Gene-Network Analysis Identifies Susceptibility Genes Related to Glycobiology in Autism

The recent identification of copy-number variation in the human genome has opened up new avenues for the discovery of positional candidate genes underlying complex genetic disorders, especially in the field of psychiatric disease. One major challenge that remains is pinpointing the susceptibility genes in the multitude of disease-associated loci. This challenge may be tackled by reconstruction of functional gene-networks from the genes residing in these loci. We applied this approach to autism spectrum disorder (ASD), and identified the copy-number changes in the DNA of 105 ASD patients and 267 healthy individuals with Illumina Humanhap300 Beadchips. Subsequently, we used a human reconstructed gene-network, Prioritizer, to rank candidate genes in the segmental gains and losses in our autism cohort. This analysis highlighted several candidate genes already known to be mutated in cognitive and neuropsychiatric disorders, including RAI1, BRD1, and LARGE. In addition, the LARGE gene was part of a sub-network of seven genes functioning in glycobiology, present in seven copy-number changes specifically identified in autism patients with limited co-morbidity. Three of these seven copy-number changes were de novo in the patients. In autism patients with a complex phenotype and healthy controls no such sub-network was identified. An independent systematic analysis of 13 published autism susceptibility loci supports the involvement of genes related to glycobiology as we also identified the same or similar genes from those loci. Our findings suggest that the occurrence of genomic gains and losses of genes associated with glycobiology are important contributors to the development of ASD

Social responsiveness scale-aided analysis of the clinical impact of copy number variations in autism

Recent array-based studies have detected a wealth of copy number variations (CNVs) in patients with autism spectrum disorders (ASD). Since CNVs also occur in healthy individuals, their contributions to the patient’s phenotype remain largely unclear. In a cohort of children with symptoms of ASD, diagnosis of the index patient using ADOS-G and ADI-R was performed, and the Social Responsiveness Scale (SRS) was administered to the index patients, both parents, and all available siblings. CNVs were identified using SNP arrays and confirmed by FISH or array CGH. To evaluate the clinical significance of CNVs, we analyzed three families with multiple affected children (multiplex) and six families with a single affected child (simplex) in which at least one child carried a CNV with a brain-transcribed gene. CNVs containing genes that participate in pathways previously implicated in ASD, such as the phosphoinositol signaling pathway (PIK3CA, GIRDIN), contactin-based networks of cell communication (CNTN6), and microcephalin (MCPH1) were found not to co-segregate with ASD phenotypes. In one family, a loss of CNTN5 co-segregated with disease. This indicates that most CNVs may by themselves not be sufficient to cause ASD, but still may contribute to the phenotype by additive or epistatic interactions with inherited (transmitted) mutations or non-genetic factors. Our study extends the scope of genome-wide CNV profiling beyond de novo CNVs in sporadic patients and may aid in uncovering missing heritability in genome-wide screening studies of complex psychiatric disorders

Wnt Signalling Pathway Parameters for Mammalian Cells

Wnt/β-catenin signalling regulates cell fate, survival, proliferation and differentiation at many stages of mammalian development and pathology. Mutations of two key proteins in the pathway, APC and β-catenin, have been implicated in a range of cancers, including colorectal cancer. Activation of Wnt signalling has been associated with the stabilization and nuclear accumulation of β-catenin and consequential up-regulation of β-catenin/TCF gene transcription. In 2003, Lee et al. constructed a computational model of Wnt signalling supported by experimental data from analysis of time-dependent concentration of Wnt signalling proteins in Xenopus egg extracts. Subsequent studies have used the Xenopus quantitative data to infer Wnt pathway dynamics in other systems. As a basis for understanding Wnt signalling in mammalian cells, a confocal live cell imaging measurement technique is developed to measure the cell and nuclear volumes of MDCK, HEK293T cells and 3 human colorectal cancer cell lines and the concentrations of Wnt signalling proteins β-catenin, Axin, APC, GSK3β and E-cadherin. These parameters provide the basis for formulating Wnt signalling models for kidney/intestinal epithelial mammalian cells. There are significant differences in concentrations of key proteins between Xenopus extracts and mammalian whole cell lysates. Higher concentrations of Axin and lower concentrations of APC are present in mammalian cells. Axin concentrations are greater than APC in kidney epithelial cells, whereas in intestinal epithelial cells the APC concentration is higher than Axin. Computational simulations based on Lee's model, with this new data, suggest a need for a recalibration of the model

Mapping autism risk loci using genetic linkage and chromosomal rearrangements.

International audienceAutism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,181 [corrected] families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs

The Cambrian-Silurian tectonic evolution of the northern Appalachians and British Caledonides: history of a complex, west and southwest Pacific-type segment of Iapetus

This paper is included in the Special Publication entitled 'Lyell: the past is the key to the present', edited by D.J. Blundell and A.C. Scott. This paper presents new ideas on the Early Palaeozoic geography and tectonic history of the Iapetus Ocean involved in the formation of the northern Appalachian-British Caledonide Orogen. Based on an extensive compilation of data along the length of the orogen, particularly using well-preserved relationships in Newfoundland as a template, we show that this orogen may have experienced a very complicated tectonic evolution that resembles parts of the present west and southwest Pacific Ocean in its tectonic complexities. Closure of the west and southwest Pacific Ocean by forward modelling of the oblique collision between Australia and Asia shows that transpressional flattening and non-coaxial strain during terminal collision may impose a deceptively simple linearity and zonation to the resultant orogen and, hence, may produce a linear orogen like the Appalachian-Caledonian Belt. Oceanic elements may preserve along-strike coherency for up to several thousands of kilometres, but excision and strike-slip duplication, as a result of oblique convergence and terminal collisional processes, is expected to obscure elucidation of the intricacies of their accretion and collisional processes. Applying these lessons to the northern Appalachian-Caledonian belt, we rely principally on critical relationships preserved in different parts of the orogen to constrain tectonic models of kinematically-related rock assemblages. The rift-drift transition, and opening of the Iapetus Ocean took place between c.590-550 Ma. Opening of Iapetus was temporally and spatially related to final closure of the Brazilide Ocean and amalgamation of Gondwanaland. During the Early Ordovician, the Laurentian margin experienced obduction of young, supra-subduction-zone oceanic lithosphere along the length of the northern Appalachian-British Caledonian Belt. Remnants of this lithosphere are best preserved in western Newfoundland and are referred to as the Baie Verte Oceanic Tract. Convergence between Laurentia and the Baie Verte Oceanic Tract was probably dextrally oblique. Slab break-off and a subsequent subduction polarity reversal produced a continental magmatic arc, the Notre Dame Arc, on the edge of the composite Laurentian margin. The Notre Dame Arc was mainly active during the late Tremadoc-Caradoc interval and was flanked by a southeast- or south-facing accretionary complex, the Annieopsquotch Accretionary Tract. Southerly drift of Laurentia to intermediate latitudes of c.20-25°S was associated with the compressive (Andean) nature of the arc and the accompanying backthrusting of the already-accreted Baie Verte Oceanic Tract further onto the Laurentian foreland. Equivalents of the Notre Dame Arc and its forearc elements in the British Isles have been preserved as independent slices in the Midland Valley and possibly the Northern Belt of the Southern Uplands. During the late Tremadoc (c.485 Ma), the passive margin on the eastern side of Iapetus also experienced obduction of primitive oceanic arc lithosphere. This arc is referred to as the Penobscot Arc. The eastern passive margin was built upon a Gondwanan fragment (Ganderia) that rifted off Amazonia during the Early Ordovician and probably travelled together with the Avalonian terranes as one microcontinent. The departure of Ganderia and Avalonia from Gondwana opened the Rheic Ocean. Equivalents of the Penobscot Arc may be preserved in New Brunswick and Maine, Leinster in eastern Ireland, and Anglesey in Wales. An arc-polarity reversal along the Ganderian margin after the soft Penobscot collision produced a new arc: the west-facing Popelogan-Victoria Arc, which probably formed a continuous arc system with the Bronson Hill Arc in New England. The Popelogan-Victoria Arc transgressed from a continental to an oceanic substrate from southern to northeastern Newfoundland. Rapid roll-back rifted the Popelogan-Victoria Arc away from Ganderia during the late Arenig (c.473 Ma) and opened a wide back-arc basin; the Tetagouche-Exploits back-arc basin. The Popelogan-Victoria Arc was accreted sinistrally oblique to the Notre Dame Arc and, by implication, Laurentia during the Late Ordovician. After accretion, the northwestward-dipping subduction zone stepped eastwards into the Tetagouche-Exploits back-arc basin

Petrogenesis of the Dunite Peak ophiolite, south-central Yukon, and the distinction between upper-plate and lower-plate settings: A new hypothesis for the late Paleozoic–early Mesozoic tectonic evolution of the Northern Cordillera

Upper-plate and lower-plate settings within subduction zones have distinct geological signatures. Identifying and discriminating between these settings is crucial to the study of accretionary orogens. We applied this distinction to the Northern Cordillera in Yukon, British Columbia, and Alaska, and we focused on the identification of upper-plate and lower-plate domains during the late Paleozoic to early Mesozoic evolution of the allochthonous Yukon-Tanana terrane, the west Laurentian margin, and the intervening Slide Mountain Ocean. We present new data from the Dunite Peak ophiolite in south-central Yukon, previously interpreted as ocean plate stratigraphy that was obducted from the subducting Slide Mountain Ocean (i.e., lower plate). Whole-rock geochemical and Sm-Nd isotopic analyses, and U-Pb zircon geochronology indicate that the Dunite Peak ophiolite formed in an intra-oceanic suprasubduction-zone setting (i.e., upper plate) with magmatism at 265 ± 4 Ma. We propose that the Dunite Peak ophiolite correlates with other mid-Permian suprasubduction-zone ophiolites of the Slide Mountain terrane, collectively defining the previously unrecognized mid-Permian “Dunite Peak intra-oceanic arc.” This intra-oceanic arc was active from ca. 280 to 260 Ma, located within the Slide Mountain Ocean, between the Yukon-Tanana terrane and west Laurentia. Existence of this arc is incompatible with previous models proposing that accretion of the Yukon-Tanana terrane to Laurentia was facilitated by Permian subduction of the Slide Mountain Ocean beneath the Yukon-Tanana terrane. Our results, combined with existing data sets, suggest that during the mid- to Late Permian (Late Permian = Guadalupian to Lopingian, 272 Ma to 252 Ma), the Yukon-Tanana terrane was subducted eastward beneath the Dunite Peak intra-oceanic arc. Subsequent collision and accretion of the Yukon-Tanana–Dunite Peak composite terrane with Laurentia must have occurred after the Middle Triassic

Age and setting of Permian Slide Mountain terrane ophiolitic ultramafic-mafic complexes in the Yukon: Implications for late Paleozoic-early Mesozoic tectonic models in the northern Canadian Cordillera

The Yukon Tanana (YTT) and Slide Mountain terranes (SMT) of the Cordillera in Canada and Alaska were interpreted in terms of opening and closing of a Late Devonian-Permian Japan Sea-style backarc basin behind a continental arc built upon YTT, which rifted from Laurentia during the Famennian-early Mississippian. Formation of Famennian transitional oceanic lithosphere supports rifting, but a combination of existing and new data on the setting and age of SMT ophiolites do not support the Japan Sea model. The studied Clinton Creek and Midnight Dome complexes represent suprasubduction zone ophiolites formed at ca. 265 Ma, consistent with analyses of other SMT ophiolites. Ultramafic rocks dominate most ophiolites. They lack sheeted dikes and contain relatively minor volumes of mafic plutonic and volcanic rocks, suggesting they formed in oceanic core complexes characterised by slow spreading and low magma productivity. The Permian ophiolites formed during or immediately after eclogite formation in YTT, coeval with or immediately preceding emplacement of orogenic peridotites into YTT due to hyperextension. Several tectonic scenarios are discussed. We propose that YTT is a composite terrane comprising a continental block and an oceanic arc-backarc complex with the latter obducted onto the former during the middle Permian-early Triassic Klondike orogeny. Obduction may have come from the west or east, but east-directed obduction is most consistent with geological constraints. Obduction was followed by initiation of west-dipping subduction east of the composite YTT; slab roll back causing extension in the composite upper plate, leading to exhumation of orogenic peridotites. Tectonic relationships show many analogies to the collision between Australia and the New Britain arc, in which collision in the Huon Peninsula of New Guinea is contemporaneous with extension in Australian crust in the adjacent Woodlark basin. Syn-orogenic Permian Klondike calc-alkaline magmatism is attributed to extension in a Woodlark basin-like setting rather than a representing a continental arc

Age and setting of Permian Slide Mountain terrane ophiolitic ultramafic-mafic complexes in the Yukon: Implications for late Paleozoic-early Mesozoic tectonic models in the northern Canadian Cordillera

The Yukon Tanana (YTT) and Slide Mountain terranes (SMT) of the Cordillera in Canada and Alaska were interpreted in terms of opening and closing of a Late Devonian-Permian Japan Sea-style backarc basin behind a continental arc built upon YTT, which rifted from Laurentia during the Famennian-early Mississippian. Formation of Famennian transitional oceanic lithosphere supports rifting, but a combination of existing and new data on the setting and age of SMT ophiolites do not support the Japan Sea model. The studied Clinton Creek and Midnight Dome complexes represent suprasubduction zone ophiolites formed at ca. 265 Ma, consistent with analyses of other SMT ophiolites. Ultramafic rocks dominate most ophiolites. They lack sheeted dikes and contain relatively minor volumes of mafic plutonic and volcanic rocks, suggesting they formed in oceanic core complexes characterised by slow spreading and low magma productivity. The Permian ophiolites formed during or immediately after eclogite formation in YTT, coeval with or immediately preceding emplacement of orogenic peridotites into YTT due to hyperextension. Several tectonic scenarios are discussed. We propose that YTT is a composite terrane comprising a continental block and an oceanic arc-backarc complex with the latter obducted onto the former during the middle Permian-early Triassic Klondike orogeny. Obduction may have come from the west or east, but east-directed obduction is most consistent with geological constraints. Obduction was followed by initiation of west-dipping subduction east of the composite YTT; slab roll back causing extension in the composite upper plate, leading to exhumation of orogenic peridotites. Tectonic relationships show many analogies to the collision between Australia and the New Britain arc, in which collision in the Huon Peninsula of New Guinea is contemporaneous with extension in Australian crust in the adjacent Woodlark basin. Syn-orogenic Permian Klondike calc-alkaline magmatism is attributed to extension in a Woodlark basin-like setting rather than a representing a continental arc