Recent advances in the detection of repeat expansions with short-read next-generation sequencing

Short tandem repeats (STRs), also known as microsatellites, are commonly defined as consisting of tandemly repeated nucleotide motifs of 2-6 base pairs in length. STRs appear throughout the human genome, and about 239,000 are documented in the Simple Repeats Track available from the UCSC (University of California, Santa Cruz) genome browser. STRs vary in size, producing highly polymorphic markers commonly used as genetic markers. A small fraction of STRs (about 30 loci) have been associated with human disease whereby one or both alleles exceed an STR-specific threshold in size, leading to disease. Detection of repeat expansions is currently performed with polymerase chain reaction-based assays or with Southern blots for large expansions. The tests are expensive and time-consuming and are not always conclusive, leading to lengthy diagnostic journeys for patients, potentially including missed diagnoses. The advent of whole exome and whole genome sequencing has identified the genetic cause of many genetic disorders; however, analysis pipelines are focused primarily on the detection of short nucleotide variations and short insertions and deletions (indels). Until recently, repeat expansions, with the exception of the smallest expansion (SCA6), were not detectable in next-generation short-read sequencing datasets and would have been ignored in most analyses. In the last two years, four analysis methods with accompanying software (ExpansionHunter, exSTRa, STRetch, and TREDPARSE) have been released. Although a comprehensive comparative analysis of the performance of these methods across all known repeat expansions is still lacking, it is clear that these methods are a valuable addition to any existing analysis pipeline. Here, we detail how to assess short-read data for evidence of expansions, reviewing all four methods and outlining their strengths and weaknesses. Implementation of these methods should lead to increased diagnostic yield of repeat expansion disorders for known STR loci and has the potential to detect novel repeat expansions

Aeolianite and barrier dune construction spanning the last two glacial-interglacial cycles from the southern Cape coast, South Africa

The southern Cape region of South Africa has extensive coastal aeolianites and barrier dunes. Whilst previously reported, limited knowledge of their age has precluded an understanding of their relationship with the climatic and sea-level fluctuations that have taken place during the Late Quaternary. Sedimentological and geomorphological studies combined with an optical dating programme reveal aeolianite development and barrier dune construction spanning at least the last two glacial–interglacial cycles. Aeolianite deposition has occurred on the southern Cape coast at ca 67–80, 88–90, 104–128, 160–189 and >200 ka before the present. Using this and other published data coupled with a better understanding of Late Quaternary sea-level fluctuations and palaeocoastline configurations, it is concluded that these depositional phases appear to be controlled by interglacial and subsequent interstadial sea-level high stands. These marine transgressions and regressions allowed onshore carbonate-rich sediment movement and subsequent aeolian reworking to occur at similar points in the landscape on a number of occasions. The lack of carbonates in more recent dunes (Oxygen Isotope Stages 1/2 and 4/5) is attributed not to leaching but to changes to carbonate production in the sediment source area caused by increased terrigenous material and/or changes in the balance between the warm Agulhas and nutrient-rich Benguela ocean current

R.A.Fisher, design theory, and the Indian connection

Design Theory, a branch of mathematics, was born out of the experimental statistics research of the population geneticist R. A. Fisher and of Indian mathematical statisticians in the 1930s. The field combines elements of combinatorics, finite projective geometries, Latin squares, and a variety of further mathematical structures, brought together in surprising ways. This essay will present these structures and ideas as well as how the field came together, in itself an interesting story.Comment: 11 pages, 3 figure

PRIMA1 mutation: A new cause of nocturnal frontal lobe epilepsy

Objective Nocturnal frontal lobe epilepsy (NFLE) can be sporadic or autosomal dominant; some families have nicotinic acetylcholine receptor subunit mutations. We report a novel autosomal recessive phenotype in a single family and identify the causative gene. Methods Whole exome sequencing data was used to map the family, thereby narrowing exome search space, and then to identify the mutation. Results Linkage analysis using exome sequence data from two affected and two unaffected subjects showed homozygous linkage peaks on chromosomes 7, 8, 13, and 14 with maximum LOD scores between 1.5 and 1.93. Exome variant filtering under these peaks revealed that the affected siblings were homozygous for a novel splice site mutation (c.93+2T>C) in the PRIMA1 gene on chromosome 14. No additional PRIMA1 mutations were found in 300 other NFLE cases. The c.93+2T>C mutation was shown to lead to skipping of the first coding exon of the PRIMA1 mRNA using a minigene system. Interpretation PRIMA1 is a transmembrane protein that anchors acetylcholinesterase (AChE), an enzyme hydrolyzing acetycholine, to membrane rafts of neurons. PRiMA knockout mice have reduction of AChE and accumulation of acetylcholine at the synapse; our minigene analysis suggests that the c.93+2T>C mutation leads to knockout of PRIMA1. Mutations with gain of function effects in acetylcholine receptor subunits cause autosomal dominant NFLE. Thus, enhanced cholinergic responses are the likely cause of the severe NFLE and intellectual disability segregating in this family, representing the first recessive case to be reported and the first PRIMA1 mutation implicated in disease

Framing alleged Islamist plots: a case study of British press coverage since 9/11

In the decade post 9/11 , the UK terrorist threat was associated with a series of high profile counter terrorism operations, linked to specific plots. These terrorism related episodes received significant media attention and, as a consequence, were a visible sign of the contemporary terrorist threat. This paper seeks to identify the dominant frames rendered in news media reporting on these episodes. Through a longitudinal study of UK press coverage, the analysis reveals that two prominent frames were present, an inevitability and preparedness frame, with alleged plots serving to underline the risk posed by contemporary terrorism,and a belonging and responsibility frame, which cast later episodes as belonging to the Muslim communities disrupted by polic

Adolescent Religiosity and Selective Exposure to Television

Relying on the Adolescent Media Practice Model and selective exposure theory, this study investigated whether religious adolescents watch less mature television entertainment programs than their less religious peers. Program maturity was measured using V-chip ratings, with higher maturity scores indicating content that included more sexuality, violence, and/or adult and sexual language. The responses from 1,335 16- to 18-year-olds who completed Wave 2 of the National Study of Youth and Religion (NSYR) survey were analyzed. Findings indicate that religiosity contributes to explaining the variance in television maturity means, with more religious adolescents indicating a preference for less mature television entertainment. Gender, race, income, and parents’ monitoring of teens’ media were also found to influence television maturity. Teens’ attitudes toward premarital sex appeared to mediate the effect of religiosity on their television entertainment choices

The 'new majority' and the academization of journalism

The academization of journalism is reliant on the development of the field founded in scholarship demonstrated through the publication of research in peer-reviewed specialist journals. Given the profile of journalism faculty, this means inducting practitioners into a culture of critical research. In Australia at least, this cohort of neophytes is predominantly comprised of middle-aged women who were surveyed about their personal attitudes to research. They were mostly open to the idea of becoming researchers but were inclined to proceed cautiously without necessarily severing their ties with practice. There was evidence to suggest that a generally positive orientation to research was not capitalized on and that they remained uncertain about the role of research. On the other hand, they appeared not to have adopted the orthodoxy of implacable opposition to scholarly inquiry. The change in gender composition in the academy may provide, contrary to historical, but more in line with contemporary, evidence, a renewed impetus to the project of academizing the field

Tectono-stratigraphic evolution and crustal architecture of the Orphan Basin during North Atlantic rifting

The Orphan Basin is located in the deep offshore of the Newfoundland margin, and it is bounded by the continental shelf to the west, the Grand Banks to the south, and the continental blocks of Orphan Knoll and Flemish Cap to the east. The Orphan Basin formed in Mesozoic time during the opening of the North Atlantic Ocean between eastern Canada and western Iberia–Europe. This work, based on well data and regional seismic reflection profiles across the basin, indicates that the continental crust was affected by several extensional episodes between the Jurassic and the Early Cretaceous, separated by events of uplift and erosion. The preserved tectono-stratigraphic sequences in the basin reveal that deformation initiated in the eastern part of the Orphan Basin in the Jurassic and spread towards the west in the Early Cretaceous, resulting in numerous rift structures filled with a Jurassic–Lower Cretaceous syn-rift succession and overlain by thick Upper Cretaceous to Cenozoic post-rift sediments. The seismic data show an extremely thinned crust (4–16 km thick) underneath the eastern and western parts of the Orphan Basin, forming two sub-basins separated by a wide structural high with a relatively thick crust (17 km thick). Quantifying the crustal architecture in the basin highlights the large discrepancy between brittle extension localized in the upper crust and the overall crustal thinning. This suggests that continental deformation in the Orphan Basin involved, in addition to the documented Jurassic and Early Cretaceous rifting, an earlier brittle rift phase which is unidentifiable in seismic data and a depth-dependent thinning of the crust driven by localized lower crust ductile flow

Theory and practice of social norms interventions: eight common pitfalls.

BACKGROUND: Recently, Global Health practitioners, scholars, and donors have expressed increased interest in "changing social norms" as a strategy to promote health and well-being in low and mid-income countries (LMIC). Despite this burgeoning interest, the ability of practitioners to use social norm theory to inform health interventions varies widely. MAIN BODY: Here, we identify eight pitfalls that practitioners must avoid as they plan to integrate a social norms perspective in their interventions, as well as eight learnings. These learnings are: 1) Social norms and attitudes are different; 2) Social norms and attitudes can coincide; 3) Protective norms can offer important resources for achieving effective social improvement in people's health-related practices; 4) Harmful practices are sustained by a matrix of factors that need to be understood in their interactions; 5) The prevalence of a norm is not necessarily a sign of its strength; 6) Social norms can exert both direct and indirect influence; 7) Publicising the prevalence of a harmful practice can make things worse; 8) People-led social norm change is both the right and the smart thing to do. CONCLUSIONS: As the understanding of how norms evolve in LMIC advances, practitioners will develop greater understanding of what works to help people lead change in harmful norms within their contexts. Awareness of these pitfalls has helped several of them increase the effectiveness of their interventions addressing social norms in the field. We are confident that others will benefit from these reflections as well

Genetic variants associated with longitudinal changes in brain structure across the lifespan

Human brain structure changes throughout the lifespan. Altered brain growth or rates of decline are implicated in a vast range of psychiatric, developmental and neurodegenerative diseases. In this study, we identified common genetic variants that affect rates of brain growth or atrophy in what is, to our knowledge, the first genome-wide association meta-analysis of changes in brain morphology across the lifespan. Longitudinal magnetic resonance imaging data from 15,640 individuals were used to compute rates of change for 15 brain structures. The most robustly identified genes GPR139, DACH1 and APOE are associated with metabolic processes. We demonstrate global genetic overlap with depression, schizophrenia, cognitive functioning, insomnia, height, body mass index and smoking. Gene set findings implicate both early brain development and neurodegenerative processes in the rates of brain changes. Identifying variants involved in structural brain changes may help to determine biological pathways underlying optimal and dysfunctional brain development and aging