Amino acid substitutions in structurally related proteins. A pattern recognition approach. Determination of a new and efficient scoring matrix.

Amino acid substitutions in evolutionarily related proteins have been studied from a structural point of view. We consider here that an amino acid al in a protein p1 has been replaced by the amino acid a2 in the structurally similar protein p2 if, after superposition of the p1 and p2 structures, the a1 and a2 C alpha atoms are no more than 1.2 A apart. Thirty-two proteins, grouped in 11 classes, have been analysed by this method. This produced 2860 amino acid pairs (substitutions), which were analysed by multi-dimensional statistical methods. The main results are as follows: (1) according to the observed exchangeability of amino acid side-chains, only four groups (strong clusters) could be delineated; (i) Ile and Val, (ii) Leu and Met, (iii) Lys, Arg and Gln, and (iv) Tyr and Phe. The other residues could not be classified. (2) The matrix of distances between amino acids, or scoring matrix, determined from this study, is different from any other published matrix. (3) Except for the distance matrices based on the chemical properties of amino acid side-chains, which can be grouped together, all other published matrices are different from one another. (4) The distance matrix determined in this study seems to be very efficient for aligning distantly related protein sequences.

Merging of distance matrices and classification by dynamic clustering.

The graphical representation of distance matrices in a Euclidean space allows the merging of two distance matrices since the two matrices have shared elements. The graphical representation of the merging of the two distance matrices is associated with a robust method of classification that allows one to distinguish species for which membership to a cluster cannot be established with certainty. These possibilities are exploited to test the consistency of phylogenetic trees, and to establish exact relations between species for which one possesses different independent distance measurements (distance matrices established from several types of sequences for instance). The whole set of programs is written in BASIC and runs on microcomputers.

Codon usage is imposed by the gene location in the transcription unit.

A characteristic profile of the fluctuations of codon usage is observed in bacteriophages and mitochondria. By following the DNA in the direction of transcription, one moves slowly from a region where selective pressure favours codons ending with C to a region where the bias is in favour of codons ending with T; then, abruptly, one again enters a region of codons ending in C. The transcription end point takes place in the area of abrupt change in codon usage. By comparing Drosophila yakuba and mouse mitochondrial genomes, it is possible to show that the strategy of codon usage for a given gene depends on its location along the transcription unit and not on the encoded protein. The choice of codons ending in T or C allows large scale variations of DNA stability which could regulate the speed of propagation of the RNA polymerase.

DosDNA occurs along yeast chromosomes, regardless of functional significance of the sequence.

Complex genomes contain numerous simple sequence repeats, the biological significance of which remains obscure. Recently it has been shown that several human diseases are the result of changes in such sequences. Thus it has become urgent to undertake a systematic study of their properties. We have set the task of describing as completely as possible the set of sequences which contain bases organized according to symmetrical elements, the dosDNA: defined ordered sequence. Examination of local anomalies in dinucleotide composition serves to identify dosDNA zones in the genome. The study of chromosomes II, III, VIII and XI of Saccharomyces cerevisiae reveals these dosDNA zones comprise about 2% of the genome. They are regularly distributed along the chromosomes, regardless of the functional significance of the sequence. A more detailed analysis of dosDNA segments seems to indicate that simple repeats are the consequence of local properties of the chromosome, and not due to any motif in particular.

Detection of significant patterns by compression algorithms: the case of approximate tandem repeats in DNA sequences.

MOTIVATION: Compression algorithms can be used to analyse genetic sequences. A compression algorithm tests a given property on the sequence and uses it to encode the sequence: if the property is true, it reveals some structure of the sequence which can be described briefly, this yields a description of the sequence which is shorter than the sequence of nucleotides given in extenso. The more a sequence is compressed by the algorithm, the more significant is the property for that sequence. RESULTS: We present a compression algorithm that tests the presence of a particular type of dosDNA (defined ordered sequence-DNA): approximate tandem repeats of small motifs (i.e. of lengths < 4). This algorithm has been experimented with on four yeast chromosomes. The presence of approximate tandem repeats seems to be a uniform structural property of yeast chromosomes.