Hemizygous deletion of COL3A1, COL5A2, and MSTN causes a complex phenotype with aortic dissection: a lesson for and from true haploinsufficiency

Aortic dilatation/dissection (AD) can occur spontaneously or in association with genetic syndromes, such as Marfan syndrome (MFS; caused by FBN1 mutations), MFS type 2 and Loeys-Dietz syndrome (associated with TGFBR1/TGFBR2 mutations), and Ehlers-Danlos syndrome (EDS) vascular type (caused by COL3A1 mutations). Although mutations in FBN1 and TGFBR1/TGFBR2 account for the majority of AD cases referred to us for molecular genetic testing, we have obtained negative results for these genes in a large cohort of AD patients, suggesting the involvement of additional genes or acquired factors. In this study we assessed the effect of COL3A1 deletions/duplications in this cohort. Multiplex ligation-dependent probe amplification (MLPA) analysis of 100 unrelated patients identified one hemizygous deletion of the entire COL3A1 gene. Subsequent microarray analyses and sequencing of breakpoints revealed the deletion size of 3,408,306 bp at 2q32.1q32.3. This deletion affects not only COL3A1 but also 21 other known genes (GULP1, DIRC1, COL5A2, WDR75, SLC40A1, ASNSD1, ANKAR, OSGEPL1, ORMDL1, LOC100129592, PMS1, MSTN, C2orf88, HIBCH, INPP1, MFSD6, TMEM194B, NAB1, GLS, STAT1, and STAT4), mutations in three of which (COL5A2, SLC40A1, and MSTN) have also been associated with an autosomal dominant disorder (EDS classical type, hemochromatosis type 4, and muscle hypertrophy). Physical and laboratory examinations revealed that true haploinsufficiency of COL3A1, COL5A2, and MSTN, but not that of SLC40A1, leads to a clinical phenotype. Our data not only emphasize the impact/role of COL3A1 in AD patients but also extend the molecular etiology of several disorders by providing hitherto unreported evidence for true haploinsufficiency of the underlying gene.

Modeling tree water deficit from microclimate: an approach to quantifying drought stress

Tree water deficit estimated by measuring water-related changes in stem radius (DeltaW) was compared with tree water deficit estimated from the output of a simple, physiologically reasonable model (DeltaW(E)), with soil water potential (Psi(soil)) and atmospheric vapor pressure deficit (VPD) as inputs. Values of DeltaW were determined by monitoring stem radius changes with dendrometers and detrending the results for growth, We followed changes in DeltaW and DeltaW(E) in Pinus sylvestris L. and Quercus pubescens Willd. over 2 years at a dry site (2001-2002; Salgesch, Wallis) and in Picea abies (L.) Karst. for 1 year at a wet site (1998; Davos, Graubuenden) in the Swiss Alps. The seasonal courses of DeltaW in deciduous species and in conifers at the same site were similar and could be largely explained by variation in DeltaW(E). This finding strongly suggests that DeltaW, despite the known species-specific differences in stomatal response to microclimate, is mainly explained by a combination of atmospheric and soil conditions. Consequently, we concluded that trees are unable to maintain any particular DeltaW. Either Psi(soil) or VPD alone provided poorer estimates of AWthan a model incorporating both factors. As a first approximation of DeltaW(E), Psi(soil) can be weighted so that the negative mean Psi(soil) reaches 65 to 75% of the positive mean daytime VPD over a season (Q. pubescens: similar to65%, P abies: similar to70%, P sylvestris: similar to75%). The differences in DeltaW among species can be partially explained by a different weighting of Psi(soil) against VPD. The DeltaW of P. sylvestris was more dependent on Psi(soil) than that of Q. pubescens, but less than that of P. abies, and was less dependent on VPD than that of P. abies and Q. pubescens. The model worked well for P. abies at the wet site and for Q. pubescens and P. sylvestris at the dry site, and may be useful for estimating water deficit in other tree species.

Long-term summer temperature variations in the Pyrenees from detrended stable carbon isotopes

Substantial effort has recently been put into the development of climate reconstructions from tree-ring stable carbon isotopes, though the interpretation of long-term trends retained in such timeseries remains challenging. Here we use detrended δ13C measurements in Pinus uncinata tree-rings, from the Spanish Pyrenees, to reconstruct decadal variations in summer temperature back to the 13th century. The June-August temperature signal of this reconstruction is attributed using decadally as well as annually resolved, 20th century δ13C data. Results indicate that late 20th century warming has not been unique within the context of the past 750 years. Our reconstruction contains greater am-plitude than previous reconstructions derived from traditional tree-ring density data, and describes particularly cool conditions during the late 19th century. Some of these differences, including early warm periods in the 14th and 17th centuries, have been retained via δ13C timeseries detrending - a novel approach in tree-ring stable isotope chronology development. The overall reduced variance in earlier studies points to an underestimation of pre-instrumental summer temperature variability de-rived from traditional tree-ring parameters.

Climate-pollen relationships AD 1901-1996 in two small mires near the forest limit in the northern and central Swiss Alps

Climatic relationships were established in two 210Pb dated pollen sequences from small mires closely surrounded by forest just below actual forest limits (but about 300 m below potential climatic forest limits) in the northern Swiss Alps (suboceanic in climate; mainly with Picea) and the central Swiss Alps (subcontinental; mainly Pinus cembra and Larix) at annual or near-annual resolution from ad 1901 to 1996. Effects of vegetational succession were removed by splitting the time series into early and late periods and by linear detrending. Both pollen concentrations detrended by the depth-age model and modified percentages (in which counts of dominant pollen types are down-weighted) are correlated by simple linear regression with smoothed climatic parameters with one-and two-year timelags, including average monthly and April/September daylight air temperatures and with seasonal and annual precipitation sums. Results from detrended pollen concentrations suggest that peat accumulation is favoured in the northern-Alpine mire either by early snowmelt or by summer precipitation, but in the central-Alpine mire by increased precipitation and cooler summers, suggesting a position of the northern-Alpine mire near the upper altitudinal limit of peat formation, but of the central-Alpine mire near the lower limit. Results from modified pollen percentages indicate that pollen pro duction by plants growing near their upper altitudinal limit is limited by insufficient warmth in summer, and pollen production by plants growing near their lower altitudinal limit is limited by too-high temperatures. Only weakly significant pollen/climate relationships were found for Pinus cembra and Larix, probably because they experience little climatic stress growing 300 m below the potential climatic forest limit.

Continuous CO2/CH4/CO measurements (2012–2014) at Beromünster tall tower station in Switzerland

The understanding of the continental carbon budget is essential to predict future climate change. In order to quantify CO₂ and CH₄ fluxes at the regional scale, a measurement system was installed at the former radio tower in Beromünster as part of the Swiss greenhouse gas monitoring network (CarboCount CH). We have been measuring the mixing ratios of CO₂, CH₄ and CO on this tower with sample inlets at 12.5, 44.6, 71.5, 131.6 and 212.5 m above ground level using a cavity ring down spectroscopy (CRDS) analyzer. The first 2-year (December 2012–December 2014) continuous atmospheric record was analyzed for seasonal and diurnal variations and interspecies correlations. In addition, storage fluxes were calculated from the hourly profiles along the tower. The atmospheric growth rates from 2013 to 2014 determined from this 2-year data set were 1.78 ppm yr⁻¹, 9.66 ppb yr⁻¹ and and -1.27 ppb yr⁻¹ for CO₂, CH₄ and CO, respectively. After detrending, clear seasonal cycles were detected for CO₂ and CO, whereas CH₄ showed a stable baseline suggesting a net balance between sources and sinks over the course of the year. CO and CO₂ were strongly correlated (r² > 0.75) in winter (DJF), but almost uncorrelated in summer. In winter, anthropogenic emissions dominate the biospheric CO₂ fluxes and the variations in mixing ratios are large due to reduced vertical mixing. The diurnal variations of all species showed distinct cycles in spring and summer, with the lowest sampling level showing the most pronounced diurnal amplitudes. The storage flux estimates exhibited reasonable diurnal shapes for CO₂, but underestimated the strength of the surface sinks during daytime. This seems plausible, keeping in mind that we were only able to calculate the storage fluxes along the profile of the tower but not the flux into or out of this profile, since no Eddy covariance flux measurements were taken at the top of the tower.