A Phenomic Scan of the Norfolk Island Genetic Isolate Identifies a Major Pleiotropic Effect Locus Associated with Metabolic and Renal Disorder Markers

Multiphenotype genome-wide association studies (GWAS) may reveal pleiotropic genes, which would remain undetected using single phenotype analyses. Analysis of large pedigrees offers the added advantage of more accurately assessing trait heritability, which can help prioritise genetically influenced phenotypes for GWAS analysis. In this study we performed a principal component analysis (PCA), heritability (h2) estimation and pedigree-based GWAS of 37 cardiovascular disease -related phenotypes in 330 related individuals forming a large pedigree from the Norfolk Island genetic isolate. PCA revealed 13 components explaining >75% of the total variance. Nine components yielded statistically significant h2 values ranging from 0.22 to 0.54 (P<0.05). The most heritable component was loaded with 7 phenotypic measures reflecting metabolic and renal dysfunction. A GWAS of this composite phenotype revealed statistically significant associations for 3 adjacent SNPs on chromosome 1p22.2 (P<1x10-8). These SNPs form a 42kb haplotype block and explain 11% of the genetic variance for this renal function phenotype. Replication analysis of the tagging SNP (rs1396315) in an independent US cohort supports the association (P = 0.000011). Blood transcript analysis showed 35 genes were associated with rs1396315 (P<0.05). Gene set enrichment analysis of these genes revealed the most enriched pathway was purine metabolism (P = 0.0015). Overall, our findings provide convincing evidence for a major pleiotropic effect locus on chromosome 1p22.2 influencing risk of renal dysfunction via purine metabolism pathways in the Norfolk Island population. Further studies are now warranted to interrogate the functional relevance of this locus in terms of renal pathology and cardiovascular disease risk.

Set theoretic operations on polygons using the scan-grid approach

This paper describes an algorithm to compute the union, intersection and difference of two polygons using a scan-grid approach. Basically, in this method, the screen is divided into cells and the algorithm is applied to each cell in turn. The output from all the cells is integrated to yield a representation of the output polygon. In most cells, no computation is required and thus the algorithm is a fast one. The algorithm has been implemented for polygons but can be extended to polyhedra as well. The algorithm is shown to take O(N) time in the average case where N is the total number of edges of the two input polygons.

New approach to improved detection and tracking performance in track-while-scan radars. Part 1: Introduction and review

The paper presents a new approach to improve the detection and tracking performance of a track-while-scan (TWS) radar. The contribution consists of three parts. In Part 1 the scope of various papers in this field is reviewed. In Part 2, a new approach for integrating the detection and tracking functions is presented. It shows how a priori information from the TWS computer can be used to improve detection. A new multitarget tracking algorithm has also been developed. It is specifically oriented towards solving the combinatorial problems in multitarget tracking. In Part 3, analytical derivations are presented for quantitatively assessing, a priori, the performance of a track-while-scan radar system (true track initiation, false track initiation, true track continuation and false track deletion characteristics). Simulation results are also shown.

New approach to improved detection and tracking performance in track-while-scan radars. Part 3: Performance prediction, optimisation and testing

The paper presents, in three parts, a new approach to improve the detection and tracking performance of a track-while-scan radar. Part 1 presents a review of the current status of the subject. Part 2 details the new approach. It shows how a priori information provided by the tracker can be used to improve detection. It also presents a new multitarget tracking algorithm. In the present Part, analytical derivations are presented for assessing, a priori, the performance of the TWS radar system. True track initiation, false track initiation, true track continuation and false track deletion characteristics have been studied. It indicates how the various thresholds can be chosen by the designer to optimise performance. Simulation results are also presented.

New approach to improved detection and tracking performance in track-while-scan radars. Part 2: Detection, track nitiation and association

he paper presents, in three parts, a new approach to improve the detection and tracking performance of a track-while-scan (TWS) radar. Part 1 presents a review of current status. In this part, Part 2, it is shown how the detection can be improved by utilising information from tracker. A new multitarget tracking algorithm, capable of tracking manoeuvring targets in clutter, is then presented. The algorithm is specifically tailored so that the solution to the combinatorial problem presented in a companion paper can be applied. The implementation aspects are discussed and a multiprocessor architecture identified to realise the full potential of the algorithm. Part 3 presents analytical derivations for quantitative assessment of the performance of the TWS radar system. It also shows how the performance can be optimised.

Parallel polygon scan conversion algorithms: Performance evaluation on a shared bus architecture

In this paper, three parallel polygon scan conversion algorithms have been proposed, and their performance when executed on a shared bus architecture has been compared. It has been shown that the parallel algorithm that does not use edge coherence performs better than those that use edge coherence. Further, a multiprocessing architecture has been proposed to execute the parallel polygon scan conversion algorithms more efficiently than a single shared bus architecture.

Screening of new lines of cereal grains for inclusion in Near Infra Red Scan calibrations

The project will provide enough data for a reliable and robust NIRs. It will more fully develop the in vitro method to enable less costly assessment of grains in the future. It will also provide a reliable assessment for DE which is the most expensive component of pig feed.

A genome wide linkage scan for dizygotic twinning in 525 families of mothers of dizygotic twins

BACKGROUND: The tendency to conceive dizygotic (DZ) twins is a complex trait influenced by genetic and environmental factors. To search for new candidate loci for twinning, we conducted a genome-wide linkage scan in 525 families using microsatellite and single nucleotide polymorphism marker panels. METHODS AND RESULTS: Non-parametric linkage analyses, including 523 families containing a total of 1115 mothers of DZ twins (MODZT) from Australia and New Zealand (ANZ) and The Netherlands (NL), produced four linkage peaks above the threshold for suggestive linkage, including a highly suggestive peak at the extreme telomeric end of chromosome 6 with an exponential logarithm of odds \[(exp)LOD] score of 2.813 (P = 0.0002). Since the DZ twinning rate increases steeply with maternal age independent of genetic effects, we also investigated linkage including only families where at least one MODZT gave birth to her first set of twins before the age of 30. These analyses produced a maximum expLOD score of 2.718 (P = 0.0002), largely due to linkage signal from the ANZ cohort, however, ordered subset analyses indicated this result is most likely a chance finding in the combined dataset. Linkage analyses were also performed for two large DZ twinning families from the USA, one of which produced a peak on chromosome 2 in the region of two potential candidate genes. Sequencing of FSHR and FIGLA, along with INHBB in MODZTs from two large NL families with family specific linkage peaks directly over this gene, revealed a potentially functional variant in the 5' untranslated region of FSHR that segregated with the DZ twinning phenotype in the Utah family. CONCLUSION: Our data provide further evidence for complex inheritance of familial DZ twinning.

A genome-wide linkage scan provides evidence for both new and previously reported loci influencing common migraine

Latent class analysis was performed on migraine symptom data collected in a Dutch population sample (N = 12,210, 59% female) in order to obtain empirical groupings of individuals suffering from symptoms of migraine headache. Based on these heritable groupings (h(2) = 0.49, 95% CI: 0.41-0.57) individuals were classified as affected (migrainous headache) or unaffected. Genome-wide linkage analysis was performed using genotype data from 105 families with at least 2 affected siblings. In addition to this primary phenotype, linkage analyses were performed for the individual migraine symptoms. Significance levels, corrected for the analysis of multiple traits, were determined empirically via a novel simulation approach. Suggestive linkage for migrainous headache was found on chromosomes 1 (LOD = 1.63; pointwise P = 0.0031), 13 (LOD = 1.63; P = 0.0031), and 20 (LOD = 1.85; P = 0.0018). Interestingly, the chromosome 1 peak was located close to the ATP1A2 gene, associated with familial hemiplegic migraine type 2 (FHM2). Individual symptom analysis produced a LOD score of 1.97 (P = 0.0013) on chromosome 5 (photo/phonophobia), a LOD score of 2.13 (P = 0.0009) on chromosome 10 (moderate/severe pain intensity) and a near significant LOD score of 3.31 (P = 0.00005) on chromosome 13 (pulsating headache). These peaks were all located near regions previously reported in migraine linkage studies. Our results provide important replication and support for the presence of migraine susceptibility genes within these regions, and further support the utility of an LCA-based phenotyping approach and analysis of individual symptoms in migraine genetic research. Additionally, our novel "2-step" analysis and simulation approach provides a powerful means to investigate linkage to individual trait components.

On Minimization of Peak Power for Scan Circuit during Test

Scan circuit generally causes excessive switching activity compared to normal circuit operation. The higher switching activity in turn causes higher peak power supply current which results into supply, voltage droop and eventually yield loss. This paper proposes an efficient methodology for test vector re-ordering to achieve minimum peak power supported by the given test vector set. The proposed methodology also minimizes average power under the minimum peak power constraint. A methodology to further reduce the peak power below the minimum supported peak power, by inclusion of minimum additional vectors is also discussed. The paper defines the lower bound on peak power for a given test set. The results on several benchmarks shows that it can reduce peak power by up to 27%.

Homologous pairing between nucleosome cores on a linear duplex DNA and nucleoprotein filaments of RecA protein-single stranded DNA

The ability of E coli recA protein to promote homologous pairing with linear duplex DNA bound to HU protein (Nucleosome cores) was found to be differentially affected. The formation of paranemic joint molecules was not affected whereas the formation of plectomic joint molecules was inhibited from the start of the reaction. The formation of paranemic joint molecules between nucleoprotein filaments of recA protein-circular single stranded DNA and closed circular duplex DNA is believed to generate positive supercoiling in the duplex DNA. We found that the positively superhelical duplex DNA was inert in the formation of joint molecules but could be converted into an active substrate, in situ, by the action of wheat germ topoisomerase I. These observations initiate an understanding of the structural features of E coli chromosome such as DNA supercoiling and nucleosome-like structures in homologous recombination.

Leveraging Partially Enhanced Scan for Improved Observability in Delay Fault Testing

Enhanced Scan design can significantly improve the fault coverage for two pattern delay tests at the cost of exorbitantly high area overhead. The redundant flip-flops introduced in the scan chains have traditionally only been used to launch the two-pattern delay test inputs, not to capture tests results. This paper presents a new, much lower cost partial Enhanced Scan methodology with both improved controllability and observability. Facilitating observation of some hard to observe internal nodes by capturing their response in the already available and underutilized redundant flip-flops improves delay fault coverage with minimal or almost negligible cost. Experimental results on ISCAS'89 benchmark circuits show significant improvement in TDF fault coverage for this new partial enhance scan methodology.

Metal-ion-mediated tuning of duplex DNA binding by bis(2-(2-pyridyl)-1H-benzimidazole)

Studies of double-stranded-DNA binding have been performed with three isomeric bis)2-(n-pyridyl)-1H-benzimidazole)s (n = 2, 3, 4). Like the well-known Hoechst 33258, which is a bisbenzimidazole compound, these three isomers bind to the minor groove of duplex DNA. DNA binding by the three isomers was investigated in the presence of the divalent metal ions Mg2+, Co2+, Ni2+, Cu2+, and Zn2+. Ligand-DNA interactions were probed with fluorscence and circular dichroism spectroscopy. These studies revealed that the binding of the 2-pyridyl derivative to DNA is dramatically reduced in the presence of Co2+, Ni2+, and Cu2+ ions and is abolished completely at a ligand/metal-cation ratio of 1:1. Control experiments done with the isomeric 3- and 4-pyridyl derivatives showed that their binding to DNA is unaffected by the aforementioned transition-metal ions. The ability of 2-(2-pyridyl)benzimidazole changes of the ligand associated with ion chelation probably ledto such unusual binding results for the ortho isomer. The addition of ethylenediaminetetraacetic acid (EDTA) reversed the effects completely.

DNA duplex with the potential to change handedness after every half a turn

Polymorphic forms of the DNA duplex with long stretches of structural monotony are known. Several alternating purine-pyrimidine sequences have been shown to adopt left-handed Z-conformation. We report a DNA sequence d(CGCGCGATCGAT)n exhibiting alternating right-handed B and left-handed Z helical conformation after every half a turn. Further, this unusual conformation with change in handedness after every six base pairs was induced at physiological superhelical density.

Interaction between the Z-type DNA duplex and 1,3-propanediamine:crystal structure of d(CACGTG)(2) at 1.2 angstrom resolution

The crystal structure of a hexamer duplex d(CACGTG)(2) has been determined and refined to an R-factor of 18.3% using X-ray data up to 1.2 angstrom resolution. The sequence crystallizes as a left-handed Z-form double helix with Watson-Crick base pairing. There is one hexamer duplex, a spermine molecule, 71 water molecules, and an unexpected diamine (Z-5, 1,3-propanediamine, C3H10N2)) in the asymmetric unit. This is the high-resolution non-disordered structure of a Z-DNA hexamer containing two AT base pairs in the interior of a duplex with no modifications such as bromination or methylation on cytosine bases. This structure does not possess multivalent cations such as cobalt hexaammine that are known to stabilize Z-DNA. The overall duplex structure and its crystal interactions are similar to those of the pure-spermine form of the d(CGCGCG)(2) structure. The spine of hydration in the minor groove is intact except in the vicinity of the T5A8 base pair. The binding of the Z-5 molecule in the minor grove of the d(CACGTG)(2) duplex appears to have a profound effect in conferring stability to a Z-DNA conformation via electrostatic complementarity and hydrogen bonding interactions. The successive base stacking geometry in d(CACGTG)(2) is similar to the corresponding steps in d(CG)(3). These results suggest that specific polyamines such as Z-5 could serve as powerful inducers of Z-type conformation in unmodified DNA sequences with AT base pairs. This structure provides a molecular basis for stabilizing AT base pairs incorporated into an alternating d(CG) sequence.