Comparison Of Homologous Sequences Research Articles

Syntenic global alignment and its application to the gene prediction problem

Abstract Given the increasing number of available genomic sequences, one now faces the task of identifying their protein coding regions. The gene prediction problem can be addressed in several ways, and one of the most promising methods makes use of information derived from the comparison of homologous sequences. In this work, we develop a new comparative-based gene prediction program, called Exon_Finder2. This tool is based on a new type of alignment we propose, called syntenic global alignment, that can deal satisfactorily with sequences that share regions with different rates of conservation. In addition to this new type of alignment itself, we also describe a dynamic programming algorithm that computes a best syntenic global alignment of two sequences, as well as its related score. The applicability of our approach was validated by the promising initial results achieved by Exon_Finder2. On a benchmark including 120 pairs of human and mouse genomic sequences, most of their encoded genes were successfully identified by our program.

High-quality sequence clustering guided by network topology and multiple alignment likelihood

Proteins can be naturally classified into families of homologous sequences that derive from a common ancestor. The comparison of homologous sequences and the analysis of their phylogenetic relationships provide useful information regarding the function and evolution of genes. One important difficulty of clustering methods is to distinguish highly divergent homologous sequences from sequences that only share partial homology due to evolution by protein domain rearrangements. Existing clustering methods require parameters that have to be set a priori. Given the variability in the evolution pattern among proteins, these parameters cannot be optimal for all gene families. We propose a strategy that aims at clustering sequences homologous over their entire length, and that takes into account the pattern of substitution specific to each gene family. Sequences are first all compared with each other and clustered into pre-families, based on pairwise similarity criteria, with permissive parameters to optimize sensitivity. Pre-families are then divided into homogeneous clusters, based on the topology of the similarity network. Finally, clusters are progressively merged into families, for which we compute multiple alignments, and we use a model selection technique to find the optimal tradeoff between the number of families and multiple alignment likelihood. To evaluate this method, called HiFiX, we analyzed simulated sequences and manually curated datasets. These tests showed that HiFiX is the only method robust to both sequence divergence and domain rearrangements. HiFiX is fast enough to be used on very large datasets. The Python software HiFiX is freely available at http://lbbe.univ-lyon1.fr/hifix.

Human Y Chromosome Base-Substitution Mutation Rate Measured by Direct Sequencing in a Deep-Rooting Pedigree

SummaryUnderstanding the key process of human mutation is important for many aspects of medical genetics and human evolution. In the past, estimates of mutation rates have generally been inferred from phenotypic observations or comparisons of homologous sequences among closely related species [1–3]. Here, we apply new sequencing technology to measure directly one mutation rate, that of base substitutions on the human Y chromosome. The Y chromosomes of two individuals separated by 13 generations were flow sorted and sequenced by Illumina (Solexa) paired-end sequencing to an average depth of 11× or 20×, respectively [4]. Candidate mutations were further examined by capillary sequencing in cell-line and blood DNA from the donors and additional family members. Twelve mutations were confirmed in ∼10.15 Mb; eight of these had occurred in vitro and four in vivo. The latter could be placed in different positions on the pedigree and led to a mutation-rate measurement of 3.0 × 10−8 mutations/nucleotide/generation (95% CI: 8.9 × 10−9–7.0 × 10−8), consistent with estimates of 2.3 × 10−8–6.3 × 10−8 mutations/nucleotide/generation for the same Y-chromosomal region from published human-chimpanzee comparisons [5] depending on the generation and split times assumed.

Geometric nomenclature and classification of RNA base pairs.

Non-Watson-Crick base pairs mediate specific interactions responsible for RNA-RNA self-assembly and RNA-protein recognition. An unambiguous and descriptive nomenclature with well-defined and nonoverlapping parameters is needed to communicate concisely structural information about RNA base pairs. The definitions should reflect underlying molecular structures and interactions and, thus, facilitate automated annotation, classification, and comparison of new RNA structures. We propose a classification based on the observation that the planar edge-to-edge, hydrogen-bonding interactions between RNA bases involve one of three distinct edges: the Watson-Crick edge, the Hoogsteen edge, and the Sugar edge (which includes the 2'-OH and which has also been referred to as the Shallow-groove edge). Bases can interact in either of two orientations with respect to the glycosidic bonds, cis or trans relative to the hydrogen bonds. This gives rise to 12 basic geometric types with at least two H bonds connecting the bases. For each geometric type, the relative orientations of the strands can be easily deduced. High-resolution examples of 11 of the 12 geometries are presently available. Bifurcated pairs, in which a single exocyclic carbonyl or amino group of one base directly contacts the edge of a second base, and water-inserted pairs, in which single functional groups on each base interact directly, are intermediate between two of the standard geometries. The nomenclature facilitates the recognition of isosteric relationships among base pairs within each geometry, and thus facilitates the recognition of recurrent three-dimensional motifs from comparison of homologous sequences. Graphical conventions are proposed for displaying non-Watson-Crick interactions on a secondary structure diagram. The utility of the classification in homology modeling of RNA tertiary motifs is illustrated.

Mitochondrial cytochrome b gene analysis of Aspergillus fumigatus and related species.

Nucleotide sequences of 426 bp from the mitochondrial (mt) cytochrome b genes of six anamorph species and two species of Neosartorya teleomophs of Aspergillus section Fumigati were determined. These sequences were used to build nucleotide- and amino acid-based trees for phylogenetic analysis. Thirteen strains of A. fumigatus including 10 clinical isolates of A. fumigatus, 1 type culture of A. fumigatus var. fumigatus, 1 type culture of A. fumigatus var. ellipticus, and 1 strain of A. fumigatus var. albus, had the same nucleotide sequences. One strain of A. fumisynnematus, two strains labeled A. neoellipticus, two strains of A. viridinutans, and one strain of A. duricaulis had distinct nucleotide and amino acid sequences. Two strains of A. brevipes were divided into two types. One produced a 1,500-bp fragment that included an intron. The nucleotide sequences of its two exons were similar to those of the A. fumigatus, and the derived amino acid sequence was the same as that for A. fumigatus. The other produced a 426-bp fragment and had the same nucleotide and amino acid sequences as A. unilateralis. Neosartorya fischeri var. fischeri and N. stramenia had nucleotide sequences that differed from that of A. fumigatus. These species possessed their own characteristic nucleotide sequences that differed from each other. In comparisons of homologous sequences from four other pathogenic species of Aspergillus, regions specific to section Fumigati were found. The mt cytochrome b gene analysis was valuable for the identification, classification, and phylogenetic analysis of isolates of section Fumigati.

Prediction of the secondary structure of myosin light chains from comparison of homologous sequences. Implications for the interaction between myosin heavy and light chains

The primary sequences of seventeen essential and seventeen regulatory myosin light chains were analyzed and compared, using algorithms based on the different structural properties of their amino acid residues. This process allowed estimation of the structural homology between the proteins studied, and improved the prediction of their mean secondary structure and functionally important segments or residues. On the basis of the crystal structure of troponin C, a model of the myosin essential light chain with a fairly compact form is proposed. The possible sites of interaction between myosin light and heavy chains from rabbit skeletal muscle were also investigated by a complementarity method adapted to helix-rich proteins. Segments 139–149 and 65–75 in the essential light chain and segments 27–37, 67–77 and 97–107 in the regulatory light chain are suggested to constitute some of these sites, as most of them were found to have the features of surface-seeking helices.