Common variation at 10p12.31 near MLLT10 influences meningioma risk

To identify susceptibility loci for meningioma, we conducted a genome-wide association study of 859 affected individuals (cases) and 704 controls with validation in two independent sample sets totaling 774 cases and 1,764 controls. We identified a new susceptibility locus for meningioma at 10p12.31 (MLLT10, rs11012732, odds ratio = 1.46, P(combined) = 1.88 × 10(-14)). This finding advances our understanding of the genetic basis of meningioma development.     

Breeding biology and flower visitors of the rare White River penstemon, Penstemon scariosus var. albifluvis (Scrophulariaceae)

We studied the breeding system and flower visitors of White River penstemon, a rare endemic from the Uintah Basin of eastern Utah and western Colorado. Bagging treatments and hand-pollination treatments showed that Penstemon scariosus var. albifluvis has a mixed mating system: while some seeds and fruits are produced through selfpollination (both autogamy and geitonogamy), significantly more are produced when flowers are cross-pollinated. The primary flower visitors, and likely pollinators, were several species of native twig- and ground-nesting bees in the families Apidae, Halictidae, and Megachilidae. We found no differences in fruit or seed production between open-pollinated controls and hand-outcrossed flowers, suggesting that pollinator visits were sufficient to maximize female reproductive success. Management plans to conserve White River penstemon must recognize that full reproductive success of this rare plant taxon relies on a suite of pollinating bees, and that the species richness and abundances of bee visitors should be maintained.     

Human trampling effects on regeneration and age structures of Pinus edulis and Juniperus monosperma

We examined effects of human foot traffic on age structures and densities of seedlings and saplings of Pinus edulis (Colorado pinyon) and Junisperus monosperma (one-seed juniper) in a heavily used urban park, Garden of the Gods, Colorado. Age structures show no stand-destroying disturbances, but they do contain small peaks 85-95 yr ago (minimum age), which have been interpreted as responses to heavy grazing. For Pinus edulis reverse J-shaped age structures indicate a strongly reproducing population, while flat age structures of J. monosperma show low present reproduction. Young trees showed strong preferences for establishing under existing trees and shrubs and not among herbs or on bare soil. Pinus edulis seedling density was reduced by 73% in heavily trampled areas compared to lightly trampled areas. However, there were no differences in density when only the area protected by rocks, shrubs, or trees was considered. This indicates that direct effects such as physical damage and soil erosion kill young trees, and indirect effects, such as lower seed production, do not cause the lower densities in heavily trampled areas. Pinus edulis saplings and J. monosperma seedlings and saplings showed no differences in density across trampling intensities. In heavily trampled areas of Garden of the Gods Park, recent increases in use have apparently reduced Pinus edulis seedling establishment enough that long-term regeneration is threatened. Managers of all pinyon-juniper woodlands must recognize that in areas strongly impacted by foot traffic, and also presumably by similar disturbances such as vehicle traffic, sufficient regeneration likely does not occur to replace trees. The areal extent of severely disturbed areas should be limited, and managers should seek to avoid further degradation of less damaged areas.     

Genome-wide association study of leaf architecture in the maize nested association mapping population

US maize yield has increased eight-fold in the past 80 years, with half of the gain attributed to selection by breeders. During this time, changes in maize leaf angle and size have altered plant architecture, allowing more efficient light capture as planting density has increased. Through a genome-wide association study (GWAS) of the maize nested association mapping panel, we determined the genetic basis of important leaf architecture traits and identified some of the key genes. Overall, we demonstrate that the genetic architecture of the leaf traits is dominated by small effects, with little epistasis, environmental interaction or pleiotropy. In particular, GWAS results show that variations at the liguleless genes have contributed to more upright leaves. These results demonstrate that the use of GWAS with specially designed mapping populations is effective in uncovering the basis of key agronomic traits.     

Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome

3MC syndrome has been proposed as a unifying term encompassing the overlapping Carnevale, Mingarelli, Malpuech and Michels syndromes. These rare autosomal recessive disorders exhibit a spectrum of developmental features, including characteristic facial dysmorphism, cleft lip and/or palate, craniosynostosis, learning disability and genital, limb and vesicorenal anomalies. Here we studied 11 families with 3MC syndrome and identified two mutated genes, COLEC11 and MASP1, both of which encode proteins in the lectin complement pathway (collectin kidney 1 (CL-K1) and MASP-1 and MASP-3, respectively). CL-K1 is highly expressed in embryonic murine craniofacial cartilage, heart, bronchi, kidney and vertebral bodies. Zebrafish morphants for either gene develop pigmentary defects and severe craniofacial abnormalities. Finally, we show that CL-K1 serves as a guidance cue for neural crest cell migration. Together, these findings demonstrate a role for complement pathway factors in fundamental developmental processes and in the etiology of 3MC syndrome.     

Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease

The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.     

Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis

Hajdu-Cheney syndrome is a rare autosomal dominant skeletal disorder with facial anomalies, osteoporosis and acro-osteolysis. We sequenced the exomes of six unrelated individuals with this syndrome and identified heterozygous nonsense and frameshift mutations in NOTCH2 in five of them. All mutations cluster to the last coding exon of the gene, suggesting that the mutant mRNA products escape nonsense-mediated decay and that the resulting truncated NOTCH2 proteins act in a gain-of-function manner.     

The sheddase activity of ADAM17/TACE is regulated by the tetraspanin CD9

ADAM17/TACE is a metalloproteinase responsible for the shedding of the proinflammatory cytokine TNF-α and many other cell surface proteins involved in development, cell adhesion, migration, differentiation, and proliferation. Despite the important biological function of ADAM17, the mechanisms of regulation of its metalloproteinase activity remain largely unknown. We report here that the tetraspanin CD9 and ADAM17 partially co-localize on the surface of endothelial and monocytic cells. In situ proximity ligation, co-immunoprecipitation, crosslinking, and pull-down experiments collectively demonstrate a direct association between these molecules. Functional studies reveal that treatment with CD9-specific antibodies or neoexpression of CD9 exert negative regulatory effects on ADAM17 sheddase activity. Conversely, CD9 silencing increased the activity of ADAM17 against its substrates TNF-α and ICAM-1. Taken together, our results show that CD9 associates with ADAM17 and, through this interaction, negatively regulates the sheddase activity of ADAM17.     

Cdk5 targets active Src for ubiquitin-dependent degradation by phosphorylating Src(S75)

The non-receptor tyrosine kinase Src is a critical regulator of cytoskeletal contraction, cell adhesion, and migration. In normal cells, Src activity is stringently controlled by Csk-dependent phosphorylation of Src(Y530), and by Cullin-5-dependent ubiquitinylation, which affects active Src(pY419) exclusively, leading to its degradation by the proteosome. Previous work has shown that Src activity is also limited by Cdk5, a proline-directed kinase, which has been shown to phosphorylate Src(S75). Here we show that this phosphorylation promotes the ubiquitin-dependent degradation of Src, thus restricting the availability of active Src. We demonstrate that Src(S75) phosphorylation occurs in vivo in epithelial cells, and like ubiquitinylation, is associated only with active Src. Preventing Cdk5-dependent phosphorylation of Src(S75), by site-specific mutation of S75 or by Cdk5 inhibition or suppression, increases Src(Y419) phosphorylation and kinase activity, resulting in Src-dependent cytoskeletal changes. In transfected cells, ubiquitinylation of Src(S75A) is about 35% that of wild-type Src-V5, and its half-life is approximately 2.5-fold greater. Cdk5 suppression leads to a comparable decrease in the ubiquitinylation of endogenous Src and a similar increase in Src stability. Together, these findings demonstrate that Cdk5-dependent phosphorylation of Src(S75) is a physiologically significant mechanism of regulating intracellular Src activity.