ESTIMATING GENOME-WIDE COPY NUMBER USING ALLELE SPECIFIC MIXTURE MODELS

Genomic changes such as copy number alterations are thought to be one of the major underlying causes of human phenotypic variation among normal and disease subjects [23,11,25,26,5,4,7,18]. These include chromosomal regions with so-called copy number alterations: instead of the expected two copies, a section of the chromosome for a particular individual may have zero copies (homozygous deletion), one copy (hemizygous deletions), or more than two copies (amplifications). The canonical example is Down syndrome which is caused by an extra copy of chromosome 21. Identification of such abnormalities in smaller regions has been of great interest, because it is believed to be an underlying cause of cancer. More than one decade ago comparative genomic hybridization (CGH)technology was developed to detect copy number changes in a high-throughput fashion. However, this technology only provides a 10 MB resolution which limits the ability to detect copy number alterations spanning small regions. It is widely believed that a copy number alteration as small as one base can have significant downstream effects, thus microarray manufacturers have developed technologies that provide much higher resolution. Unfortunately, strong probe effects and variation introduced by sample preparation procedures have made single-point copy number estimates too imprecise to be useful. CGH arrays use a two-color hybridization, usually comparing a sample of interest to a reference sample, which to some degree removes the probe effect. However, the resolution is not nearly high enough to provide single-point copy number estimates. Various groups have proposed statistical procedures that pool data from neighboring locations to successfully improve precision. However, these procedure need to average across relatively large regions to work effectively thus greatly reducing the resolution. Recently, regression-type models that account for probe-effect have been proposed and appear to improve accuracy as well as precision. In this paper, we propose a mixture model solution specifically designed for single-point estimation, that provides various advantages over the existing methodology. We use a 314 sample database, constructed with public datasets, to motivate and fit models for the conditional distribution of the observed intensities given allele specific copy numbers. With the estimated models in place we can compute posterior probabilities that provide a useful prediction rule as well as a confidence measure for each call. Software to implement this procedure will be available in the Bioconductor oligo packagehttp://www.bioconductor.org)

Potential for Supernova Neutrino Detection in MiniBooNE

The MiniBooNE detector at Fermilab is designed to search for $\nu_\mu \to \nu_e$ oscillation appearance at $E_\nu \sim 1 {\rm GeV}$ and to make a decisive test of the LSND signal. The main detector (inside a veto shield) is a spherical volume containing 0.680 ktons of mineral oil. This inner volume, viewed by 1280 phototubes, is primarily a \v{C}erenkov medium, as the scintillation yield is low. The entire detector is under a 3 m earth overburden. Though the detector is not optimized for low-energy (tens of MeV) events, and the cosmic-ray muon rate is high (10 kHz), we show that MiniBooNE can function as a useful supernova neutrino detector. Simple trigger-level cuts can greatly reduce the backgrounds due to cosmic-ray muons. For a canonical Galactic supernova at 10 kpc, about 190 supernova $\bar{\nu}_e + p \to e^+ + n$ events would be detected. By adding MiniBooNE to the international network of supernova detectors, the possibility of a supernova being missed would be reduced. Additionally, the paths of the supernova neutrinos through Earth will be different for MiniBooNE and other detectors, thus allowing tests of matter-affected mixing effects on the neutrino signal.Comment: Added references, version to appear in PR

Simulacral, genealogical, auratic and representational failure: Bushman authenticity as methodological collapse

This article engages with the concept of authenticity as deployed in anthropology. The first section critiques authenticity as a simple reference to cultural purity, a traditional isomorphism or historical verisimilitude or as an ‘ethnographic authenticity’. Demarcation of authenticity must take into account philosophical literature that argues that authenticity is an existential question of the ‘modern’ era. Thus, authenticity is offered to us as individuals as a remedy for the maladies of modernity: alienation, anomie and alterity. Authenticity is then discussed as a question of value within an economy of cultural politics that often draws on simulacra, creating cultural relics of dubious origin. The final section discusses various methodological failures and problematiques that are highlighted by the concern for, and scrutiny of, authenticity. The first is the simulacral failure. The subjects of anthropology are mostly real flesh-and-blood people-on-the-ground with real needs. In contrast is the simulacral subject, the brand, the tourist image, the media image or the ever-familiar hyper-real bushmen. Lastly, the article considers what Spivak calls ‘withholding’ – a resistance to authentic representation by the Other. Resistance suggests a need for a radically altered engagement with the Other that includes both a deepening, and an awareness, of anthropology as a process of common ontological unfolding

Maternal pre-pregnancy obesity, offspring cord blood DNA methylation, and offspring cardiometabolic health in early childhood: an epigenome-wide association study

Pre-pregnancy obesity is an established risk factor for adverse sex-specific cardiometabolic health in offspring. Epigenetic alterations, such as in DNA methylation (DNAm), are a hypothesized link; however, sex-specific epigenomic targets remain unclear. Leveraging data from the Newborn Epigenetics Study (NEST) cohort, linear regression models were used to identify CpG sites in cord blood leukocytes associated with pre-pregnancy obesity in 187 mother-female and 173 mother-male offsprings. DNAm in cord blood was measured using the Illumina HumanMethylation450k BeadChip. Replication analysis was conducted among the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Associations between pre-pregnancy obesity-associated CpG sites and offspring BMI z-score (BMIz) and blood pressure (BP) percentiles at 4–5-years of age were also examined. Maternal pre-pregnacy obesity was associated with 876 CpGs in female and 293 CpGs in male offspring (false discovery rate <5%). Among female offspring, 57 CpG sites, including the top 18, mapped to the TAPBP gene (range of effect estimates: −0.83% decrease to 4.02% increase in methylation). CpG methylation differences in the TAPBP gene were also observed among males (range of effect estimates: −0.30% decrease to 2.59% increase in methylation). While technically validated, none of the TAPBP CpG sites were replicated in ALSPAC. In NEST, methylation differences at CpG sites of the TAPBP gene were associated with BMI z-score (cg23922433 and cg17621507) and systolic BP percentile (cg06230948) in female and systolic (cg06230948) and diastolic (cg03780271) BP percentile in male offspring. Together, these findings suggest sex-specific effects, which, if causal, may explain observed sex-specific effects of maternal obesity

Current assessment of the Red Rectangle band problem

In this paper we discuss our insights into several key problems in the identification of the Red Rectangle Bands (RRBs). We have combined three independent sets of observations in order to try to define the constraints guiding the bands. We provide a summary of the general behavior of the bands and review the evidence for a molecular origin of the bands. The extent, composition, and possible absorption effects of the bands are discussed. Comparison spectra of the strongest band obtained at three different spectral resolutions suggests that an intrinsic line width of individual rotational lines can be deduced. Spectroscopic models of several relatively simple molecules were examined in order to investigate where the current data are weak. Suggestions are made for future studies to enhance our understanding of these enigmatic bands

DNA methylation of blood cells is associated with prevalent type 2 diabetes in a meta-analysis of four European cohorts

Background: Type 2 diabetes (T2D) is a heterogeneous disease with well-known genetic and environmental risk factors contributing to its prevalence. Epigenetic mec

Maternal depression during pregnancy and cord blood DNA methylation: findings from the Avon Longitudinal Study of Parents and Children

Up to 13% of women may experience symptoms of depression during pregnancy or in the postpartum period. Depression during pregnancy has been associated with an increased risk of adverse neurodevelopmental outcomes in the child and epigenetic mechanisms could be one of the biological pathways to explain this association. In 844 mother–child pairs from the Avon Longitudinal Study of Parents and Children, we carried out an epigenome-wide association study (EWAS) to investigate associations between prospectively collected data on maternal depression ascertained by the Edinburgh Postnatal Depression Scale in pregnancy and DNA methylation in the cord blood of newborn offspring. In individual site analysis, we identified two CpG sites associated with maternal depression in the middle part of pregnancy. In our regional analysis, we identified 39 differentially methylated regions (DMRs). Seven DMRs were associated with depression at any time point during pregnancy, 7 associated with depression in mid-pregnancy, 23 were associated with depression in late pregnancy, and 2 DMRs were associated with depression throughout pregnancy. Several of these map to genes associated with psychiatric disease and brain development. We attempted replication in The Generation R Study and could not replicate our results. Although our findings in ALSPAC suggest that maternal depression could be associated with cord blood DNA methylation the results should be viewed as preliminary and hypothesis generating until further replicated in a larger sample