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Germline mutation is the mechanism by which genetic variation in a population is created. Inferences derived from mutation rate models are fundamental to many population genetics inference methods. Previous models have demonstrated that nucleotides flanking polymorphic sites – the local sequence context – explain variation in the probability that a site is polymorphic. However, limitations to these models exist as the size of the local sequence context window expands. These include a lack of robustness to data sparsity at typical sample sizes, lack of regularization to generate parsimonious models and lack of quantified uncertainty in estimated rates to facilitate comparison between models. To address these limitations, we developed Baymer, a regularized Bayesian hierarchical tree model that captures the heterogeneous effect of sequence contexts on polymorphism probabilities. Baymer implements an adaptive Metropolis-within-Gibbs Markov Chain Monte Carlo sampling scheme to estimate the posterior distributions of sequence-context based probabilities that a site is polymorphic. We show that Baymer accurately infers polymorphism probabilities and well-calibrated posterior distributions, robustly handles data sparsity, appropriately regularizes to return parsimonious models, and scales computationally at least up to 9-mer context windows. We demonstrate application of Baymer in three ways – first, identifying differences in polymorphism probabilities between continental populations in the 1000 Genomes Phase 3 dataset, second, in a sparse data setting to examine the use of polymorphism models as a proxy forde novomutation probabilities as a function of variant age, sequence context window size, and demographic history, and third, comparing model concordance between different great ape species. We find a shared context-dependent mutation rate architecture underlying our models, enabling a transfer-learning inspired strategy for modeling germline mutations. In summary, Baymer is an accurate polymorphism probability estimation algorithm that automatically adapts to data sparsity at different sequence context levels, thereby making efficient use of the available data.AUTHOR SUMMARYMany biological questions rely on accurate estimates of where and how frequently mutations arise in populations. One factor that has been shown to predict the probability that a mutation occurs is the local DNA sequence surrounding a potential site for mutation. It has been shown that increasing the size of local DNA sequence immediately surrounding a site improves prediction of where, what type, and how frequently the site is mutated. However, current methods struggle to take full advantage of this trend as well as capturing how certain our estimates are, in practice. We have designed a model, implemented in software (namedBaymer), that is able to use large windows of sequence context to accurately model mutation probabilities in a computationally efficient manner. We use Baymer to identify specific DNA sequences that have the biggest impacts on mutability and apply the model to find motifs that have potentially evolved mutability between different human populations. We also apply it to show that germline mutations observed as polymorphic sites in humans - those that have occurred in our recent evolutionary history - can model very young mutations (de novomutations) as well as polymorphism observed in populations of closely related great ape species.

Permian Parapara Group and Triassic Topfer Formation are small clastic sedimentary outliers that rest on Cambrian to Devonian basement terranes in the Western Province of South Island, New Zealand....

In the Murihiku Terrane of New Zealand, U-Pb detrital zircon ages in Murihiku Supergroup sandstones of Late Triassic, Jurassic and possibly earliest Cretaceous age have a marked youngest age component that is close to, and sometimes coincident with, established biostratigraphic ages, thus reflecting contemporary volcanism. However, youngest Huriwai Group samples yield 137–142 Ma zircon age components (earliest Early Cretaceous) in conflict with palynofloras that suggest only a latest Jurassic age. This is resolved if the age of the Jurassic/Cretaceous boundary is lowered to ca. 140 Ma. Older, reworked zircons are mainly Early Jurassic, Late Triassic and Late Permian reflecting an enduring exhumed magmatic arc source nearby. This might be in the adjacent Median Batholith but as a Murihiku sediment source its Jurassic, Triassic and Permian elements are not well-matched in terms of extent, age and bulk compositions. A connection between the Murihiku (proximal forearc) and Waipapa Composite (distal accretionary wedge) terranes is probable, with a common magmatic arc, speculatively situated in the New England Orogen, eastern Australia.

Detrital zircon U–Pb ages are reported from the Haast Schist in western Otago and Marlborough, South Island, New Zealand. The majority are from the Aspiring Lithological Association in Otago, which...

The first-year undergraduate laboratory course in chemistry at the University of Bristol has been changed in an attempt to have students focus on learning practical skills, rather than on their exp...

Fossil-bearing Late Jurassic to Early Cretaceous volcaniclastic sandstones and siltstones from the Murihiku Supergroup are described from the Kaimango Syncline South Auckland, New Zealand. These constitute the youngest known sedimentary succession within the Murihiku Supergroup (Murihiku Terrane). We concentrate on the youngest Matira Siltstone Formation which has yielded a rich but relatively low-diversity macroflora of ferns and gymnosperms, diverse miospore palynofloras, with fair to good preservation, and sporadic occurrences of bivalve and gastropod faunas. Collectively, the paleontology and sedimentology of this formation is interpreted to represent paludal and lacustrine deposition, with intercalated sandstones thought to represent fluvial channelised or deltaic settings. U-Pb dating of detrital zircons (DZ) from sandstones in the youngest formations, Mangatara Measures and Matira Siltstone, have provided significant components in the age range 140 to 143 Ma, possibly straddling the Jurassic-Cretaceous boundary, although miospores suggest a Late Jurassic correlation. Lacustrine and paludal depositional environments have not previously been recognised from the Murihiku Supergroup and this raises the prospect of their enhanced petroleum source rock potential in frontier basins to the north and east of New Zealand.

U–Pb detrital zircon age patterns in sandstones from the Wellington and eastern Cook Strait area have broad Permian–Triassic and Precambrian–early Paleozoic age groups that confirm a previously established Triassic Rakaia Terrane correlation. Along the western Cook Strait coast, meta-psammitic Marlborough Schist samples have zircon patterns with a single age group, either Late Triassic or Jurassic, indicating a Waipapa Terrane ancestry. Similar data from the central Cook Strait region suggest that Waipapa Terrane basement continues northeastwards from Marlborough through Fishermans Rock to Kapiti Island. The Rakaia–Waipapa terrane boundary thus lies east of Kapiti Island and Fishermans Rock. The position of a Caples–Waipapa terrane boundary within the Marlborough Schist is less certain but most of the eastern Marlborough Schist is Waipapa Terrane.

Hsp70 chaperones interact with substrate proteins in a coordinated fashion that is regulated by nucleotides and enhanced by assisting cochaperones. There are numerous homologues and isoforms of Hsp70 that participate in a wide variety of cellular functions. This diversity can facilitate adaption or specialization based on particular biological activity and location within the cell. In this review, we highlight two specialized binding partner proteins, Tim44 and IRE1, that interact with Hsp70 at the membrane in order to serve their respective roles in protein translocation and unfolded protein response signalling. Recent mechanistic data suggest analogy in the way the two Hsp70 homologues (BiP and mtHsp70) can bind and release from IRE1 and Tim44 upon substrate engagement. These shared mechanistic features may underlie how Hsp70 interacts with specialized binding partners and may extend our understanding of the mechanistic repertoire that Hsp70 chaperones possess.

Detrital zircon U–Pb and muscovite 39Ar/40Ar ages from sandstones in the fluviatile to shallow marine mid-Jurassic Clent Hills Group and Wakaepa Formation of mid-Canterbury, South Island, New Zeala...

Uranium–lead age patterns of detrital zircons in Otago Schist meta-sandstones from eastern Otago, including areas of orogenic gold mineralisation, are mostly consistent with a Rakaia Terrane (Torlesse Composite Terrane) accretionary wedge protolith. Southwest of the Hyde-Macraes and Rise & Shine shear zones the depositional age is regarded as Middle–Late Triassic. At the south and west margins, there are two areas in the Late Triassic Waipapa Terrane protolith. Northeast of the Hyde-Macraes Shear Zone, the schist protolith has Middle to Late Triassic and middle to late Permian depositional ages of Rakaia Terrane affinity. At the northeastern margin of the Hyde-Macraes Shear Zone, there is a narrow strip with a mid-Carboniferous protolith, which may be a counterpart of the Carboniferous accretionary wedge in the New England Orogen, eastern Australia. Ordovician–Silurian zircons are a minor but distinctive feature in many of the protolith age patterns and form significant age components at hard-rock...

A mechanochemical strategy for the synthesis of N-heterocyclic carbene complexes is described, in which 1,3-dibenzylimidazole complexes of palladium and platinum are produced in a two-step process by grinding together the reactants with a mortar and pestle. Crystallographic characterization reveals that unlike the solution syntheses, which produce a mixture of products, the solid-state reactions occur under topochemical conditions affording isomerically and polymorphically pure products.

A c. 30 cm thick hydrothermal dike (tuffisite) cuts Early Cretaceous Waipapa Composite Terrane basement on Great Barrier Island. The dike was previously, and erroneously, described as a conglomerate band in the Waipapa Composite Terrane. Zircon from a granite clast in the dike gives a U–Pb age of 17.1 ± 0.6 Ma. The age contributes to a growing dataset of geochronological information from the Miocene Northland Arc.

Diagnosis at the edges of our knowledge calls upon clinicians to be data driven, cross-disciplinary, and collaborative in unprecedented ways. Exact disease recognition, an element of the concept of precision in medicine, requires new infrastructure that spans geography, institutional boundaries, and the divide between clinical care and research. The National Institutes of Health (NIH) Common Fund supports the Undiagnosed Diseases Network (UDN) as an exemplar of this model of precise diagnosis. Its goals are to forge a strategy to accelerate the diagnosis of rare or previously unrecognized diseases, to improve recommendations for clinical management, and to advance research, especially into disease mechanisms. The network will achieve these objectives by evaluating patients with undiagnosed diseases, fostering a breadth of expert collaborations, determining best practices for translating the strategy into medical centers nationwide, and sharing findings, data, specimens, and approaches with the scientific and medical communities. Building the UDN has already brought insights to human and medical geneticists. The initial focus has been on data sharing, establishing common protocols for institutional review boards and data sharing, creating protocols for referring and evaluating patients, and providing DNA sequencing, metabolomic analysis, and functional studies in model organisms. By extending this precision diagnostic model nationally, we strive to meld clinical and research objectives, improve patient outcomes, and contribute to medical science.

Whole-exome sequencing (WES) has increasingly enabled new pathogenic gene variant identification for undiagnosed neurodevelopmental disorders and provided insights into both gene function and disease biology. Here, we describe seven children with a neurodevelopmental disorder characterized by microcephaly, profound developmental delays and/or intellectual disability, cataracts, severe epilepsy including infantile spasms, irritability, failure to thrive, and stereotypic hand movements. Brain imaging in these individuals reveals delay in myelination and cerebral atrophy. We observe an identical recurrent de novo heterozygous c.892C>T (p.Arg298Trp) variant in the nucleus accumbens associated 1 ( NACC1 ) gene in seven affected individuals. One of the seven individuals is mosaic for this variant. NACC1 encodes a transcriptional repressor implicated in gene expression and has not previously been associated with germline disorders. The probability of finding the same missense NACC1 variant by chance in 7 out of 17,228 individuals who underwent WES for diagnoses of neurodevelopmental phenotypes is extremely small and achieves genome-wide significance (p = 1.25 × 10 −14 ). Selective constraint against missense variants in NACC1 makes this excess of an identical missense variant in all seven individuals more remarkable. Our findings are consistent with a germline recurrent mutational hotspot associated with an allele-specific neurodevelopmental phenotype in NACC1 .

Early B cell factor 3 (EBF3) is a member of the highly evolutionarily conserved Collier/Olf/EBF (COE) family of transcription factors. Prior studies on invertebrate and vertebrate animals have shown that EBF3 homologs are essential for survival and that loss-of-function mutations are associated with a range of nervous system developmental defects, including perturbation of neuronal development and migration. Interestingly, aristaless-related homeobox (ARX), a homeobox-containing transcription factor critical for the regulation of nervous system development, transcriptionally represses EBF3 expression. However, human neurodevelopmental disorders related to EBF3 have not been reported. Here, we describe three individuals who are affected by global developmental delay, intellectual disability, and expressive speech disorder and carry de novo variants in EBF3. Associated features seen in these individuals include congenital hypotonia, structural CNS malformations, ataxia, and genitourinary abnormalities. The de novo variants affect a single conserved residue in a zinc finger motif crucial for DNA binding and are deleterious in a fly model. Our findings indicate that mutations in EBF3 cause a genetic neurodevelopmental syndrome and suggest that loss of EBF3 function might mediate a subset of neurologic phenotypes shared by ARX-related disorders, including intellectual disability, abnormal genitalia, and structural CNS malformations.

Plants are treated with synthetic or organic nitrogen sources to increase growth and yield, the most common being calcium ammonium nitrate. However, some nitrogen sources are used in illicit activities. Ammonium nitrate is used in explosive manufacture and ammonium sulphate in the cultivation and extraction of the narcotic cocaine from Erythroxylum spp. Here we show that hyperspectral sensing, multispectral imaging and machine learning image analysis can be used to visualise and differentiate plants exposed to different nefarious nitrogen sources. Metabolomic analysis of leaves from plants exposed to different nitrogen sources reveals shifts in colourful metabolites that may contribute to altered reflectance signatures. Overall this suggests that different nitrogen feeding regimes alter plant secondary metabolism leading to changes in the reflectance spectrum detectable via machine learning of multispectral data but not the naked eye. Our results could facilitate the development of technologies to monitor illegal activities involving various nitrogen sources and further inform nitrogen application requirements in agriculture.

BiP is a major endoplasmic reticulum (ER) chaperone and is suggested to act as primary sensor in the activation of the unfolded protein response (UPR). How BiP operates as a molecular chaperone and as an ER stress sensor is unknown. Here, by reconstituting components of human UPR, ER stress and BiP chaperone systems, we discover that the interaction of BiP with the luminal domains of UPR proteins IRE1 and PERK switch BiP from its chaperone cycle into an ER stress sensor cycle by preventing the binding of its co-chaperones, with loss of ATPase stimulation. Furthermore, misfolded protein-dependent dissociation of BiP from IRE1 is primed by ATP but not ADP. Our data elucidate a previously unidentified mechanistic cycle of BiP function that explains its ability to act as an Hsp70 chaperone and ER stress sensor.

Blocks of greywacke sandstone were dredged from the Colville Knolls, on the margin of the Zealandia continent, in 1989. Re-examination shows them to be quartz-poor feldspathic litharenites similar to those recorded from the basement, rather than sedimentary cover, of the North Island. U-Pb dating of detrital zircons reveals significant age populations at 107, 115, 122, and 245 Ma. These compositions and ages best match those of Waipapa Composite Terrane greywacke basement on nearby Great Barrier Island. As such, an earlier Waipapa correlation is preferred, but Colville Knolls detrital petrography and zircon ages also resemble those from some Early Cretaceous Torlesse Composite Terrane greywackes. Irrespective of terrane correlation, Colville Knolls is a submarine outcrop of Cretaceous greywacke deposited at the toe of the Gondwana Mesozoic accretionary wedge, and likely represents the outer, northeastern margin of Zealandia continental crust.

Detrital zircon U–Pb ages in 37 sandstones from late Early – Late Cretaceous marine and non-marine successions across southern Zealandia indicate a provenance from local basement within present-day Zealandia. Samples from Taranaki Basin were derived from Median and Karamea batholith granitoids with transport directions from west to east. Samples from West Coast, Western Southland and Great South basins contain components derived more locally and more variably from Median Batholith and Rahu Suite granitoids and/or the Palaeozoic Buller Terrane. West Coast Basin samples have more plutonic contributions and Great South Basin localities have more Albian-aged ( c. 110–100 Ma) zircons. Samples from Canterbury Basin were sourced from Torlesse Composite Terrane basement. The provenance variations are present in both marine and non-marine sandstones and suggest localized watersheds. This fits an interpretation of Late Cretaceous deposition in rift-controlled basins across southern Zealandia during pre-Gondwana break-up regional extension. More speculatively, some additional source areas may have been created at the rifted margins of Zealandia during this break-up.

Hf-isotope data of >1100 detrital zircon grains from the Palaeozoic, south-central Andean Gondwana margin record the complete crustal evolution of South America, which was the predominant source. The oldest grains, with crustal residence ages of 3.8-4.0Ga, are consistent with complete recycling of existing continental crust around 4Ga. We confirm three major Archaean, Palaeoproterozoic (Transamazonian) and late Mesoproterozoic to early Neoproterozoic crust-addition phases as well as six igneous phases during Proterozoic to Palaeozoic time involving mixing of juvenile and crustally reworked material. A late Mesoproterozoic to early Neoproterozoic, Grenville-age igneous belt can be postulated along the palaeo-margin of South America. This belt was the basement for later magmatic arcs and accreted allochthonous microcontinents as recorded by similar crustal residence ages. Crustal reworking likely dominated over juvenile addition during the Palaeozoic era, and Proterozoic and Archaean zircon was mainly crustally reworked from the eroding, thickened Ordovician Famatinian arc.

The endoplasmic reticulum (ER) is an important site for protein folding and maturation in eukaryotes. The cellular requirement to synthesize proteins within the ER is matched by its folding capacity. However, the physiological demands or aberrations in folding may result in an imbalance which can lead to the accumulation of misfolded protein, also known as “ER stress.” The unfolded protein response (UPR) is a cell-signaling system that readjusts ER folding capacity to restore protein homeostasis. The key UPR signal activator, IRE1, responds to stress by propagating the UPR signal from the ER to the cytosol. Here, we discuss the structural and molecular basis of IRE1 stress signaling, with particular focus on novel mechanistic advances. We draw a comparison between the recently proposed allosteric model for UPR induction and the role of Hsp70 during polypeptide import to the mitochondrial matrix.

Intraplate volcanism across Zealandia, South Eastern Australia, the Ross Sea Embayment and Marie Byrd Land in Antarctica define a magmatic province characterised by basalts with elevated 206Pb/204Pb (18.9–22.5), 87Sr/86Sr = ∼0.7035, Light Rare Earth enrichment [(Ce/Yb)n > 10], and convex-up mantle normalised incompatible multi-element patterns, peaking at Nb-Ta, with negative K and Pb anomalies. Trace element abundances and ratios (e.g. Zr/Nb, Y/Zr) resemble Ocean Island Basalts (OIB), distinct from Mid-Ocean Ridge Basalt (MORB), suggesting derivation from OIB-like reservoirs. Our preferred scenario envisages partial melting across the garnet-spinel stability fields involving asthenospheric and lithospheric mantle components. Melts accumulate in a column where the deep (asthenospheric) source is PM and the shallower source a melange of PM and subcontinental lithospheric mantle (DMM+1) enriched by carbonatite. Evolution of primary and near-primary magmas is controlled by olivine + clinopyroxene fractionation. Trachybasalts, trachytes and rhyolites show isotopic evidence for interaction with continental crust.

We acknowledge financial support from the Scottish Funding Council (through EaStCHEM and SRD-Grant HR07003) and from EPSRC (PhD studentship for JAGT, EP/M506631/1). Computational support was provided via the EaStCHEM Research Computing Facility. Modern electronic devices perform their defined action because of the complete reliability of their individual active components (transistors, switches, diodes, and so forth). For instance, to encode basic computer units (bits) an electrical switch can be used. The reliability of the switch ensures that the desired outcome (the component’s final state, 0 or 1) can be selected with certainty. No practical data storage device would otherwise exist. This reliability criterion will necessarily need to hold true for future molecular electronics to have the opportunity to emerge as a viable miniaturization alternative to our current silicon-based technology. Molecular electronics target the use of single-molecules to perform the actions of individual electronic components. On-demand final state control over a bistable unimolecular component has therefore been one of the main challenges in the past decade (1−5) but has yet to be achieved. In this Letter, we demonstrate how control of the final state of a surface-supported bistable single molecule switch can be realized. On the basis of the observations and deductions presented here, we further suggest an alternative strategy to achieve final state control in unimolecular bistable switches. Postprint Postprint

Detrital zircon ages are presented for 34 early Palaeozoic sandstones from Buller and Takaka terranes, New Zealand, and formerly adjacent parts of Australia–Antarctica. The Buller–Takaka datasets always have two major groups: Ordovician–late Neoproterozoic, 444–700 Ma (but mainly 540–700 Ma), termed ‘Gondwana Assembly’ (GA), and early Neoproterozoic–Mesoproterozoic, 700–1600 Ma (but mainly 900–1200 Ma), termed ‘Rodinia Assembly’ (RA). In both terranes, significant age components within these groups are strikingly similar and also have RA/GA ratios, 0.6–1.8. The Cambrian volcanic arc of the Takaka Terrane has contributed little to the zircon patterns. Proportions of Late Cambrian–Early Ordovician zircons, characteristic of granitoid sources in the Ross–Delamerian Orogen are low. The zircons are predominantly reworked with contemporary zircons only evident in a few Buller datasets. The zircon patterns suggest that two major sources (late Mesoproterozoic and late Neoproterozoic), enduring over 120 Ma, were w...

The two-step mechanochemical preparation of carbene-pyridine complexes of palladium and platinum is reported. The organometallic products, which represent a class of commercially available catalysts, are rapidly formed in excellent yield proving solvent-free synthesis to be a viable synthetic alternative even in the case of NHC-containing compounds.

The unfolded protein response (UPR) is a key signaling system that regulates protein homeostasis within the endoplasmic reticulum (ER). The primary step in UPR activation is the detection of misfolded proteins, the mechanism of which is unclear. We have previously suggested an allosteric mechanism for UPR induction (Carrara et al., 2015) based on qualitative pull-down assays. Here, we develop an in vitro Förster resonance energy transfer (FRET) UPR induction assay that quantifies IRE1 luminal domain and BiP association and dissociation upon addition of misfolded proteins. Using this technique, we reassess our previous observations and extend mechanistic insight to cover other general ER misfolded protein substrates and their folded native state. Moreover, we evaluate the key BiP substrate-binding domain mutant V461F. The new experimental approach significantly enhances the evidence suggesting an allosteric model for UPR induction upon ER stress.

PurposeTo describe examples of missed pathogenic variants on whole-exome sequencing (WES) and the importance of deep phenotyping for further diagnostic testing.MethodsGuided by phenotypic information, three children with negative WES underwent targeted single-gene testing.ResultsIndividual 1 had a clinical diagnosis consistent with infantile systemic hyalinosis, although WES and a next-generation sequencing (NGS)-based ANTXR2 test were negative. Sanger sequencing of ANTXR2 revealed a homozygous single base pair insertion, previously missed by the WES variant caller software. Individual 2 had neurodevelopmental regression and cerebellar atrophy, with no diagnosis on WES. New clinical findings prompted Sanger sequencing and copy number testing of PLA2G6. A novel homozygous deletion of the noncoding exon 1 (not included in the WES capture kit) was detected, with extension into the promoter, confirming the clinical suspicion of infantile neuroaxonal dystrophy. Individual 3 had progressive ataxia, spasticity, and magnetic resonance image changes of vanishing white matter leukoencephalopathy. An NGS leukodystrophy gene panel and WES showed a heterozygous pathogenic variant in EIF2B5; no deletions/duplications were detected. Sanger sequencing of EIF2B5 showed a frameshift indel, probably missed owing to failure of alignment.ConclusionThese cases illustrate potential pitfalls of WES/NGS testing and the importance of phenotype-guided molecular testing in yielding diagnoses.

A 4.9 Mkm2 region of the southwest Pacific Ocean is made up of continental crust. The region has elevated bathymetry relative to surrounding oceanic crust, diverse and silica-rich rocks, and relatively thick and low-velocity crustal structure. Its isolation from Australia and large area support its definition as a continent— Zealandia. Zealandia was formerly part of Gondwana. Today it is 94% submerged, mainly as a result of widespread Late Cretaceous crustal thinning preceding supercontinent breakup and consequent isostatic balance. The identification of Zealandia as a geological continent, rather than a collection of continental islands, fragments, and slices, more correctly represents the geology of this part of Earth. Zealandia provides a fresh context in which to investigate processes of continental rifting, thinning, and breakup.

One major challenge encountered with interpreting human genetic variants is the limited understanding of the functional impact of genetic alterations on biological processes. Furthermore, there remains an unmet demand for an efficient survey of the wealth of information on human homologs in model organisms across numerous databases. To efficiently assess the large volume of publically available information, it is important to provide a concise summary of the most relevant information in a rapid user-friendly format. To this end, we created MARRVEL (model organism aggregated resources for rare variant exploration). MARRVEL is a publicly available website that integrates information from six human genetic databases and seven model organism databases. For any given variant or gene, MARRVEL displays information from OMIM, ExAC, ClinVar, Geno2MP, DGV, and DECIPHER. Importantly, it curates model organism-specific databases to concurrently display a concise summary regarding the human gene homologs in budding and fission yeast, worm, fly, fish, mouse, and rat on a single webpage. Experiment-based information on tissue expression, protein subcellular localization, biological process, and molecular function for the human gene and homologs in the seven model organisms are arranged into a concise output. Hence, rather than visiting multiple separate databases for variant and gene analysis, users can obtain important information by searching once through MARRVEL. Altogether, MARRVEL dramatically improves efficiency and accessibility to data collection and facilitates analysis of human genes and variants by cross-disciplinary integration of 18 million records available in public databases to facilitate clinical diagnosis and basic research.

Detrital zircon U–Pb LAM-ICPMS age patterns for sandstones from the mid-Permian –Triassic part (Rakaia Terrane) of the accretionary wedge forming the Torlesse Composite Terrane in Otago, New Zealand, and from the early Permian Nambucca Block of the New England Orogen, eastern Australia, constrain the development of the early Gondwana margin. In Otago, the Triassic Torlesse samples have a major (64%), younger group of Permian–Early Triassic age components at ca 280, 255 and 240 Ma, and a minor (30%) older age group with a Precambrian–early Paleozoic range (ca 1000, 600 and 500 Ma). In Permian sandstones nearby, the younger, Late Permian age components are diminished (30%) with respect to the older Precambrian–early Paleozoic age group, which now also contains major (50%) and unusual Carboniferous age components at ca 350–330 Ma. Sandstones from the Nambucca Block, an early Permian extensional basin in the southern New England Orogen, follow the Torlesse pattern: the youngest. Early Permian age components a...

Background Exome sequencing has advanced to clinical practice and proven useful for obtaining molecular diagnoses in rare diseases. In approximately 75 % of cases, however, a clinical exome study does not produce a definitive molecular diagnosis. These residual cases comprise a new diagnostic challenge for the genetics community. The Undiagnosed Diseases Program of the National Institutes of Health routinely utilizes exome sequencing for refractory clinical cases. Our preliminary data suggest that disease-causing variants may be missed by current standard-of-care clinical exome analysis. Such false negatives reflect limitations in experimental design, technical performance, and data analysis. Results We present examples from our datasets to quantify the analytical performance associated with current practices, and explore strategies to improve the completeness of data analysis. In particular, we focus on patient ascertainment, exome capture, inclusion of intronic variants, and evaluation of medium-sized structural variants. Conclusions The strategies we present may recover previously-missed, disease causing variants in second-pass exome analysis. Understanding the limitations of the current clinical exome search space provides a rational basis to improve methods for disease variant detection using genome-scale sequencing techniques. Electronic supplementary material The online version of this article (doi:10.1186/s12920-016-0216-3) contains supplementary material, which is available to authorized users.

Item does not contain fulltext The ASXL genes (ASXL1, ASXL2, and ASXL3) participate in body patterning during embryogenesis and encode proteins involved in epigenetic regulation and assembly of transcription factors to specific genomic loci. Germline de novo truncating variants in ASXL1 and ASXL3 have been respectively implicated in causing Bohring-Opitz and Bainbridge-Ropers syndromes, which result in overlapping features of severe intellectual disability and dysmorphic features. ASXL2 has not yet been associated with a human Mendelian disorder. In this study, we performed whole-exome sequencing in six unrelated probands with developmental delay, macrocephaly, and dysmorphic features. All six had de novo truncating variants in ASXL2. A careful review enabled the recognition of a specific phenotype consisting of macrocephaly, prominent eyes, arched eyebrows, hypertelorism, a glabellar nevus flammeus, neonatal feeding difficulties, hypotonia, and developmental disabilities. Although overlapping features with Bohring-Opitz and Bainbridge-Ropers syndromes exist, features that distinguish the ASXL2-associated condition from ASXL1- and ASXL3-related disorders are macrocephaly, absence of growth retardation, and more variability in the degree of intellectual disabilities. We were also able to demonstrate with mRNA studies that these variants are likely to exert a dominant-negative effect, given that both alleles are expressed in blood and the mutated ASXL2 transcripts escape nonsense-mediated decay. In conclusion, de novo truncating variants in ASXL2 underlie a neurodevelopmental syndrome with a clinically recognizable phenotype. This report expands the germline disorders that are linked to the ASXL genes.