Bases and spaces: resources on the web for accessing the draft human genome - II - After publication of the draft

The volume of human genome sequence and the variety of web-based tools to access it continue to grow at an impressive rate, but a working knowledge of certain key resources can be sufficient to get the most from your genome. This article provides an update to Genome Biology 2000, 1(4):reviews2001.1-2001.5

The meso-genomic era

A report from HGM2001, the sixth annual International Human Genome Meeting organized by The Human Genome Organisation (HUGO), Edinburgh, UK, 19-22 April 2001

Duplication and selection in the evolution of primate β-defensin genes

BACKGROUND: Innate immunity is the first line of defense against microorganisms in vertebrates and acts by providing an initial barrier to microorganisms and triggering adaptive immune responses. Peptides such as β-defensins are an important component of this defense, providing a broad spectrum of antimicrobial activity against bacteria, fungi, mycobacteria and several enveloped viruses. β-defensins are small cationic peptides that vary in their expression patterns and spectrum of pathogen specificity. Disruptions in β-defensin function have been implicated in human diseases, including cystic fibrosis, and a fuller understanding of the variety, function and evolution of human β-defensins might form the basis for novel therapies. Here we use a combination of laboratory and computational techniques to characterize the main human β-defensin locus on chromosome 8p22-p23. RESULTS: In addition to known genes in the region we report the genomic structures and expression patterns of four novel human β-defensin genes and a related pseudogene. These genes show an unusual pattern of evolution, with rapid divergence between second exon sequences that encode the mature β-defensin peptides matched by relative stasis in first exons that encode signal peptides. CONCLUSIONS: We conclude that the 8p22-p23 locus has evolved by successive rounds of duplication followed by substantial divergence involving positive selection, to produce a diverse cluster of paralogous genes established before the human-baboon divergence more than 23 million years ago. Positive selection, disproportionately favoring alterations in the charge of amino-acid residues, is implicated as driving second exon divergence in these genes

POCUS: mining genomic sequence annotation to predict disease genes

Here we present POCUS (prioritization of candidate genes using statistics), a novel computational approach to prioritize candidate disease genes that is based on over-representation of functional annotation between loci for the same disease. We show that POCUS can provide high (up to 81-fold) enrichment of real disease genes in the candidate-gene shortlists it produces compared with the original large sets of positional candidates. In contrast to existing methods, POCUS can also suggest counterintuitive candidates

Wave attenuation model for dephasing and measurement of conditional times

Inelastic scattering induces dephasing in mesoscopic systems. An analysis of previous models to simulate inelastic scattering in such systems is presented and also a relatively new model based on wave attenuation is introduced. The problem of Aharonov-Bohm(AB) oscillations in conductance of a mesoscopic ring is studied. We have shown that conductance is symmetric under flux reversal and visibility of AB oscillations decay to zero as function of the incoherence parameter, signalling dephasing. Further wave attenuation is applied to a fundamental problem in quantum mechanics, i.e., the conditional(reflection/transmission) times spent in a given region of space by a quantum particle before scattering off from that region.Comment: 8 pages, 6 figures. Based on presentations by A. M. J and C. B at the 2nd Winter Institute on Foundations of Quantum theory, Quantum Optics and QIP held at S N Bose National Centre for Basic Sciences, Kolkata, India, from January 2-11, 200

Comparison of the Near-Threshold Production of eta- and K-Mesons in Proton-Proton Collisions

The pp -> pp eta and pp -> pLambda K^+ reactions near threshold are dominated by the first and second S_11 resonance respectively. It is shown that a one-pion-exchange model exciting these isobars reproduces well the ratio of the production cross sections. The consequences for this and other channels are discussed.Comment: 10 pages, LaTeX2e, 1 eps-figur

Chromatin structure and evolution in the human genome

<p>Abstract</p> <p>Background</p> <p>Evolutionary rates are not constant across the human genome but genes in close proximity have been shown to experience similar levels of divergence and selection. The higher-order organisation of chromosomes has often been invoked to explain such phenomena but previously there has been insufficient data on chromosome structure to investigate this rigorously. Using the results of a recent genome-wide analysis of open and closed human chromatin structures we have investigated the global association between divergence, selection and chromatin structure for the first time.</p> <p>Results</p> <p>In this study we have shown that, paradoxically, synonymous site divergence (dS) at non-CpG sites is highest in regions of open chromatin, primarily as a result of an increased number of transitions, while the rates of other traditional measures of mutation (intergenic, intronic and ancient repeat divergence as well as SNP density) are highest in closed regions of the genome. Analysis of human-chimpanzee divergence across intron-exon boundaries indicates that although genes in relatively open chromatin generally display little selection at their synonymous sites, those in closed regions show markedly lower divergence at their fourfold degenerate sites than in neighbouring introns and intergenic regions. Exclusion of known Exonic Splice Enhancer hexamers has little affect on the divergence observed at fourfold degenerate sites across chromatin categories; however, we show that closed chromatin is enriched with certain classes of ncRNA genes whose RNA secondary structure may be particularly important.</p> <p>Conclusion</p> <p>We conclude that, overall, non-CpG mutation rates are lowest in open regions of the genome and that regions of the genome with a closed chromatin structure have the highest background mutation rate. This might reflect lower rates of DNA damage or enhanced DNA repair processes in regions of open chromatin. Our results also indicate that dS is a poor measure of mutation rates, particularly when used in closed regions of the genome, as genes in closed regions generally display relatively strong levels of selection at their synonymous sites.</p

Cross modal perception of body size in domestic dogs (Canis familiaris)

While the perception of size-related acoustic variation in animal vocalisations is well documented, little attention has been given to how this information might be integrated with corresponding visual information. Using a cross-modal design, we tested the ability of domestic dogs to match growls resynthesised to be typical of either a large or a small dog to size- matched models. Subjects looked at the size-matched model significantly more often and for a significantly longer duration than at the incorrect model, showing that they have the ability to relate information about body size from the acoustic domain to the appropriate visual category. Our study suggests that the perceptual and cognitive mechanisms at the basis of size assessment in mammals have a multisensory nature, and calls for further investigations of the multimodal processing of size information across animal species

The complexity of selection at the major primate β-defensin locus

BACKGROUND: We have examined the evolution of the genes at the major human β-defensin locus and the orthologous loci in a range of other primates and mouse. For the first time these data allow us to examine selective episodes in the more recent evolutionary history of this locus as well as the ancient past. We have used a combination of maximum likelihood based tests and a maximum parsimony based sliding window approach to give a detailed view of the varying modes of selection operating at this locus. RESULTS: We provide evidence for strong positive selection soon after the duplication of these genes within an ancestral mammalian genome. Consequently variable selective pressures have acted on β-defensin genes in different evolutionary lineages, with episodes both of negative, and more rarely positive selection, during the divergence of primates. Positive selection appears to have been more common in the rodent lineage, accompanying the birth of novel, rodent-specific β-defensin genes. These observations allow a fuller understanding of the evolution of mammalian innate immunity. In both the rodent and primate lineages, sites in the second exon have been subject to positive selection and by implication are important in functional diversity. A small number of sites in the mature human peptides were found to have undergone repeated episodes of selection in different primate lineages. Particular sites were consistently implicated by multiple methods at positions throughout the mature peptides. These sites are clustered at positions predicted to be important for the specificity of the antimicrobial or chemoattractant properties of β-defensins. Surprisingly, sites within the prepropeptide region were also implicated as being subject to significant positive selection, suggesting previously unappreciated functional significance for this region. CONCLUSIONS: Identification of these putatively functional sites has important implications for our understanding of β-defensin function and for novel antibiotic design