Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm

Loeys-Dietz syndrome (LDS) associates with a tissue signature for high transforming growth factor (TGF)-β signaling but is often caused by heterozygous mutations in genes encoding positive effectors of TGF-β signaling, including either subunit of the TGF-β receptor or SMAD3, thereby engendering controversy regarding the mechanism of disease. Here, we report heterozygous mutations or deletions in the gene encoding the TGF-β2 ligand for a phenotype within the LDS spectrum and show upregulation of TGF-β signaling in aortic tissue from affected individuals. Furthermore, haploinsufficient Tgfb2(+/-) mice have aortic root aneurysm and biochemical evidence of increased canonical and noncanonical TGF-β signaling. Mice that harbor both a mutant Marfan syndrome (MFS) allele (Fbn1(C1039G/+)) and Tgfb2 haploinsufficiency show increased TGF-β signaling and phenotypic worsening in association with normalization of TGF-β2 expression and high expression of TGF-β1. Taken together, these data support the hypothesis that compensatory autocrine and/or paracrine events contribute to the pathogenesis of TGF-β-mediated vasculopathies.     

Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer

Human non-small cell lung cancers (NSCLCs) with activating mutations in EGFR frequently respond to treatment with EGFR-targeted tyrosine kinase inhibitors (TKIs), such as erlotinib, but responses are not durable, as tumors acquire resistance. Secondary mutations in EGFR (such as T790M) or upregulation of the MET kinase are found in over 50% of resistant tumors. Here, we report increased activation of AXL and evidence for epithelial-to-mesenchymal transition (EMT) in multiple in vitro and in vivo EGFR-mutant lung cancer models with acquired resistance to erlotinib in the absence of the EGFR p.Thr790Met alteration or MET activation. Genetic or pharmacological inhibition of AXL restored sensitivity to erlotinib in these tumor models. Increased expression of AXL and, in some cases, of its ligand GAS6 was found in EGFR-mutant lung cancers obtained from individuals with acquired resistance to TKIs. These data identify AXL as a promising therapeutic target whose inhibition could prevent or overcome acquired resistance to EGFR TKIs in individuals with EGFR-mutant lung cancer.     

Genome stability, progressive kidney failure and aging

Two new studies report mutations in FAN1 and three other genome-stability genes that tie the DNA damage response to progressive kidney failure and the dysfunction of several other organs. These findings provide clues to the underlying causes of tissue decline and may add a series of genes to the growing list of genome maintenance factors that protect against premature aging.     

Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) is a common, heritable neuropsychiatric disorder of unknown etiology. We performed a whole-genome copy number variation (CNV) study on 1,013 cases with ADHD and 4,105 healthy children of European ancestry using 550,000 SNPs. We evaluated statistically significant findings in multiple independent cohorts, with a total of 2,493 cases with ADHD and 9,222 controls of European ancestry, using matched platforms. CNVs affecting metabotropic glutamate receptor genes were enriched across all cohorts (P = 2.1 × 10(-9)). We saw GRM5 (encoding glutamate receptor, metabotropic 5) deletions in ten cases and one control (P = 1.36 × 10(-6)). We saw GRM7 deletions in six cases, and we saw GRM8 deletions in eight cases and no controls. GRM1 was duplicated in eight cases. We experimentally validated the observed variants using quantitative RT-PCR. A gene network analysis showed that genes interacting with the genes in the GRM family are enriched for CNVs in ～10% of the cases (P = 4.38 × 10(-10)) after correction for occurrence in the controls. We identified rare recurrent CNVs affecting glutamatergic neurotransmission genes that were overrepresented in multiple ADHD cohorts.     

Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus

Coats plus is a highly pleiotropic disorder particularly affecting the eye, brain, bone and gastrointestinal tract. Here, we show that Coats plus results from mutations in CTC1, encoding conserved telomere maintenance component 1, a member of the mammalian homolog of the yeast heterotrimeric CST telomeric capping complex. Consistent with the observation of shortened telomeres in an Arabidopsis CTC1 mutant and the phenotypic overlap of Coats plus with the telomeric maintenance disorders comprising dyskeratosis congenita, we observed shortened telomeres in three individuals with Coats plus and an increase in spontaneous γH2AX-positive cells in cell lines derived from two affected individuals. CTC1 is also a subunit of the α-accessory factor (AAF) complex, stimulating the activity of DNA polymerase-α primase, the only enzyme known to initiate DNA replication in eukaryotic cells. Thus, CTC1 may have a function in DNA metabolism that is necessary for but not specific to telomeric integrity.     

Conditional and joint multiple-SNP analysis of GWAS summary statistics identifies additional variants influencing complex traits

We present an approximate conditional and joint association analysis that can use summary-level statistics from a meta-analysis of genome-wide association studies (GWAS) and estimated linkage disequilibrium (LD) from a reference sample with individual-level genotype data. Using this method, we analyzed meta-analysis summary data from the GIANT Consortium for height and body mass index (BMI), with the LD structure estimated from genotype data in two independent cohorts. We identified 36 loci with multiple associated variants for height (38 leading and 49 additional SNPs, 87 in total) via a genome-wide SNP selection procedure. The 49 new SNPs explain approximately 1.3% of variance, nearly doubling the heritability explained at the 36 loci. We did not find any locus showing multiple associated SNPs for BMI. The method we present is computationally fast and is also applicable to case-control data, which we demonstrate in an example from meta-analysis of type 2 diabetes by the DIAGRAM Consortium.     

Habitat and nesting biology of Mountain Plovers in Wyoming

Although previous research has considered habitat associations and breeding biology of Mountain Plovers in Wyoming at discrete sites, no study has considered these attributes at a statewide scale. We located 55 Mountain Plover nests in 6 counties across Wyoming during 2002 and 2003. Nests occurred in 2 general habitat types: grassland and desert-shrub. Mean estimated hatch date was 26 June ( n = 31) in 2002 and 21 June ( n = 24) in 2003. Mean hatch date was not related to latitude or elevation. Hatch success of nests was inferred in 2003 by the presence of eggshell fragments in the nest scrape. Eggs in 14 of 22 (64%) known-fate nests hatched. All grassland sites and 90% of desert sites were host to ungulate grazers, although prairie dogs were absent at 64% of nest sites. Nest plots had less grass coverage and reduced grass height compared with random plots. More than 50% of nests occurred on elevated plateaus. The Mountain Plover's tendency to nest on arid, elevated plateaus further substantiates claims that the bird is also a disturbed- prairie species.     

Early brood-rearing habitat use and productivity of Greater Sage-Grouse in Wyoming

Populations of Greater Sage-Grouse ( Centrocercus urophasianus ) have been declining throughout their range since the 1960s. Productivity, which includes production and survival of young, is often cited as a factor in these declines. We monitored radio-equipped Greater Sage-Grouse at 3 sites in western Wyoming to assess early brood-rearing habitat use (through 14 days post-hatch) and productivity. Logistic and linear regression analyses with Akaike's Information Criterion were used to evaluate early brooding habitat use and to examine relationships between productivity and vegetation, insect size and abundance, and weather parameters. Females with broods were found in areas with greater sagebrush canopy and grass cover, and fewer invertebrates compared to random areas. The number of juveniles per female (estimated from wing barrel collections during fall harvest) was positively related to the abundance of medium-length Hymenoptera and grass cover, and the proportion of females with confirmed chicks 14 days post-hatch was positively related to abundance of medium-length Coleoptera and total herbaceous cover. Although the specific parameters varied slightly, Greater Sage-Grouse productivity in Wyoming appeared to be associated with a combination of insect and herbaceous cover elements. Managing for abundant and diverse insect communities within dense protective sagebrush stands should help ensure high-quality early brood-rearing habitat and increased Greater Sage-Grouse productivity.     

Canids from the late Pleistocene of Utah

Two canids, Vulpes vulpes and Canis lupus , are recorded from shoreline deposits of Lake Bonneville in north central Utah. Both species are new records in the Pleistocene sediments of Utah and add to our scarce knowledge of the large carnivores that inhabited the shoreline environments of Lake Bonneville.