleotides, several four-base-pair palindromes tend to be under-represented in phage sequences, probably as a means of restriction avoidance. The tetranucleotide CTAG is observed to be rare in virtually all bacterial genomes and some phage genomes. Explanations for these over- and under-representations in terms of DNA/RNA structures and regulatory mechanisms are considered.

Animals↗
PubMed1992

Significant similarity and dissimilarity in homologous proteins.

Common practice emphasizes significant sequence similarities between different members of protein families. These similarities presumably reflect on evolutionary conservation of structurally and functionally essential residues. The nonconserved regions, on the other hand, may be either selectively neutral or differentiated. We propose several distributional sequence statistics (e.g., clustering of charged residues, compositional biases, and repetitive patterns) as indicators of differentiation events. These ideas are illustrated with various examples, including comparisons among G protein-coupled receptors, herpesvirus proteins, and GTPase-activating proteins.

GTP-Binding Proteins↗
PubMed1992

Quantile distributions of amino acid usage in protein classes.

A comparative study of the compositional properties of various protein sets from both cellular and viral organisms is presented. Invariants and contrasts of amino acid usages have been discerned for different protein function classes and for different species using robust statistical methods based on quantile distributions and stochastic ordering relationships. In addition, a quantitative criterion to assess amino acid compositional extremes relative to a reference protein set is proposed and applied. Invariants of amino acid usage relate mainly to the central range of quantile distributions, whereas contrasts occur mainly in the tails of the distributions, especially contrasts between eukaryote and prokaryote species. Influences from genomic constraint are evident, for example, in the arginine:lysine ratios and the usage frequencies of residues encoded by G + C-rich versus A + T-rich codon types. The structurally similar amino acids, glutamate versus aspartate and phenylalanine versus tyrosine, show stochastic dominance relationships for most species protein sets favoring glutamate and phenylalanine respectively. The quantile distribution of hydrophobic amino acid usages in prokaryote data dominates the corresponding quantile distribution in human data. In contrast, glutamate, cysteine, proline and serine usages in human proteins dominate the corresponding quantile distributions in Escherichia coli. E. coli dominates human in the use of basic residues, but no dominance ordering applies to acidic residues. The discussion centers on commonalities and anomalies of the amino acid compositional spectrum in relation to species, function, cellular localization, biochemical and steric attributes, complexity of the amino acid biosynthetic pathway, amino acid relative abundances and founder effects.

Amino Acids↗
PubMed1991

An efficient algorithm for identifying matches with errors in multiple long molecular sequences.

An efficient algorithm is described for finding matches, repeats and other word relations, allowing for errors, in large data sets of long molecular sequences. The algorithm entails hashing on fixed-size words in conjunction with the use of a linked list connecting all occurrences of the same word. The average memory and run time requirement both increase almost linearly with the total sequence length. Some results of the program's performance on a database of Escherichia coli DNA sequences are presented.

Algorithms↗
PubMed1991

Assessment of inhomogeneities in an E. coli physical map.

A statistical method based on r-fragments, sums of distances between (r + 1) consecutive restriction enzyme sites, is introduced for detecting nonrandomness in the distribution or too markers in sequence data. The technique is applicable whenever large numbers of markers are available and will detect clumping, excessive dispersion or too much evenness of spacing of the markers. It is particularly adapted to varying the scale on which inhomogeneities can be detected, from nearest neighbor interactions to more distant interactions. The r-fragment procedure is applied primarily to the Kohara et al. (1) physical map of E. coli. Other applications to DAM methylation sites in E. coli and NotI sites in human chromosome 21 are presented. Restriction sites for the eight enzymes used in (1) appear to be randomly distributed, although at widely differing densities. These conclusions are substantially in agreement with the analysis of Churchill et al. (3). Extreme variability in the density of the eight restriction enzyme sites cannot be explained by variability in mono-, di- or trinucleotide frequencies.

Base Sequence↗
PubMed1991

Very long charge runs in systemic lupus erythematosus-associated autoantigens.

Systemic lupus erythematosus and other chronic systemic autoimmune diseases are associated with circulating autoantibodies reactive with a limited set of mostly nuclear proteins. Using rigorous statistical methods we have identified segments of highly significant charge concentration in the majority of the characteristic nuclear and cytoplasmic autoantigens. Extremely long runs of charged residues, including some sequences of greater than 20 consecutive charged residues (purely acidic or mixed basic and acidic), occur in about a third of these proteins, whereas equivalent runs are found in less than 3% of other mammalian proteins. The other sequences have less extreme charge clusters, the type and location of which are often conserved between several otherwise nonsimilar antigens. We propose that supercharged surfaces render the targeted host proteins strongly immunogenic and that antinuclear antibody profiles might result from chronic exposure to intracellular contents, possibly in conjunction with crossreactive viral products. The limited number of potential systemic autoantigens may partly be due to the rarity of requisite charge properties.

Amino Acid Sequence↗
PubMed1991

Evidence for selective evolution in codon usage in conserved amino acid segments of human alphaherpesvirus proteins.

The genomes of human viruses herpes simplex 1 (HSV1) and varicella zoster (VZV), although similar in biology, largely concordant in gene order, and identical in many amino acid segments, differ widely in their genomic G + C (abbreviated S) content, which is high in HSV1 (68%) and low in VZV (46%). This paper analyzes several striking codon usage contrasts. The S difference in coding regions is dramatically large in codon site 3, S3, about 42%. The large difference in S3 is maintained at the same level in a subset of closely similar genes and even in corresponding identical amino acid blocks. A similar difference in S levels in silent site 1 (S1) is found in leucine and arginine. The difference in S3 levels occurs in every gene and in every multicodon amino acid form. The S difference also exists in amino acid usage, with HSV1 using significantly more codon types SSN, while VZV uses more codon types WWN (where W stands for A or T). The nonoverlapping and narrow histograms of S3 gene frequencies in both viruses suggest that the difference has arisen and been maintained by a process of selective rather than nonselective effects. This is in sharp contrast to the relatively large variance seen for highly similar genes in the human versus yeast analysis. Interpretations and hypotheses to explain the HSV1 vs VZV codon usage disparity relate to virus-host interactions, to the role of viral genes in DNA metabolism, to availability of molecular resources (molecular Gause exclusion principle), and to differences in genomic structure.

Amino Acids↗
PubMed1990

Global convergence properties in multilocus viability selection models: the additive model and the Hardy-Weinberg law.

A natural coordinate system is introduced for the analysis of the global stability of the Hardy-Weinberg (HW) polymorphism under the general multilocus additive viability model. A global convergence criterion is developed and used to prove that the HW polymorphism is globally stable when each of the loci is diallelic, provided the loci are overdominant and the multilocus recombination is positive. As a corollary the multilocus Hardy-Weinberg law for neutral selection is derived.

Genetics, Population↗
PubMed1990

Evolution of sexual preferences in quantitative characters.

An analysis of equilibria and dynamics of the means, variances, and covariances of female mating preference for a quantitative male secondary sexual character following a Gaussian model is presented. For many combinations of viability and sexual selection parameters the evolving Gaussian distribution of phenotypes can diverge. The results on the cases of convergence and their limiting forms suggest some reinterpretations of Fisher's "runaway" process of sexual selection. One possibility is to interpret Fisher's postulated "initial advantage not due to female preference" as a shift in viability selection where runaway evolution occurs if the mean preferred trait evolves beyond its new viability optimum (due to sexual selection). This definition is contrasted with situations in which the new viability optimum is undershot. The quantitative and qualitative conclusions differ from models that approximate genetic covariance evolution involving a constant covariance.

Biological Evolution↗
PubMed1990

Levels of multiallelic overdominance fitness, heterozygote excess and heterozygote deficiency.

Concepts and results on selection balance in multiallelic systems are described. These include a multidimensional concept of heterozygote excess and heterozygote deficiency, a hierarchy of means of assessment of heterozygote advantage, comparisons and contrasts of allelic versus gametic polymorphic states, and conditions defining stable equilibria of complementary gametic sets. The concepts are illustrated in the context of viability selection and behavioral models of kin selection and for two major categories of multilocus selection regimes.

Alleles↗
PubMed1990

Methods for assessing the statistical significance of molecular sequence features by using general scoring schemes.

An unusual pattern in a nucleic acid or protein sequence or a region of strong similarity shared by two or more sequences may have biological significance. It is therefore desirable to know whether such a pattern can have arisen simply by chance. To identify interesting sequence patterns, appropriate scoring values can be assigned to the individual residues of a single sequence or to sets of residues when several sequences are compared. For single sequences, such scores can reflect biophysical properties such as charge, volume, hydrophobicity, or secondary structure potential; for multiple sequences, they can reflect nucleotide or amino acid similarity measured in a wide variety of ways. Using an appropriate random model, we present a theory that provides precise numerical formulas for assessing the statistical significance of any region with high aggregate score. A second class of results describes the composition of high-scoring segments. In certain contexts, these permit the choice of scoring systems which are "optimal" for distinguishing biologically relevant patterns. Examples are given of applications of the theory to a variety of protein sequences, highlighting segments with unusual biological features. These include distinctive charge regions in transcription factors and protooncogene products, pronounced hydrophobic segments in various receptor and transport proteins, and statistically significant subalignments involving the recently characterized cystic fibrosis gene.

Amino Acid Sequence↗