Temple F. Smith

Prediction of Gene Structure

We have developed a hierarchical rule base system for identifying genes in DNA sequences. Atomic sites (such as initiation codons, stop codons, acceptor sites and donor sites) are identified by a number of different methods and evaluated by a set of filters and rules chosen to maximize sensitivity; these are combined into higher-order gene elements (such as exons), evaluated, filtered and combined as equivalence classes into probable genes, which are evaluated and ranked. The system has been tested on an extensive collection of vertebrate genes smaller than 15,000 bases. Results obtained show that, on average, 88% of the predicted coding region for a transcription unit is actually coding, and 80% of the actual coding is correctly predicted. This will, in most applications, be sufficient for a search against protein sequence databases for the identification of probable gene function. In addition, the system provides a general test platform for both gene atomic site identification and the rules for their evaluation and assembly.

Rapid dynamic programming algorithms for RNA secondary structure

Prediction of RNA secondary structure from the linear RNA sequence is an important mathematical problem in molecular biology. Dynamic programming methods are currently the most useful computer technique but are frequently very expensive in running time. In this paper new dynamic programming algorithms are presented which reduce the required computation. The first polynomial time algorithm is given for predicting general secondary structure.

ARIADNE: pattern-directed inference and hierarchical abstraction in protein structure recognition

The macro-molecular structural conformations of proteins exhibit higher order regularities whose recognition is complicated by many factors. ARIADNE searches for similarities between structural descriptors and hypothesized protein structure at levels more abstract than the primary sequence.

New stratigraphic correlation techniques

Cross-association is a standard correlation technique. It is valid for theoretically complete stratigraphie sequences, but not for stratigraphie sequences as they commonly occur. A major problem is its inability to include correlations across gaps caused by local nondeposition or eroded strata. The methods proposed in this paper do include correlations across gaps and allow for completely general measurements of strata similarity. In addition, they are extended to include correlation of a fragmentary sequence with a longer complete sequence and to include correlations of more than two sequences. Using these techniques, most problems can be handled by hand calculation.

Mapping the order of DNA restriction fragments.

A straightforward method was designed for mapping the order of DNA restriction fragments obtained by a double and two single digestions, without the necessity of using a computer or a radioactive label. All possible solutions compatible with a pre-set level of error in the determination of sequence lengths are obtained. The primary assumptions are given, and the appropriate modifications of the algorithm are presented as a function of any assumptions one is unable (or unwilling) to make. Use of the method in connection with end-labeled fragments is also described.

Recognition of characteristic patterns in sets of functionally equivalent DNA sequences

An algorithm has been developed for the identification of unknown patterns which are distinctive for a set of short DNA sequences believed to be functionally equivalent. A pattern is defined as being a string, containing fully or partially specified nucleotides at each position of the string. The advantage of this vague definition of the pattern is that it imposes minimum constraints on the characterization of patterns. A new feature of the approach developed here is that it allows a fair simultaneous testing of patterns of all degrees of degeneracy. This analysis is based on an evaluation of inhomogeneity in the empirical occurrence distribution of any such pattern within a set of sequences. The use of the nonparametric kernel density estimation of Parzen allows one to assess small disturbances among the sequence alignments. The method also makes it possible to identify sequence subsets with different characteristic patterns. This algorithm was implemented in the analysis of patterns characteristic of sets of promoters, terminators and splice junction sequences. The results are compared with those obtained by other methods.

Biogenesis as an evolutionary process

SummaryThe earliest fossil stromatolites present evidence of a complex ecosystem of photosynthetic organisms. Because the origin of present life can be dated within a few hundred million years prior to these fossils, their complexity poses a problem. A heuristic model outlines the first radiation leading to the universal ancestor.

β-Turn-driven early evolution: The genetic code and biosynthesis pathways

SummaryThe physicochemical properties of β-turns suggest their biological importance prior to the formation of the genetic code. These properties include ones potentially affecting the preference for eitherl- ord-amino acids. The abundance of certain amino acids in β-turns is correlated with their assignment to a small, well-defined part of the genetic code and with their role as metabolic precursors for other amino acids. It is proposed that in the prebiotic environment, β-turns became objects of selection that influenced the evolution of the genetic code and biosynthetic pathways for amino acids.

A modified Chou and Fasman protein structure algorithm

A FORTRAN program PRSTRC has been developed for protein secondary structure prediction, which is a modified Chou and Fasman (1978) analysis. This implementation carries out a running average of amino acid structure occurrence frequencies, utilizes a simple set of nucleation conditions, and allows user control over nucleation threshold and cutoff parameters. The algorithm includes prediction of the newly defined secondary structure elements: omega loops (1986). It also generates a charge distribution and hydropathy profile. Output includes a simple graphic display for a printer, or a CRT using color addition. Correct structures are predicted for T. dyscritum hemerythrin and the variable domain of mouse immunoglobin k-chain.

New analytical tool for analysis of splice site sequence determinants

A new analytical method has been used to examine the set of 40 exon/intron boundaries within the rat embryonic myosin heavy chain (MHCemb) gene. It has also been applied to an additional set of 850 splice sequences selected from GenBank. Strong evidence is obtained for the involvement of 3 ends but not 5 ends of exon sequences in splice site recognition. It can be determined that signal sequences of 5 intron ends concentrate near the splice borders, while the distributions of the 3 intron ends have a diffuse character. The possibility of re-interpreting some known features, in terms of the absence of certain elements rather than the presence of elements forming sequence determinants, is discussed. The analysis undertaken enabled us to work out a more detailed set of recognition sequence requirements for the splicing of nuclear pre-mRNA. In addition to requirements which have already been established we suggest the following: the AG-absence in the immediate 3 terminal intron sequences; and a minimal match between a particular sequence and the known exon/intron consensus sequence of 5 splice junctions.