Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas

To identify somatic mutations in pediatric diffuse intrinsic pontine glioma (DIPG), we performed whole-genome sequencing of DNA from seven DIPGs and matched germline tissue and targeted sequencing of an additional 43 DIPGs and 36 non-brainstem pediatric glioblastomas (non-BS-PGs). We found that 78% of DIPGs and 22% of non-BS-PGs contained a mutation in H3F3A, encoding histone H3.3, or in the related HIST1H3B, encoding histone H3.1, that caused a p.Lys27Met amino acid substitution in each protein. An additional 14% of non-BS-PGs had somatic mutations in H3F3A causing a p.Gly34Arg alteration.     

Dynamics of a dwarf bear-poppy ( Arctomecon humilis ) population over a sixteen-year period

A population of the dwarf bear-poppy ( Arctomecon humilis Coville, Papaveraceae) at Red Bluff, Washington County, Utah, was monitored twice annually between 1987 and 2002. This is a narrowly endemic, gypsophilous species that has been formally listed as endangered since 1979. During the 16 years of observation, density of this species has fluctuated between 3 and 1336 individuals on the 0.07-ha monitoring plot. Moderate to large recruitments of seedlings occurred in 1992, 1995, and 2001. Seedling recruitments from a large, long-lived seed bank are triggered by abundant precipitation during the February-April period. At least 5.0 cm of rainfall is required during that interval to produce any seedlings. Seedlings experienced considerable mortality in the 1st few months of life in all observed cases. The average seedling initiated in the very large recruitment event of 1992 survived for only 2.6 years. Seedlings in that cohort that were alive 1 year after germination had an average longevity of 4.6 years. None of the seedlings that emerged in 1992 were still alive in October 2002. Mortality in this species was poorly correlated with fluctuations in precipitation or temperature. No epidemics of parasites or herbivores were observed. Mortality in the species appears to be caused by a variety of factors acting over a cohort's lifetime.     

The coiled-coil domain containing protein CCDC40 is essential for motile cilia function and left-right axis formation

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous autosomal recessive disorder characterized by recurrent infections of the respiratory tract associated with the abnormal function of motile cilia. Approximately half of individuals with PCD also have alterations in the left-right organization of their internal organ positioning, including situs inversus and situs ambiguous (Kartagener's syndrome). Here, we identify an uncharacterized coiled-coil domain containing a protein, CCDC40, essential for correct left-right patterning in mouse, zebrafish and human. In mouse and zebrafish, Ccdc40 is expressed in tissues that contain motile cilia, and mutations in Ccdc40 result in cilia with reduced ranges of motility. We further show that CCDC40 mutations in humans result in a variant of PCD characterized by misplacement of the central pair of microtubules and defective assembly of inner dynein arms and dynein regulatory complexes. CCDC40 localizes to motile cilia and the apical cytoplasm and is required for axonemal recruitment of CCDC39, disruption of which underlies a similar variant of PCD.     

Genome-wide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2

A combined genome-wide association and linkage study was used to identify loci causing variation in cystic fibrosis lung disease severity. We identified a significant association (P = 3.34 × 10(-8)) near EHF and APIP (chr11p13) in p.Phe508del homozygotes (n = 1,978). The association replicated in p.Phe508del homozygotes (P = 0.006) from a separate family based study (n = 557), with P = 1.49 × 10(-9) for the three-study joint meta-analysis. Linkage analysis of 486 sibling pairs from the family based study identified a significant quantitative trait locus on chromosome 20q13.2 (log(10) odds = 5.03). Our findings provide insight into the causes of variation in lung disease severity in cystic fibrosis and suggest new therapeutic targets for this life-limiting disorder.     

Genome-wide association study identifies a new melanoma susceptibility locus at 1q21.3

We performed a genome-wide association study of melanoma in a discovery cohort of 2,168 Australian individuals with melanoma and 4,387 control individuals. In this discovery phase, we confirm several previously characterized melanoma-associated loci at MC1R, ASIP and MTAP-CDKN2A. We selected variants at nine loci for replication in three independent case-control studies (Europe: 2,804 subjects with melanoma, 7,618 control subjects; United States 1: 1,804 subjects with melanoma, 1,026 control subjects; United States 2: 585 subjects with melanoma, 6,500 control subjects). The combined meta-analysis of all case-control studies identified a new susceptibility locus at 1q21.3 (rs7412746, P = 9.0 × 10(-11), OR in combined replication cohorts of 0.89 (95% CI 0.85-0.95)). We also show evidence suggesting that melanoma associates with 1q42.12 (rs3219090, P = 9.3 × 10(-8)). The associated variants at the 1q21.3 locus span a region with ten genes, and plausible candidate genes for melanoma susceptibility include ARNT and SETDB1. Variants at the 1q21.3 locus do not seem to be associated with human pigmentation or measures of nevus density.     

Suitability of shrub establishment on Wyoming mined lands reclaimed for wildlife habitat

Restoring coal mined land to pre-mining shrub cover, density, height, community composition, and diversity to renew wildlife habitat quality is a priority for reclamation specialists. Long-term shrub reestablishment success on reclaimed mined land in Wyoming and suitability of these lands for wildlife habitat are unknown. Fourteen reclaimed study sites, 10 yr old or older, were selected on 8 mines in Wyoming to evaluate shrub reestablishment and wildlife habitat value for antelope ( Antilocapra americana ) and sage grouse ( Centrocercus urophasianus ). Five sites were categorized as fourwing saltbush ( Atriplex canescens ) sites and 9 as fourwing saltbush/big sagebrush ( A. canescens/Artemisia tridentata spp. wyomingensis ) sites. Published data describing antelope and sage grouse-preferred habitat requirements in sagebrush-grassland steppe ecosystems were used to evaluate shrub community value of sampled sites for wildlife habitat. Mean shrub canopy cover, density, and height for fourwing saltbush sites were 5.8%, 0.23 m -2 , and 41.6 cm, respectively, compared to 5.6%, 0.61 m -2 , and 31.1 cm for fourwing saltbush/big sagebrush sites. Two fourwing saltbush and 4 fourwing saltbush/big sagebrush sites provided sufficient cover for antelope, while 2 fourwing saltbush and 4 fourwing saltbush/big sagebrush sites were adequate for sage grouse. Only 1 fourwing saltbush/big sagebrush site provided high enough shrub densities for sage grouse. One fourwing saltbush and 7 fourwing saltbush/big sagebrush sites provided ample shrub heights for antelope, while 1 fourwing saltbush and 8 fourwing saltbush/big sagebrush sites were sufficient for sage grouse. One fourwing saltbush and 1 fourwing saltbush/big sagebrush site provided enough grass, forb, and shrub composition for antelope, while no site in either reclamation type was satisfactory for sage grouse. Shrub diversity was 3 times higher for fourwing saltbush/big sagebrush sites (0.984) than for fourwing saltbush sites (0.328). Individually, sites seeded with multiple shrub species had higher canopy cover, density, and diversity compared with single-species shrub seedings. Achieving premining shrub cover, density, height, community composition, and diversity within existing bond-release time frames is unrealistic, considering that some native shrublands require 30-60 yr to reach maturity.