Coastal oceanography and sedimentology in New Zealand, 1967-91.

This paper reviews research that has taken place on physical oceanography and sedimentology on New Zealand's estuaries and the inner shelf since c. 1967. It includes estuarine sedimentation, tidal inlets, beach morphodynamics, nearshore and inner shelf sedimentation, tides and coastal currents, numerical modelling, short-period waves, tsunamis, and storm surges. An extensive reference list covering both published and unpublished material is included. Formal teaching and research programmes dealing with coastal landforms and the processes that shape them were only introduced to New Zealand universities in 1964; the history of the New Zealand Journal of Marine and Freshwater Research parallels and chronicles the development of physical coastal science in New Zealand, most of which has been accomplished in last 25 years

The rise of linear borders in world politics

This article argues that the dominance of precise, linear borders as an ideal in the demarcation of territory is an outcome of a relatively recent and ongoing historical process, and that this process has had important effects on international politics since circa 1900. Existing accounts of the origins of territorial sovereignty are in wide disagreement largely because they fail to specify the relationship between territory and borders, often conflating the two concepts. I outline a history of the linearization of borders which is separate from that of territorial sovereignty, having a very different timeline and featuring different actors, and offer an explanation for the dominance of this universalizing system of managing and demarcating space, based on the concept of rationalization. Finally I describe two broad ways in which linearizing borders has affected international politics, by making space divisible in new ways, and underpinning hierarchies by altering the distribution of geographical knowledge resources

International Undiagnosed Diseases Programs (UDPs): components and outcomes

Over the last 15 years, Undiagnosed Diseases Programs have emerged to address the significant number of individuals with suspected but undiagnosed rare genetic diseases, integrating research and clinical care to optimize diagnostic outcomes. This narrative review summarizes the published literature surrounding Undiagnosed Diseases Programs worldwide, including thirteen studies that evaluate outcomes and two commentary papers. Commonalities in the diagnostic and research process of Undiagnosed Diseases Programs are explored through an appraisal of available literature. This exploration allowed for an assessment of the strengths and limitations of each of the six common steps, namely enrollment, comprehensive clinical phenotyping, research diagnostics, data sharing and matchmaking, results, and follow-up. Current literature highlights the potential utility of Undiagnosed Diseases Programs in research diagnostics. Since participants have often had extensive previous genetic studies, research pipelines allow for diagnostic approaches beyond exome or whole genome sequencing, through reanalysis using research-grade bioinformatics tools and multi-omics technologies. The overall diagnostic yield is presented by study, since different selection criteria at enrollment and reporting processes make comparisons challenging and not particularly informative. Nonetheless, diagnostic yield in an undiagnosed cohort reflects the potential of an Undiagnosed Diseases Program. Further comparisons and exploration of the outcomes of Undiagnosed Diseases Programs worldwide will allow for the development and improvement of the diagnostic and research process and in turn improve the value and utility of an Undiagnosed Diseases Program

Local alignment of two-base encoded DNA sequence

<p>Abstract</p> <p>Background</p> <p>DNA sequence comparison is based on optimal local alignment of two sequences using a similarity score. However, some new DNA sequencing technologies do not directly measure the base sequence, but rather an encoded form, such as the two-base encoding considered here. In order to compare such data to a reference sequence, the data must be decoded into sequence. The decoding is deterministic, but the possibility of measurement errors requires searching among all possible error modes and resulting alignments to achieve an optimal balance of fewer errors versus greater sequence similarity.</p> <p>Results</p> <p>We present an extension of the standard dynamic programming method for local alignment, which simultaneously decodes the data and performs the alignment, maximizing a similarity score based on a weighted combination of errors and edits, and allowing an affine gap penalty. We also present simulations that demonstrate the performance characteristics of our two base encoded alignment method and contrast those with standard DNA sequence alignment under the same conditions.</p> <p>Conclusion</p> <p>The new local alignment algorithm for two-base encoded data has substantial power to properly detect and correct measurement errors while identifying underlying sequence variants, and facilitating genome re-sequencing efforts based on this form of sequence data.</p

Different types of disease-causing non-coding variants revealed by genomic and gene expression analyses in families with X-linked intellectual disability

The pioneering discovery research of X-linked intellectual disability (XLID) genes has benefitted thousands of individuals worldwide however, approximately 30% of XLID families still remain unresolved. We postulated that non-coding variants that affect gene regulation or splicing may account for the lack of a genetic diagnosis in some cases. Detecting pathogenic, gene-regulatory variants with the same sensitivity and specificity as structural and coding variants is a major challenge for Mendelian disorders. Here, we describe three pedigrees with suggestive XLID where distinctive phenotypes associated with known genes guided the identification of three different non-coding variants. We used comprehensive structural, single nucleotide and repeat expansion analyses of genome sequencing. RNA-Seq from patient-derived cell lines, RT-PCRs, western blots and reporter gene assays were used to confirm the functional effect of three fundamentally different classes of pathogenic non-coding variants: a retrotransposon insertion, a novel intronic splice donor and a canonical splice variant of an untranslated exon. In one family, we excluded a rare coding variant in ARX, a known XLID gene, in favour of a regulatory non-coding variant in OFD1 that correlated with the clinical phenotype. Our results underscore the value of genomic research on unresolved XLID families to aid novel, pathogenic non-coding variant discovery.Michael J. Field, Raman Kumar, Anna Hackett, Sayaka Kayumi, Cheryl A. Shoubridge, Lisa J. Ewans, Atma M. Ivancevic, Tracy Dudding, Byth, Renée Carroll, Thessa Kroes, Alison E. Gardner, Patricia Sullivan, Thuong T. Ha, Charles E. Schwartz, Mark J. Cowley, Marcel E. Dinger, Elizabeth E. Palmer, Louise Christie, Marie Shaw, Tony Roscioli, Jozef Gecz, Mark A. Corbet

Disorders of sex development : insights from targeted gene sequencing of a large international patient cohort

Background: Disorders of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or phenotypic sex is atypical. Clinical management of DSD is often difficult and currently only 13% of patients receive an accurate clinical genetic diagnosis. To address this we have developed a massively parallel sequencing targeted DSD gene panel which allows us to sequence all 64 known diagnostic DSD genes and candidate genes simultaneously. Results: We analyzed DNA from the largest reported international cohort of patients with DSD (278 patients with 46, XY DSD and 48 with 46, XX DSD). Our targeted gene panel compares favorably with other sequencing platforms. We found a total of 28 diagnostic genes that are implicated in DSD, highlighting the genetic spectrum of this disorder. Sequencing revealed 93 previously unreported DSD gene variants. Overall, we identified a likely genetic diagnosis in 43% of patients with 46, XY DSD. In patients with 46, XY disorders of androgen synthesis and action the genetic diagnosis rate reached 60%. Surprisingly, little difference in diagnostic rate was observed between singletons and trios. In many cases our findings are informative as to the likely cause of the DSD, which will facilitate clinical management. Conclusions: Our massively parallel sequencing targeted DSD gene panel represents an economical means of improving the genetic diagnostic capability for patients affected by DSD. Implementation of this panel in a large cohort of patients has expanded our understanding of the underlying genetic etiology of DSD. The inclusion of research candidate genes also provides an invaluable resource for future identification of novel genes

De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome.

Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here we identify the non-coding RNA RNU4-2 as a syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 base pair region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals in whom it could be determined, the de novo variants were all on the maternal allele. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to RNU4-1 and other U4 homologues. Using RNA sequencing, we show how 5 splice-site use is systematically disrupted in individuals with RNU4-2 variants, consistent with the known role of this region during spliceosome activation. Finally, we estimate that variants in this 18 base pair region explain 0.4% of individuals with NDD. This work underscores the importance of non-coding genes in rare disorders and will provide a diagnosis to thousands of individuals with NDD worldwide

Negative nominal interest rates: history and current proposals

Given the renewed interest in negative interest rates as a means for overcoming the zero bound on nominal interest rates, this article reviews the history of negative nominal interest rates and gives a brief survey over the current proposals that received popular attention in the wake of the financial crisis of 2007/08. It is demonstrated that taxing money proposals have a long intellectual history and that instead of being the conjecture of a monetary crank, they are a serious policy proposal. In a second step the article points out that, besides the more popular debate on a Gesell tax as a means to remove the zero bound on nominal interest rates, there is a class of neoclassical search-models that advocates a negative tax on money as efficiency enhancing. This strand of the literature has so far been largely ignored by the policy debate on negative interest rates