PCI-SS: MISO dynamic nonlinear protein secondary structure prediction

<p>Abstract</p> <p>Background</p> <p>Since the function of a protein is largely dictated by its three dimensional configuration, determining a protein's structure is of fundamental importance to biology. Here we report on a novel approach to determining the one dimensional secondary structure of proteins (distinguishing α-helices, β-strands, and non-regular structures) from primary sequence data which makes use of Parallel Cascade Identification (PCI), a powerful technique from the field of nonlinear system identification.</p> <p>Results</p> <p>Using PSI-BLAST divergent evolutionary profiles as input data, dynamic nonlinear systems are built through a black-box approach to model the process of protein folding. Genetic algorithms (GAs) are applied in order to optimize the architectural parameters of the PCI models. The three-state prediction problem is broken down into a combination of three binary sub-problems and protein structure classifiers are built using 2 layers of PCI classifiers. Careful construction of the optimization, training, and test datasets ensures that no homology exists between any training and testing data. A detailed comparison between PCI and 9 contemporary methods is provided over a set of 125 new protein chains guaranteed to be dissimilar to all training data. Unlike other secondary structure prediction methods, here a web service is developed to provide both human- and machine-readable interfaces to PCI-based protein secondary structure prediction. This server, called PCI-SS, is available at <url>http://bioinf.sce.carleton.ca/PCISS</url>. In addition to a dynamic PHP-generated web interface for humans, a Simple Object Access Protocol (SOAP) interface is added to permit invocation of the PCI-SS service remotely. This machine-readable interface facilitates incorporation of PCI-SS into multi-faceted systems biology analysis pipelines requiring protein secondary structure information, and greatly simplifies high-throughput analyses. XML is used to represent the input protein sequence data and also to encode the resulting structure prediction in a machine-readable format. To our knowledge, this represents the only publicly available SOAP-interface for a protein secondary structure prediction service with published WSDL interface definition.</p> <p>Conclusion</p> <p>Relative to the 9 contemporary methods included in the comparison cascaded PCI classifiers perform well, however PCI finds greatest application as a consensus classifier. When PCI is used to combine a sequence-to-structure PCI-based classifier with the current leading ANN-based method, PSIPRED, the overall error rate (Q3) is maintained while the rate of occurrence of a particularly detrimental error is reduced by up to 25%. This improvement in BAD score, combined with the machine-readable SOAP web service interface makes PCI-SS particularly useful for inclusion in a tertiary structure prediction pipeline.</p

Williams syndrome: An exploration of neurocognitive and genetic features.

Abstract We report here on signi®cant attempts to forge links between neurodevelopmental disorders, development of speci®c neuropsychological abilities, and the functional establishment of patterns of brain organization. Such research programs are providing converging evidence for the coherence or dissociability of components of cognition (e.g. language, spatial cognition) and will allow development of theoretical explanations for the underlying architecture of human cognition. Williams syndrome involves focal rather than generalized cognitive de®cits, and offers an important opportunity for linking brain ®ndings to speci®c atypical cognitive pro®les. The unusual neurocognitive pro®le of Williams syndrome makes it a compelling model of the pathways between genes and human cognition. It is becoming clear that the syndrome&apos;s unique genomic organization may also make it an important model of human chromosomal evolution and disease. These studies with a speci®c neurodevelopmental disorder that presents a rare dissociation of higher cortical functioning may provide opportunities to explore some of the central issues of cognitive neuroscience that tie cognitive functions to brain organization and ultimately to the human genome.

Intelligence in Williams Syndrome Is Related to STX1A, Which Encodes a Component of the Presynaptic SNARE Complex

Although genetics is the most significant known determinant of human intelligence, specific gene contributions remain largely unknown. To accelerate understanding in this area, we have taken a new approach by studying the relationship between quantitative gene expression and intelligence in a cohort of 65 patients with Williams Syndrome (WS), a neurodevelopmental disorder caused by a 1.5 Mb deletion on chromosome 7q11.23. We find that variation in the transcript levels of the brain gene STX1A correlates significantly with intelligence in WS patients measured by principal component analysis (PCA) of standardized WAIS-R subtests, r  = 0.40 (Pearson correlation, Bonferroni corrected p-value  = 0.007), accounting for 15.6% of the cognitive variation. These results suggest that syntaxin 1A, a neuronal regulator of presynaptic vesicle release, may play a role in WS and be a component of the cellular pathway determining human intelligence

Mapping Genetically Controlled Neural Circuits of Social Behavior and Visuo-Motor Integration by a Preliminary Examination of Atypical Deletions with Williams Syndrome

In this study of eight rare atypical deletion cases with Williams-Beuren syndrome (WS; also known as 7q11.23 deletion syndrome) consisting of three different patterns of deletions, compared to typical WS and typically developing (TD) individuals, we show preliminary evidence of dissociable genetic contributions to brain structure and human cognition. Univariate and multivariate pattern classification results of morphometric brain patterns complemented by behavior implicate a possible role for the chromosomal region that includes: 1) GTF2I/GTF2IRD1 in visuo-spatial/motor integration, intraparietal as well as overall gray matter structures, 2) the region spanning ABHD11 through RFC2 including LIMK1, in social cognition, in particular approachability, as well as orbitofrontal, amygdala and fusiform anatomy, and 3) the regions including STX1A, and/or CYLN2 in overall white matter structure. This knowledge contributes to our understanding of the role of genetics on human brain structure, cognition and pathophysiology of altered cognition in WS. The current study builds on ongoing research designed to characterize the impact of multiple genes, gene-gene interactions and changes in gene expression on the human brain

A preliminary study of orbitofrontal activation and hypersociability in Williams Syndrome

Individuals with Williams syndrome (WS) demonstrate an abnormally positive social bias. However, the neural substrates of this hypersociability, i.e., positive attribution bias and increased drive toward social interaction, have not fully been elucidated. Methods: We performed an event-related functional magnetic resonance imaging study while individuals with WS and typically developing controls (TD) matched positive and negative emotional faces. WS compared to TD showed reduced right amygdala activation during presentation of negative faces, as in the previous literature. In addition, WS showed a unique pattern of right orbitofrontal cortex activation. While TD showed medial orbitofrontal cortex activation in response to positive, and lateral orbitofrontal cortex activation to negative, WS showed the opposite pattern. In light of the general notion of a medial/lateral gradient of reward/punishment processing in the orbitofrontal cortex, these findings provide an additional biological explanation for, or correlate of positive attribution bias and hypersociability in WS

From Amplification to Gene in Thyroid Cancer: A High-Resolution Mapped Bacterial-Artificial-Chromosome Resource for Cancer Chromosome Aberrations Guides Gene Discovery after Comparative Genome Hybridization

SummaryChromosome rearrangements associated with neoplasms provide a rich resource for definition of the pathways of tumorigenesis. The power of comparative genome hybridization (CGH) to identify novel genes depends on the existence of suitable markers, which are lacking throughout most of the genome. We now report a general approach that translates CGH data into higher-resolution genomic-clone data that are then used to define the genes located in aneuploid regions. We used CGH to study 33 thyroid-tumor DNAs and two tumor-cell-line DNAs. The results revealed amplifications of chromosome band 2p21, with less-intense amplification on 2p13, 19q13.1, and 1p36 and with least-intense amplification on 1p34, 1q42, 5q31, 5q33-34, 9q32-34, and 14q32. To define the 2p21 region amplified, a dense array of 373 FISH-mapped chromosome 2 bacterial artificial chromosomes (BACs) was constructed, and 87 of these were hybridized to a tumor-cell line. Four BACs carried genomic DNA that was amplified in these cells. The maximum amplified region was narrowed to 3–6 Mb by multicolor FISH with the flanking BACs, and the minimum amplicon size was defined by a contig of 420 kb. Sequence analysis of the amplified BAC 1D9 revealed a fragment of the gene, encoding protein kinase C epsilon (PKCɛ), that was then shown to be amplified and rearranged in tumor cells. In summary, CGH combined with a dense mapped resource of BACs and large-scale sequencing has led directly to the definition of PKCɛ as a previously unmapped candidate gene involved in thyroid tumorigenesis

Enrichment analysis of Alu elements with different spatial chromatin proximity in the human genome

Transposable elements (TEs) have no longer been totally considered as “junk DNA” for quite a time since the continual discoveries of their multifunctional roles in eukaryote genomes. As one of the most important and abundant TEs that still active in human genome, Alu, a SINE family, has demonstrated its indispensable regulatory functions at sequence level, but its spatial roles are still unclear. Technologies based on 3C(chromosomeconformation capture) have revealed the mysterious three-dimensional structure of chromatin, and make it possible to study the distal chromatin interaction in the genome. To find the role TE playing in distal regulation in human genome, we compiled the new released Hi-C data, TE annotation, histone marker annotations, and the genome-wide methylation data to operate correlation analysis, and found that the density of Alu elements showed a strong positive correlation with the level of chromatin interactions (hESC: r=0.9, P<2.2×1016; IMR90 fibroblasts: r = 0.94, P < 2.2 × 1016) and also have a significant positive correlation withsomeremote functional DNA elements like enhancers and promoters (Enhancer: hESC: r=0.997, P=2.3×10−4; IMR90: r=0.934, P=2×10−2; Promoter: hESC: r = 0.995, P = 3.8 × 10−4; IMR90: r = 0.996, P = 3.2 × 10−4). Further investigation involving GC content and methylation status showed the GC content of Alu covered sequences shared a similar pattern with that of the overall sequence, suggesting that Alu elements also function as the GC nucleotide and CpG site provider. In all, our results suggest that the Alu elements may act as an alternative parameter to evaluate the Hi-C data, which is confirmed by the correlation analysis of Alu elements and histone markers. Moreover, the GC-rich Alu sequence can bring high GC content and methylation flexibility to the regions with more distal chromatin contact, regulating the transcription of tissue-specific genes

Affiliative behavior in Williams syndrome: Social perception and real-life social behavior

A frequently noted but largely anecdotal behavioral observation in Williams syndrome (WS) is an increased tendency to approach strangers, yet the basis for this behavior remains unknown. We examined the relationship between affect identification ability and affiliative behavior in participants with WS relative to a neurotypical comparison group. We quantified social behavior from self-judgments of approachability for faces, and from parent/other evaluations of real life. Relative to typical individuals, participants with WS were perceived as more sociable by others, exhibited perceptual deficits in affect identification, and judged faces of strangers as more approachable. In WS, high self-rated willingness to approach strangers was correlated with poor affect identification ability, suggesting that these two findings may be causally related. We suggest that the real-life hypersociability in WS may arise at least in part from abnormal perceptual processing of other people's faces, rather than from an overall bias at the level of behavior. While this did not achieve statistical significance, it provides preliminary evidence to suggest that impaired social-perceptual ability may play a role in increased approachability in WS

Oxytocin and Vasopressin Are Dysregulated in Williams Syndrome, a Genetic Disorder Affecting Social Behavior

The molecular and neural mechanisms regulating human social-emotional behaviors are fundamentally important but largely unknown; unraveling these requires a genetic systems neuroscience analysis of human models. Williams Syndrome (WS), a condition caused by deletion of ∼28 genes, is associated with a gregarious personality, strong drive to approach strangers, difficult peer interactions, and attraction to music. WS provides a unique opportunity to identify endogenous human gene-behavior mechanisms. Social neuropeptides including oxytocin (OT) and arginine vasopressin (AVP) regulate reproductive and social behaviors in mammals, and we reasoned that these might mediate the features of WS. Here we established blood levels of OT and AVP in WS and controls at baseline, and at multiple timepoints following a positive emotional intervention (music), and a negative physical stressor (cold). We also related these levels to standardized indices of social behavior. Results revealed significantly higher median levels of OT in WS versus controls at baseline, with a less marked increase in AVP. Further, in WS, OT and AVP increased in response to music and to cold, with greater variability and an amplified peak release compared to controls. In WS, baseline OT but not AVP, was correlated positively with approach, but negatively with adaptive social behaviors. These results indicate that WS deleted genes perturb hypothalamic-pituitary release not only of OT but also of AVP, implicating more complex neuropeptide circuitry for WS features and providing evidence for their roles in endogenous regulation of human social behavior. The data suggest a possible biological basis for amygdalar involvement, for increased anxiety, and for the paradox of increased approach but poor social relationships in WS. They also offer insight for translating genetic and neuroendocrine knowledge into treatments for disorders of social behavior