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.     

Estimating the proportion of variation in susceptibility to schizophrenia captured by common SNPs

Schizophrenia is a complex disorder caused by both genetic and environmental factors. Using 9,087 affected individuals, 12,171 controls and 915,354 imputed SNPs from the Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium (PGC-SCZ), we estimate that 23% (s.e. = 1%) of variation in liability to schizophrenia is captured by SNPs. We show that a substantial proportion of this variation must be the result of common causal variants, that the variance explained by each chromosome is linearly related to its length (r = 0.89, P = 2.6 × 10(-8)), that the genetic basis of schizophrenia is the same in males and females, and that a disproportionate proportion of variation is attributable to a set of 2,725 genes expressed in the central nervous system (CNS; P = 7.6 × 10(-8)). These results are consistent with a polygenic genetic architecture and imply more individual SNP associations will be detected for this disease as sample size increases.     

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.     

Pneumococcal genome sequencing tracks a vaccine escape variant formed through a multi-fragment recombination event

Streptococcus pneumoniae ('pneumococcus') causes an estimated 14.5 million cases of serious disease and 826,000 deaths annually in children under 5 years of age(1). The highly effective introduction of the PCV7 pneumococcal vaccine in 2000 in the United States(2,3) provided an unprecedented opportunity to investigate the response of an important pathogen to widespread, vaccine-induced selective pressure. Here, we use array-based sequencing of 62 isolates from a US national monitoring program to study five independent instances of vaccine escape recombination(4), showing the simultaneous transfer of multiple and often large (up to at least 44 kb) DNA fragments. We show that one such new strain quickly became established, spreading from east to west across the United States. These observations clarify the roles of recombination and selection in the population genomics of pneumococcus and provide proof of principle of the considerable value of combining genomic and epidemiological information in the surveillance and enhanced understanding of infectious diseases.     

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.     

Rad51 and DNA-PKcs are involved in the generation of specific telomere aberrations induced by the quadruplex ligand 360A that impair mitotic cell progression and lead to cell death

Functional telomeres are protected from non-homologous end-joining (NHEJ) and homologous recombination (HR) DNA repair pathways. Replication is a critical period for telomeres because of the requirement for reconstitution of functional protected telomere conformations, a process that involves DNA repair proteins. Using knockdown of DNA-PKcs and Rad51 expression in three different cell lines, we demonstrate the respective involvement of NHEJ and HR in the formation of telomere aberrations induced by the G-quadruplex ligand 360A during or after replication. HR contributed to specific chromatid-type aberrations (telomere losses and doublets) affecting the lagging strand telomeres, whereas DNA-PKcs-dependent NHEJ was responsible for sister telomere fusions as a direct consequence of G-quadruplex formation and/or stabilization induced by 360A on parental telomere G strands. NHEJ and HR activation at telomeres altered mitotic progression in treated cells. In particular, NHEJ-mediated sister telomere fusions were associated with altered metaphase-anaphase transition and anaphase bridges and resulted in cell death during mitosis or early G1. Collectively, these data elucidate specific molecular and cellular mechanisms triggered by telomere targeting by the G-quadruplex ligand 360A, leading to cancer cell death.     

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.     

Temperature and high salinity effects in germinating dimorphic seeds of Atriplex rosea

Atriplex rosea L. (Chenopodiaceae; tumbling orach), an annual herb, is a widely established weedy species of disturbed sites in all counties of Utah. Seeds of Atriplex rosea were collected from a salt marsh in Faust, Utah, and are dimorphic, light brown, and 2-2.5 mm wide, or black and 1-2 mm wide. Seed germination responses of the black and brown seeds were studied over a range of salinity and temperature. Both brown and black seeds germinated at 1000 mM NaCl, and the optimal temperature for germination of both types was 20°-30°C. Variation in temperature, however, affected germination of black seeds more than brown seeds. At lower thermoperiod only 40%-50% black seeds germinated in nonsaline control, and germination was almost completely inhibited with the inclusion of salinity. However, all brown seeds germinated in control at temperatures above 5°-15°C, and inhibition caused by salinity was comparatively lower. Brown seeds had a higher germination rate than black seeds at all temperature and salinity treatments. The highest rate of germination of both seeds occurred at the temperature regime of 5°-15°C. Recovery of germination for black seeds when transferred to distilled water after being in various salinity treatments for 20 days was quite variable. Recovery decreased with increase in salinity at lower temperature regimes, increased with salinity at optimal thermoperiod, and had no effect at 20°-30°C. Brown seeds recovered poorly from salinity at all thermoperiods except 5°-15°C, where recovery decreased with an increase in salinity. Brown seeds are adapted to germination in the early part of the growing season, whereas black seeds are capable of surviving harsher conditions and can germinate in later time periods. Characteristics of the dimorphic seeds increase chances for survival in the harsh saline desert environment.     

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.     

Recurrence of Mexican long-tongued bats ( Choeronycteris mexicana ) at historical sites in Arizona and New Mexico

The Mexican long-tongued bat ( Choeronycteris mexicana ) is a nectar-eating species that seasonally inhabits the southwestern United States. Since 1906, fewer than 1500 individuals of C. mexicana have been documented throughout the range of the species. We conducted a field survey in Arizona and New Mexico during summer 1999 to check historically occupied areas for recurrence of C. mexicana . We observed C. mexicana occupying a majority (75%, n = 18) of visited sites. Multiple individuals were observed at many sites, including young-of-year. Choeronycteris mexicana roosted in lighted areas close to entrances within mine adits, abandoned buildings, wide rock crevices, and caves. All occupied sites in Madrean evergreen woodlands or semidesert grasslands where species of Agave were present. Most sites were located near a water source and, with the exception of a single site, near areas of riparian vegetation. Sites at which we did not encounter C. mexicana were frequently disturbed, difficult to search, or historically occupied by single individuals. Based on the relatively high rate of bat recurrence, we do not believe that populations of C. mexicana in the region have declined dramatically over the past several decades.