Automated identification of conserved synteny after whole-genome duplication.

An important objective for inferring the evolutionary history of gene families is the determination of orthologies and paralogies. Lineage-specific paralog loss following whole-genome duplication events can cause anciently related homologs to appear in some assays as orthologs. Conserved synteny-the tendency of neighboring genes to retain their relative positions and orders on chromosomes over evolutionary time-can help resolve such errors. Several previous studies examined genome-wide syntenic conservation to infer the contents of ancestral chromosomes and provided insights into the architecture of ancestral genomes, but did not provide methods or tools applicable to the study of the evolution of individual gene families. We developed an automated system to identify conserved syntenic regions in a primary genome using as outgroup a genome that diverged from the investigated lineage before a whole-genome duplication event. The product of this automated analysis, the Synteny Database, allows a user to examine fully or partially assembled genomes. The Synteny Database is optimized for the investigation of individual gene families in multiple lineages and can detect chromosomal inversions and translocations as well as ohnologs (paralogs derived by whole-genome duplication) gone missing. To demonstrate the utility of the system, we present a case study of gene family evolution, investigating the ARNTL gene family in the genomes of Ciona intestinalis, amphioxus, zebrafish, and human.

Inferring ancestral gene order.

To explain the evolutionary mechanisms by which populations of organisms change over time, it is necessary to first understand the pathways by which genomes have changed over time. Understanding genome evolution requires comparing modern genomes with ancestral genomes, which thus necessitates the reconstruction of those ancestral genomes. This chapter describes automated approaches to infer the nature of ancestral genomes from modern sequenced genomes. Because several rounds of whole genome duplication have punctuated the evolution of animals with backbones, and current methods for ortholog calling do not adequately account for such events, we developed ways to infer the nature of ancestral chromosomes after genome duplication. We apply this method here to reconstruct the ancestors of a specific chromosome in the zebrafish Danio rerio.

Anticodon-dependent conservation of bacterial tRNA gene sequences.

The residues in tRNA that account for its tertiary fold and for its specific aminoacylation are well understood. In contrast, relatively little is known about the residues in tRNA that dictate its ability to transit the different sites of the ribosome. Yet protein synthesis cannot occur unless tRNA properly engages with the ribosome. This study analyzes tRNA gene sequences from 145 fully sequenced bacterial genomes. Grouping the sequences according to the anticodon triplet reveals that many residues in tRNA, including some that are distal to the anticodon loop, are conserved in an anticodon-dependent manner. These residues evade detection when tRNA genes are grouped according to amino acid family. The conserved residues include those at positions 32, 38, and 37 of the anticodon loop, which are already known to influence tRNA translational performance. Therefore, it seems likely that the newly detected anticodon-associated residues also influence tRNA performance on the ribosome. Remarkably, tRNA genes that belong to the same amino acid family and therefore share identical residues at the second and third anticodon positions have diverged, during bacterial evolution, into highly conserved groups that are defined by the residue at the first (wobble) anticodon position. Current ideas about the properties of tRNA and the translation mechanism do not fully account for this phenomenon. The results of the present study provide a foundation for studying the adaptation of individual tRNAs to the translation machinery and for future studies of the translation mechanism.

Aligning sequences by minimum description length.

This paper presents a new information theoretic framework for aligning sequences in bioinformatics. A transmitter compresses a set of sequences by constructing a regular expression that describes the regions of similarity in the sequences. To retrieve the original set of sequences, a receiver generates all strings that match the expression. An alignment algorithm uses minimum description length to encode and explore alternative expressions; the expression with the shortest encoding provides the best overall alignment. When two substrings contain letters that are similar according to a substitution matrix, a code length function based on conditional probabilities defined by the matrix will encode the substrings with fewer bits. In one experiment, alignments produced with this new method were found to be comparable to alignments from CLUSTALW. A second experiment measured the accuracy of the new method on pairwise alignments of sequences from the BAliBASE alignment benchmark.

A neural network model of chemotaxis predicts functions of synaptic connections in the nematode Caenorhabditis elegans.

The anatomical connectivity of the nervous system of the nematode Caenorhabditis elegans has been almost completely described, but determination of the neurophysiological basis of behavior in this system is just beginning. Here we used an optimization algorithm to search for patterns of connectivity sufficient to compute the sensorimotor transformation underlying C. elegans chemotaxis, a simple form of spatial orientation behavior in which turning probability is modulated by the rate of change of chemical concentration. Optimization produced differentiator networks capable of simulating chemotaxis. A surprising feature of these networks was inhibitory feedback connections on all neurons. Further analysis showed that feedback regulates the latency between sensory input and behavior. Common patterns of connectivity between the model and biological networks suggest new functions for previously identified connections in the C. elegans nervous system.

The origins of genome complexity.

Complete genomic sequences from diverse phylogenetic lineages reveal notable increases in genome complexity from prokaryotes to multicellular eukaryotes. The changes include gradual increases in gene number, resulting from the retention of duplicate genes, and more abrupt increases in the abundance of spliceosomal introns and mobile genetic elements. We argue that many of these modifications emerged passively in response to the long-term population-size reductions that accompanied increases in organism size. According to this model, much of the restructuring of eukaryotic genomes was initiated by nonadaptive processes, and this in turn provided novel substrates for the secondary evolution of phenotypic complexity by natural selection. The enormous long-term effective population sizes of prokaryotes may impose a substantial barrier to the evolution of complex genomes and morphologies.

The evolutionary demography of duplicate genes.

Although gene duplication has generally been viewed as a necessary source of material for the origin of evolutionary novelties, the rates of origin, loss, and preservation of gene duplicates are not well understood. Applying steady-state demographic techniques to the age distributions of duplicate genes censused in seven completely sequenced genomes, we estimate the average rate of duplication of a eukaryotic gene to be on the order of 0.01/ gene/million years, which is of the same order of magnitude as the mutation rate per nucleotide site. However, the average half-life of duplicate genes is relatively small, on the order of 4.0 million years. Significant interspecific variation in these rates appears to be responsible for differences in species-specific genome sizes that arise as a consequence of a quasi-equilibrium birth-death process. Most duplicated genes experience a brief period of relaxed selection early in their history and a minority exhibit the signature of directional selection, but those that survive more than a few million years eventually experience strong purifying selection. Thus, although most theoretical work on the gene-duplication process has focused on issues related to adaptive evolution, the origin of a new function appears to be a very rare fate for a duplicate gene. A more significant role of the duplication process may be the generation of microchromosomal rearrangements through reciprocal silencing of alternative copies, which can lead to the passive origin of post-zygotic reproductive barriers in descendant lineages of incipient species.