Integrating sequence and array data to create an improved 1000 Genomes Project haplotype reference panel

A major use of the 1000 Genomes Project (1000GP) data is genotype imputation in genome-wide association studies (GWAS). Here we develop a method to estimate haplotypes from low-coverage sequencing data that can take advantage of single-nucleotide polymorphism (SNP) microarray genotypes on the same samples. First the SNP array data are phased to build a backbone (or 'scaffold') of haplotypes across each chromosome. We then phase the sequence data 'onto' this haplotype scaffold. This approach can take advantage of relatedness between sequenced and non-sequenced samples to improve accuracy. We use this method to create a new 1000GP haplotype reference set for use by the human genetic community. Using a set of validation genotypes at SNP and bi-allelic indels we show that these haplotypes have lower genotype discordance and improved imputation performance into downstream GWAS samples, especially at low-frequency variants. © 2014 Macmillan Publishers Limited. All rights reserved

Comprehensive analysis of epigenetic clocks reveals associations between disproportionate biological ageing and hippocampal volume

The concept of age acceleration, the difference between biological age and chronological age, is of growing interest, particularly with respect to age-related disorders, such as Alzheimer’s Disease (AD). Whilst studies have reported associations with AD risk and related phenotypes, there remains a lack of consensus on these associations. Here we aimed to comprehensively investigate the relationship between five recognised measures of age acceleration, based on DNA methylation patterns (DNAm age), and cross-sectional and longitudinal cognition and AD-related neuroimaging phenotypes (volumetric MRI and Amyloid-β PET) in the Australian Imaging, Biomarkers and Lifestyle (AIBL) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Significant associations were observed between age acceleration using the Hannum epigenetic clock and cross-sectional hippocampal volume in AIBL and replicated in ADNI. In AIBL, several other findings were observed cross-sectionally, including a significant association between hippocampal volume and the Hannum and Phenoage epigenetic clocks. Further, significant associations were also observed between hippocampal volume and the Zhang and Phenoage epigenetic clocks within Amyloid-β positive individuals. However, these were not validated within the ADNI cohort. No associations between age acceleration and other Alzheimer’s disease-related phenotypes, including measures of cognition or brain Amyloid-β burden, were observed, and there was no association with longitudinal change in any phenotype. This study presents a link between age acceleration, as determined using DNA methylation, and hippocampal volume that was statistically significant across two highly characterised cohorts. The results presented in this study contribute to a growing literature that supports the role of epigenetic modifications in ageing and AD-related phenotypes

YB-1 provokes breast cancer through the induction of chromosomal instability that emerges from mitotic failure and centrosome amplification

YB-1 protein levels are elevated in most human breast cancers, and high YB-1 levels have been correlated with drug resistance and poor clinical outcome. YB-1 is a stress-responsive, cell cycle-regulated transcription factor with additional functions in RNA metabolism and translation. In this study, we show in a novel transgenic mouse model that human hemagglutinin-tagged YB-1 provokes remarkably diverse breast carcinomas through the induction of genetic instability that emerges from mitotic failure and centrosome amplification. The increase of centrosome numbers proceeds during breast cancer development and explanted tumor cell cultures show the phenotype of ongoing numerical chromosomal instability. These data illustrate a mechanism that might contribute to human breast cancer development

The multipulse Thomson scattering diagnostic on the DIII-D tokamak

This paper describes the design and operation of a 40-spatial channel Thomson scattering system that uses multiple 20 Hz Nd:YAG lasers to measure the electron temperature and density profiles periodically throughout an entire plasma discharge. Interference filter polychromators disperse the scattered light which is detected by silicon avalanche photodiodes. The measurable temperature range from 10 eV to 20 keV and the minimum detectable density is about 2 {times} 10{sup 18} m{sup {minus}3}. Laser control and data acquisition are performed in real-time by a VME-based microcomputer. Data analysis is performed by a MicroVAX 3400. Unique features of this system include burst mode'' operation, where multiple lasers are fired in rapid succession (< 10 KHz), real-time analysis capability, and laser beam quality and alignment monitoring during plasma operation. Results of component testing, calibration, and plasma operation are presented. 8 refs. 6 figs

Design and operation of the multipulse Thomson scattering diagnostic on DIII-D

This paper describes the design and operation of a 40 spatial channel Thomson scattering system that uses multiple 20 Hz Nd:YAG lasers to measure the electron temperature and density profiles periodically throughout an entire plasma discharge. As many as eight lasers may be fired alternately for an average measurement frequency of 160 Hz, or they may be fired in rapid succession (< 10 kHz), producing a burst of pulses for measuring transient events. The high spatial resolution (1.3 cm) and wide dynamic range (10 eV to 20 keV) enable this system to resolve large electron density and temperature gradients formed at the plasma edge and in the scrape-off-layer during H-mode operation. These features provide a formidable tool for studying L-H transitions, edge localized modes (ELMs), beta limits, transport, and disruptions in an efficient manner suitable for large tokamak operation where shot-to-shot scans are impractical. The scattered light is dispersed by interference filter polychromators and detected by silicon avalanche photodiodes. Laser control and data acquisition are performed in real-time by a VME based microcomputer. Data analysis is performed by a MicroVAX 3400. Additional features of this system include real-time analysis capability, full statistical treatment of error bars based on the measured background light, and laser beam quality and alignment monitoring during plasma operation. Results of component testing, calibration, plasma operation, and error analysis are presented