Globin genes on the move

Recent data published in BMC Biology from the globin gene clusters in platypus, together with data from other species, show that β-globin genes transposed from one chromosomal location to another. This resolves some controversies about vertebrate globin gene evolution but ignites new ones

Space tug propulsion system failure mode, effects and criticality analysis

For purposes of the study, the propulsion system was considered as consisting of the following: (1) main engine system, (2) auxiliary propulsion system, (3) pneumatic system, (4) hydrogen feed, fill, drain and vent system, (5) oxygen feed, fill, drain and vent system, and (6) helium reentry purge system. Each component was critically examined to identify possible failure modes and the subsequent effect on mission success. Each space tug mission consists of three phases: launch to separation from shuttle, separation to redocking, and redocking to landing. The analysis considered the results of failure of a component during each phase of the mission. After the failure modes of each component were tabulated, those components whose failure would result in possible or certain loss of mission or inability to return the Tug to ground were identified as critical components and a criticality number determined for each. The criticality number of a component denotes the number of mission failures in one million missions due to the loss of that component. A total of 68 components were identified as critical with criticality numbers ranging from 1 to 2990

Human-macaque comparisons illuminate variation in neutral substitution rates

The evolutionary distance between human and macaque is particularly attractive for investigating neutral substitution rates, which were calculated as a function of a number of genomic parameters

Revealing mammalian evolutionary relationships by comparative analysis of gene clusters

Many software tools for comparative analysis of genomic sequence data have been released in recent decades. Despite this, it remains challenging to determine evolutionary relationships in gene clusters due to their complex histories involving duplications, deletions, inversions, and conversions. One concept describing these relationships is orthology. Orthologs derive from a common ancestor by speciation, in contrast to paralogs, which derive from duplication. Discriminating orthologs from paralogs is a necessary step in most multispecies sequence analyses, but doing so accurately is impeded by the occurrence of gene conversion events. We propose a refined method of orthology assignment based on two paradigms for interpreting its definition: by genomic context or by sequence content. X-orthology (based on context) traces orthology resulting from speciation and duplication only, while N-orthology (based on content) includes the influence of conversion events

Hot Electron Capture Dissociation Distinguishes Leucine from Isoleucine in a Novel Hemoglobin Variant, Hb Askew, β54(D5)Val→Ile

Population migration has led to the global dispersion of human hemoglobinopathies and has precipitated a need for their identification. An effective mass spectrometry-based procedure involves analysis of the intact α- and β-globin chains to determine their mass, followed by location of the variant amino acid residue by direct analysis of the enzymatically digested chains and low-energy collision induced dissociation of the variant peptide. Using this procedure, a variant was identified as either β54Val→Leu or β54Val→Ile, since the amino acids leucine and isoleucine cannot be distinguished using low-energy collisions. Here, we describe how hot electron capture dissociation on a Fourier transform-ion cyclotron resonance mass spectrometer was used to distinguish isoleucine from leucine and identify the mutation as β54(D5)Val→Ile. This is a novel variant, and we have named it Hb Askew

Improvements to GALA and dbERGE II: databases featuring genomic sequence alignment, annotation and experimental results

We describe improvements to two databases that give access to information on genomic sequence similarities, functional elements in DNA and experimental results that demonstrate those functions. GALA, the database of Genome ALignments and Annotations, is now a set of interlinked relational databases for five vertebrate species, human, chimpanzee, mouse, rat and chicken. For each species, GALA records pairwise and multiple sequence alignments, scores derived from those alignments that reflect the likelihood of being under purifying selection or being a regulatory element, and extensive annotations such as genes, gene expression patterns and transcription factor binding sites. The user interface supports simple and complex queries, including operations such as subtraction and intersections as well as clustering and finding elements in proximity to features. dbERGE II, the database of Experimental Results on Gene Expression, contains experimental data from a variety of functional assays. Both databases are now run on the DB2 database management system. Improved hardware and tuning has reduced response times and increased querying capacity, while simplified query interfaces will help direct new users through the querying process. Links are available at http://www.bx.psu.edu/

Leaf trichomes affect caterpillar feeding in an instar-specific manner

Leaf trichomes play well-established roles in defense against insect herbivores, both as a physical barrier that impedes herbivore movement and by mediating chemical defenses. However, little work has examined how different trichome types influence herbivory by herbivores at different stages of development. We examined whether caterpillar instar and trichome type (glandular or non-glandular) affected the ability of the specialist herbivore caterpillar Manduca sexta to initiate feeding on 11 Solanaceous species exhibiting variation in the density and type of leaf trichomes. Our results suggest that non-glandular trichomes are far more effective than glandular trichomes in deterring the initiation of feeding by first- and second-instar caterpillars. Meanwhile, neither glandular nor non-glandular trichomes significantly affected the ability of third-instar caterpillars to commence feeding. These findings suggest that while non-glandular trichomes deter feeding initiation by early instar caterpillars, the contribution of both trichomes on later instars may depend on effects after feeding initiation

Integrating and mining the chromatin landscape of cell-type specificity using self-organizing maps

We tested whether self-organizing maps (SOMs) could be used to effectively integrate, visualize, and mine diverse genomics data types, including complex chromatin signatures. A fine-grained SOM was trained on 72 ChIP-seq histone modifications and DNase-seq data sets from six biologically diverse cell lines studied by The ENCODE Project Consortium. We mined the resulting SOM to identify chromatin signatures related to sequence-specific transcription factor occupancy, sequence motif enrichment, and biological functions. To highlight clusters enriched for specific functions such as transcriptional promoters or enhancers, we overlaid onto the map additional data sets not used during training, such as ChIP-seq, RNA-seq, CAGE, and information on cis-acting regulatory modules from the literature. We used the SOM to parse known transcriptional enhancers according to the cell-type-specific chromatin signature, and we further corroborated this pattern on the map by EP300 (also known as p300) occupancy. New candidate cell-type-specific enhancers were identified for multiple ENCODE cell types in this way, along with new candidates for ubiquitous enhancer activity. An interactive web interface was developed to allow users to visualize and custom-mine the ENCODE SOM. We conclude that large SOMs trained on chromatin data from multiple cell types provide a powerful way to identify complex relationships in genomic data at user-selected levels of granularity

Platypus globin genes and flanking loci suggest a new insertional model for beta-globin evolution in birds and mammals

Background: Vertebrate alpha (α)- and beta (β)-globin gene families exemplify the way in which genomes evolve to produce functional complexity. From tandem duplication of a single globin locus, the α- and β-globin clusters expanded, and then were separated onto different chromosomes. The previous finding of a fossil β-globin gene (ω) in the marsupial α-cluster, however, suggested that duplication of the α-β cluster onto two chromosomes, followed by lineage-specific gene loss and duplication, produced paralogous α- and β-globin clusters in birds and mammals. Here we analyse genomic data from an egg-laying monotreme mammal, the platypus (Ornithorhynchus anatinus), to explore haemoglobin evolution at the stem of the mammalian radiation. Results: The platypus α-globin cluster (chromosome 21) contains embryonic and adult α- globin genes, a β-like ω-globin gene, and the GBY globin gene with homology to cytoglobin, arranged as 5'-ζ-ζ'-αD-α3-α2-α1-ω-GBY-3'. The platypus β-globin cluster (chromosome 2) contains single embryonic and adult globin genes arranged as 5'-ε-β-3'. Surprisingly, all of these globin genes were expressed in some adult tissues. Comparison of flanking sequences revealed that all jawed vertebrate α-globin clusters are flanked by MPG-C16orf35 and LUC7L, whereas all bird and mammal β-globin clusters are embedded in olfactory genes. Thus, the mammalian α- and β-globin clusters are orthologous to the bird α- and β-globin clusters respectively. Conclusion: We propose that α- and β-globin clusters evolved from an ancient MPG-C16orf35-α-β-GBY-LUC7L arrangement 410 million years ago. A copy of the original β (represented by ω in marsupials and monotremes) was inserted into an array of olfactory genes before the amniote radiation (>315 million years ago), then duplicated and diverged to form orthologous clusters of β-globin genes with different expression profiles in different lineages.Vidushi S. Patel, Steven J.B. Cooper, Janine E. Deakin, Bob Fulton, Tina Graves, Wesley C. Warren, Richard K. Wilson and Jennifer A.M. Grave

Defining functional DNA elements in the human genome

With the completion of the human genome sequence, attention turned to identifying and annotating its functional DNA elements. As a complement to genetic and comparative genomics approaches, the Encyclopedia of DNA Elements Project was launched to contribute maps of RNA transcripts, transcriptional regulator binding sites, and chromatin states in many cell types. The resulting genome-wide data reveal sites of biochemical activity with high positional resolution and cell type specificity that facilitate studies of gene regulation and interpretation of noncoding variants associated with human disease. However, the biochemically active regions cover a much larger fraction of the genome than do evolutionarily conserved regions, raising the question of whether nonconserved but biochemically active regions are truly functional. Here, we review the strengths and limitations of biochemical, evolutionary, and genetic approaches for defining functional DNA segments, potential sources for the observed differences in estimated genomic coverage, and the biological implications of these discrepancies. We also analyze the relationship between signal intensity, genomic coverage, and evolutionary conservation. Our results reinforce the principle that each approach provides complementary information and that we need to use combinations of all three to elucidate genome function in human biology and disease