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.     

A genome-wide association study in Han Chinese identifies new susceptibility loci for ankylosing spondylitis

To identify susceptibility loci for ankylosing spondylitis, we performed a two-stage genome-wide association study in Han Chinese. In the discovery stage, we analyzed 1,356,350 autosomal SNPs in 1,837 individuals with ankylosing spondylitis and 4,231 controls; in the validation stage, we analyzed 30 suggestive SNPs in an additional 2,100 affected individuals and 3,496 controls. We identified two new susceptibility loci between EDIL3 and HAPLN1 at 5q14.3 (rs4552569; P = 8.77 × 10(-10)) and within ANO6 at 12q12 (rs17095830; P = 1.63 × 10(-8)). We also confirmed previously reported associations in Europeans within the major histocompatibility complex (MHC) region (top SNP, rs13202464; P < 5 × 10(-324)) and at 2p15 (rs10865331; P = 1.98 × 10(-8)). We show that rs13202464 within the MHC region mainly represents the risk effect of HLA-B*27 variants (including HLA-B*2704, HLA-B*2705 and HLA-B*2715) in Chinese. The two newly discovered loci implicate genes related to bone formation and cartilage development, suggesting their potential involvement in the etiology of ankylosing spondylitis.     

Rediscovered population of Mexican Plateau spotted whiptail lizard, Aspidoscelis septemvittata , from México, D.F.

Multiple surveys carried out by herpetologists in México, D.F., during the 1980s failed to find specimens of Aspidoscelis septemvitatta (Squamata: Teiidae). However, 10 specimens were recently collected to the east of México, D.F., inside a protected area, Sierra de Santa Catarina. The Sierra de Santa Catarina has been heavily modified by human activity and habitation. Morphological and natural history information about the specimens are presented, as well as notes on locality.     

Comparative life history for populations of the Sceloporus grammicus complex (Squamata: Phrynosomatidae)

A Teotihuacán population of the Sceloporus grammicus complex was compared with other previously studied populations (Parque Nacional Zoquiapan [PNZ], Monte Alegre Ajusco [MAA], Pedregal San Angel [PSA], Cantimplora [CA], Capulín, Laguna, Paredon, Michilia, and south Texas) for variations in several life history characteristics (SVL at sexual maturity, reproductive period, ovulation and gestation time, and litter size). Mean body size at sexual maturity of females from Teotihuacán was larger than PNZ, MAA, CA, and Capulín. Reproductive period (vitellogenesis, ovulation, gestation, and birth) for the Teotihuacán population was the shortest of all populations. In the Teotihuacán population, gestation time was similar to the Capulínand MAA populations but was shorter than all other populations except the Michilia population. Embryonic development at ovulation varied among populations, with Teotihuacán and Capulín showing earlier stages (stages 1) at ovulation than all other populations. Teotihuacán, PSA, PNZ, and Texas all showed similar litter size, which were larger than Laguna, Paredon, MAA, Capulín, and CA populations. Differences in reproductive characteristics of these populations could indicate phylogenetically constrained, reproductively isolated populations, or they may be explained as merely responses to different environments.     

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.     

CEP152 is a genome maintenance protein disrupted in Seckel syndrome

Functional impairment of DNA damage response pathways leads to increased genomic instability. Here we describe the centrosomal protein CEP152 as a new regulator of genomic integrity and cellular response to DNA damage. Using homozygosity mapping and exome sequencing, we identified CEP152 mutations in Seckel syndrome and showed that impaired CEP152 function leads to accumulation of genomic defects resulting from replicative stress through enhanced activation of ATM signaling and increased H2AX phosphorylation.     

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 reveals three susceptibility loci for common migraine in the general population

Migraine is a common, heterogeneous and heritable neurological disorder. Its pathophysiology is incompletely understood, and its genetic influences at the population level are unknown. In a population-based genome-wide analysis including 5,122 migraineurs and 18,108 non-migraineurs, rs2651899 (1p36.32, PRDM16), rs10166942 (2q37.1, TRPM8) and rs11172113 (12q13.3, LRP1) were among the top seven associations (P < 5 × 10(-6)) with migraine. These SNPs were significant in a meta-analysis among three replication cohorts and met genome-wide significance in a meta-analysis combining the discovery and replication cohorts (rs2651899, odds ratio (OR) = 1.11, P = 3.8 × 10(-9); rs10166942, OR = 0.85, P = 5.5 × 10(-12); and rs11172113, OR = 0.90, P = 4.3 × 10(-9)). The associations at rs2651899 and rs10166942 were specific for migraine compared with non-migraine headache. None of the three SNP associations was preferential for migraine with aura or without aura, nor were any associations specific for migraine features. TRPM8 has been the focus of neuropathic pain models, whereas LRP1 modulates neuronal glutamate signaling, plausibly linking both genes to migraine pathophysiology.     

Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder

Transitional cell carcinoma (TCC) is the most common type of bladder cancer. Here we sequenced the exomes of nine individuals with TCC and screened all the somatically mutated genes in a prevalence set of 88 additional individuals with TCC with different tumor stages and grades. In our study, we discovered a variety of genes previously unknown to be mutated in TCC. Notably, we identified genetic aberrations of the chromatin remodeling genes (UTX, MLL-MLL3, CREBBP-EP300, NCOR1, ARID1A and CHD6) in 59% of our 97 subjects with TCC. Of these genes, we showed UTX to be altered substantially more frequently in tumors of low stages and grades, highlighting its potential role in the classification and diagnosis of bladder cancer. Our results provide an overview of the genetic basis of TCC and suggest that aberration of chromatin regulation might be a hallmark of bladder cancer.     

Systematic documentation and analysis of human genetic variation in hemoglobinopathies using the microattribution approach

We developed a series of interrelated locus-specific databases to store all published and unpublished genetic variation related to hemoglobinopathies and thalassemia and implemented microattribution to encourage submission of unpublished observations of genetic variation to these public repositories. A total of 1,941 unique genetic variants in 37 genes, encoding globins and other erythroid proteins, are currently documented in these databases, with reciprocal attribution of microcitations to data contributors. Our project provides the first example of implementing microattribution to incentivise submission of all known genetic variation in a defined system. It has demonstrably increased the reporting of human variants, leading to a comprehensive online resource for systematically describing human genetic variation in the globin genes and other genes contributing to hemoglobinopathies and thalassemias. The principles established here will serve as a model for other systems and for the analysis of other common and/or complex human genetic diseases.