A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders

BACKGROUND: The recurrent ~600 kb 16p11.2 BP4-BP5 deletion is among the most frequent known genetic aetiologies of autism spectrum disorder (ASD) and related neurodevelopmental disorders. OBJECTIVE: To define the medical, neuropsychological, and behavioural phenotypes in carriers of this deletion. METHODS: We collected clinical data on 285 deletion carriers and performed detailed evaluations on 72 carriers and 68 intrafamilial non-carrier controls. RESULTS: When compared to intrafamilial controls, full scale intelligence quotient (FSIQ) is two standard deviations lower in carriers, and there is no difference between carriers referred for neurodevelopmental disorders and carriers identified through cascade family testing. Verbal IQ (mean 74) is lower than non-verbal IQ (mean 83) and a majority of carriers require speech therapy. Over 80% of individuals exhibit psychiatric disorders including ASD, which is present in 15% of the paediatric carriers. Increase in head circumference (HC) during infancy is similar to the HC and brain growth patterns observed in idiopathic ASD. Obesity, a major comorbidity present in 50% of the carriers by the age of 7 years, does not correlate with FSIQ or any behavioural trait. Seizures are present in 24% of carriers and occur independently of other symptoms. Malformations are infrequently found, confirming only a few of the previously reported associations. CONCLUSIONS: The 16p11.2 deletion impacts in a quantitative and independent manner FSIQ, behaviour and body mass index, possibly through direct influences on neural circuitry. Although non-specific, these features are clinically significant and reproducible. Lastly, this study demonstrates the necessity of studying large patient cohorts ascertained through multiple methods to characterise the clinical consequences of rare variants involved in common diseases.

Sedimentary evolution and environmental history of Lake Van (Turkey) over the past 600,000 years

The lithostratigraphic framework of Lake Van, eastern Turkey, has been systematically analysed to document the sedimentary evolution and the environmental history of the lake during the past ca 600,000 years. The lithostratigraphy and chemostratigraphy of a 219 m long drill core from Lake Van serves to separate global climate oscillations from local factors caused by tectonic and volcanic activity. An age model was established based on the climatostratigraphic alignment of chemical and lithological signatures, validated by 40Ar/39Ar ages. The drilled sequence consists of ca 76% lacustrine carbonaceous clayey silt, ca 2% fluvial deposits, ca 17% volcaniclastic deposits and 5% gaps. Six lacustrine lithotypes were separated from the fluvial and event deposits, such as volcaniclastics (ca 300 layers) and graded beds (ca 375 layers), and their depositional environments are documented. These lithotypes are: (i) graded beds frequently intercalated with varved clayey silts reflect rising lake-levels during the terminations; (ii) varved clayey silts reflect strong seasonality and an intralake oxic–anoxic boundary, for example, lake-level highstands during interglacials/interstadials; (iii) CaCO3-rich banded sediments are representative of a lowering of the oxic-anoxic boundary, for example, lake-level decreases during glacial inceptions; (iv) CaCO3-poor banded and mottled clayey silts reflect an oxic–anoxic boundary close to the sediment-water interface, for example, lake-level low-stands during glacials/stadials; (v) diatomaceous muds were deposited during the early beginning of the lake as a fresh water system; and (vi) fluvial sands and gravels indicate the initial flooding of the lake basin. The recurrence of lithologies (i) to (iv) follows the past five glacial/interglacial cycles. A 20 m thick disturbed unit reflects an interval of major tectonic activity in Lake Van at ca 414 ka BP.

Chronostratigraphy of the 600,000 year old continental record of Lake Van

Lake Van sediment cores from the Ahlat Ridge and Northern Basin drill sites of the ICDP project PALEOVAN contain a wealth of information about past environmental processes. The sedimentary sequence was dated using climatostratigraphic alignment, varve chronology, tephrostratigraphy, argon-argon single-crystal dating, radiocarbon dating, magnetostratigraphy, and cosmogenic nuclides. Based on the lithostratigraphic framework, the different age constraints are compiled and a robust and precise chronology of the 600,000 year-old Lake Van record is constructed. Proxy records of total organic carbon content and sediment color, together with the calcium/potassium-ratios and arboreal pollen percentages of the 174-meter-long Ahlat Ridge record, mimic the Greenland isotope stratotype (NGRIP). Therefore, the proxy records are systematically aligned to the onsets of interstadials reflected in the NGRIP or synthesized Greenland ice-core stratigraphy. The chronology is constructed using 27 age control points derived from visual synchronization with the GICC05 timescale, an absolutely-dated speleothem record (e.g., Hulu, Sanbao, Linzhu cave) and the Epica Dome C timescale. In addition, the uppermost part of the sequence is complemented with four ages from Holocene varve chronology and two calibrated radiocarbon ages. Furthermore, nine argon-argon ages and a comparison of the relative paleointensity record of the magnetic field with reference curve PISO-1500 confirm the accuracy of the age model. Also the identification of the Laschamp event via measurements of 10Be in the sediment confirms the presented age model. The chronology of the Ahlat Ridge record is transferred to the 79-meter-long event-corrected composite record from the Northern Basin and supplemented by additional radiocarbon dating on organic marco-remains. The basal age of the Northern Basin record is estimated at ~90 ka. The variations of the time series of total organic carbon content, the Ca/K ratio, and the arboreal pollen percentages illustrate that the presented chronology and paleoclimate data are suited for reconstructions and modeling of the Quaternary and Pleistocene climate evolution in the Near East at millennial timescales. Furthermore, the chronology of the last 250 kyr can be used to test other dating techniques.

A 13,600-year diatom oxygen isotope record from the South Carpathians (Romania): Reflection of winter conditions and possible links with North Atlantic circulation changes

This study provides a continuous lateglacial and Holocene record of diatom silica oxygen isotope changes (delta O-18(DIAT)) in a subalpine lake sediment sequence obtained from the Retezat Mts (Taul dintre Brazi, 1740 m a.s.l.). This through-flow, shallow, high-altitude lake with a surface area of only 0.4 ha has short water residence time and is predominantly fed by snowmelt and rainwater. Its delta O-18(DIAT) record principally reflects the oxygen isotope composition of the winter and spring precipitation, as diatom blooms occur mainly in the spring and early summer. Hence, changes in delta O-18(DIAT) are interpreted as seasonal scale changes: in the amount of winter precipitation. Low oxygen isotope values (27-28.5 parts per thousand) occurred during the lateglacial until 12,300 cal BP, followed by a sharp increase thereafter. In the Holocene delta O-18(DIAT) values ranged from 29 to 31 parts per thousand until 3200 cal BP, followed by generally lower values during the late Holocene (27-30 parts per thousand). Short-term decreases in the isotopic values were found between 10,140-9570, 9000-8500, 7800-7300, 6300-5800, 5500-5000 and at 8015, 4400, 4000 cal BP. After 3200 cal BP a decreasing trend was visible with the lowest values between 3100-2500 and after 2100 cal BP The general trend in the record suggests that contribution of winter precipitation was generally lower between 11,680 and 3200 cal BP, followed by increased contribution during the last millennia. The late Holocene decrease in delta O-18(DIAT) shows good agreement with the speleothem delta O-18, lake level and testate amoebae records from the Carpathian Mountains that also display gradual delta O-18 decrease and lake level/mire water table level rise after 3200 cal BR Strong positive correlation with North Atlantic circulation and solar activity proxies, such as the Austrian and Hungarian speleothem records, furthermore suggested that short-term increases in the isotopic ratios in the early and mid Holocene are likely connectable to high solar activity phases and high frequency of positive North Atlantic Oscillation indexes that may have resulted in decreased winter precipitation in this region.

16p11.2 600 kb Duplications confer risk for typical and atypical Rolandic epilepsy

Rolandic epilepsy (RE) is the most common idiopathic focal childhood epilepsy. Its molecular basis is largely unknown and a complex genetic etiology is assumed in the majority of affected individuals. The present study tested whether six large recurrent copy number variants at 1q21, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 previously associated with neurodevelopmental disorders also increase risk of RE. Our association analyses revealed a significant excess of the 600 kb genomic duplication at the 16p11.2 locus (chr16: 29.5-30.1 Mb) in 393 unrelated patients with typical (n = 339) and atypical (ARE; n = 54) RE compared with the prevalence in 65,046 European population controls (5/393 cases versus 32/65,046 controls; Fisher's exact test P = 2.83 × 10(-6), odds ratio = 26.2, 95% confidence interval: 7.9-68.2). In contrast, the 16p11.2 duplication was not detected in 1738 European epilepsy patients with either temporal lobe epilepsy (n = 330) and genetic generalized epilepsies (n = 1408), suggesting a selective enrichment of the 16p11.2 duplication in idiopathic focal childhood epilepsies (Fisher's exact test P = 2.1 × 10(-4)). In a subsequent screen among children carrying the 16p11.2 600 kb rearrangement we identified three patients with RE-spectrum epilepsies in 117 duplication carriers (2.6%) but none in 202 carriers of the reciprocal deletion. Our results suggest that the 16p11.2 duplication represents a significant genetic risk factor for typical and atypical RE.

Search for Scalar Diphoton Resonances in the Mass Range 65-600 GeV with the ATLAS Detector in pp Collision Data at √s = 8 TeV

A search for scalar particles decaying via narrow resonances into two photons in the mass range 65–600 GeV is performed using 20.3  fb −1 of s √ =8  TeV pp collision data collected with the ATLAS detector at the Large Hadron Collider. The recently discovered Higgs boson is treated as a background. No significant evidence for an additional signal is observed. The results are presented as limits at the 95% confidence level on the production cross section of a scalar boson times branching ratio into two photons, in a fiducial volume where the reconstruction efficiency is approximately independent of the event topology. The upper limits set extend over a considerably wider mass range than previous searches.

Patterns in fish radiation are compatible with Pleistocene desiccation of Lake Victoria and 14 600 year history for its cichlid species flock

Geophysical data are currently being interpreted as evidence for a late Pleistocene desiccation of Lake Victoria and its refilling 14 600 years ago. This implies that between 500 and 1000 endemic cichlid fish species must have evolved in 14 600 years, the fastest large-scale species radiation known. A recent review concludes that biological evidence clearly rejects the postulated Pleistocene desiccation of the lake: a 14 600 year history would imply exceptionally high speciation rates across a range of unrelated fish taxa. To test this suggestion, I calculated speciation rates for all 41 phylogenetic lineages of fish in the lake. Except for one cichlid lineage, accepting a 14 600 year history does not require any speciation rates that fall outside the range observed in fishes in other young lakes around the world. The exceptional taxon is a lineage of haplochromine cichlids that is also known for its rapid speciation elsewhere. Moreover, since it is unknown how many founding species it has, it is not certain that its speciation rates are really outside the range observed in fishes in other young lakes. Fish speciation rates are generally faster in younger than in older lakes, and those in Lake Victoria, by far the largest of the young lakes of the world, are no exception. From the speciation rates and from biogeographical observations that Lake Victoria endemics, which lack close relatives within the lake basin, have such relatives in adjacent drainage systems that may have had Holocene connections to Lake Victoria, I conclude that the composition of the fish assemblage does not provide biological evidence against Pleistocene desiccation. It supports a hypothesis of recent colonization from outside the lake basin rather than survival of a diverse assemblage within the basin.

A 600 years warm-season temperature record from varved sediments of Lago Plomo, Northern Patagonia, Chile (47°S)

High-resolution records of calibrated proxy data for the past millennium are fundamental to place current changes into the context of pre-industrial natural forced and unforced variability. Although the need for regional spatially-explicit comprehensive reconstructions is widely recognized, the proxy data sources are still scarce, particularly for the Southern Hemisphere and especially for South America. We present a 600-year long warm season temperature record from varved sediments of Lago Plomo, a proglacial lake of the Northern Patagonian Ice field in Southern Chile (46°59′S, 72°52′W, 203 m a.s.l.). The thickness of the bright summer sediment layer relative to the dark winter layer (measured as total brightness; % reflectance 400–730 nm) is calibrated against warm season SONDJF temperature (1900–2009; r = 0.58, p(aut) = 0.056, RE = 0.52; CE = 0.15, RMSEP = 0.28 °C; five-year triangular filtered data). In Lago Plomo, warm summer temperatures lead to enhanced glacier melt and suspended sediment transport, which results in thicker light summer layers and to brighter sediments. Although Patagonia shows pronounced regional differences in decadal temperature trends and variability, the 600 years temperature reconstruction from Lago Plomo compares favourably with other regional/continental temperature records, but also emphasizes significant regional differences for which no data and information existed so far. These regional differences seem to be real as they are also reflected in modern climate data sets (1900–2010). The reconstruction shows pronounced subdecadal – multidecadal variability with cold phases during parts of the Little Ice Age (16th and 18th centuries) and in the beginning of the 20th century. The most prominent warm phase is the 19th century which is as warm as the second half of the 20th century. The exceptional summer warmth AD 1780–1810 is also found in other archives of Northern Patagonia and Central Chile. Our record shows the delayed 20th century warming in the Southern Hemisphere. The comparison between winter precipitation and summer temperature (inter-seasonal coupling) from Lago Plomo reveals alternating phases with parallel and contrasting decadal trends of winter precipitation and summer temperature (positive and negative running correlations Rwinter PP; summer TT). This observation from the sediment proxy data is also confirmed by two sets of reanalysis data for the 20th century. Reanalysis data show that phases with negative correlations between winter precipitation and summer temperature (e.g., dry winters and warm summers) at Lago Plomo are characteristic for periods when circumpolar Westerly flow is displaced southward and enhanced around 60°S.